Preface

Spinal cord injury (SCI) remains an unsolved issue when it comes to an established treatment course. To date, the focus has been on neuroprotective and neuroregeneration therapies with several options that rely on pathophysiological pathways to inhibit and enhance what is needed to establish a better microenvironment for axonal growth after an injury. This book is aimed at a discussion of the most current management alternatives in cases of SCI for a better understanding of today's perspective on the subject.

The book contains eight chapters that start with the pathophysiological picture involved in SCI and moves on to discuss therapies in depth. Chapters focusing on pharmacological agents include neuroprotective and neuroregenerative therapies. As for those concerning non-pharmacological strategies, the book contains chapters on tissue and cell transplants, scaffolds and electrical stimulation, and the combination of therapies for regeneration.

The editors would like to express their thanks to the authors of the chapters presented in this book for their invaluable contributions.

**II**

**Chapter 7 115**

**Chapter 8 139**

Transplantation or Transference of Cultured Cells as a Treatment for

Neuroregenerative-Rehabilitative Therapy for Spinal Cord Injury *by Alok Sharma, Hemangi Sane, Nandini Gokulchandran, Prerna Badhe,* 

*Lisset Karina Navarro-Torres, Estefanía de la Cruz Castillo* 

*Amruta Paranjape, Pooja Kulkarni and Vivek Nair*

*by Roxana Rodríguez-Barrera, Karla Soria-Zavala, Julián García-Sánchez,* 

Spinal Cord Injury

*and Elisa García-Vences*

**Antonio Ibarra** Coordinador del Centro de Investigación en Ciencias de la Salud, Universidad Anáhuac México, Campus Norte, Huixquilucan, México

#### **Gabriel Guízar-Sahagún**

Unidad de Investigación Médica en Enfermedades Neurológicas, México

> **Elisa García-Vences** Centro de Investigación en Ciencias de la Salud, México

Section 1

Introduction

1

Section 1 Introduction

Chapter 1

Cord Injury

therapy for rehabilitation [2].

complications due to SCI [3].

ing mechanisms and promote beneficial effects.

phagocytize the apoptotic and necrotic waste [6].

2. Pathophysiology

3

1. Epidemiology

Introductory Chapter: Trends in

Tamara D. Frydman and Antonio Ibarra

Therapeutic Strategies after Spinal

Spinal cord injury (SCI) continues to be a diagnosis without a straightforward treatment plan, even in today's advanced medical-technological time. This is a problematic pathology not only for the patient but also for the health system since, aside from causing individual disability, it also originates an important economic cost. This is due—in great part—to the age group most affected by this type of injury, which regularly involves an average age of injury of 37.1 years old [1].

Spinal cord injury can lead to fatal consequences when autonomic processes such as respiratory or cardiovascular function are altered by injury. Otherwise, the most common repercussions are those affecting motor and sensitivity skills. This generates a scenario where the patient's clinical prognosis may vary from complete paralysis to an optimum case of injury where the patient could only need physical

The reported prevalence as of 2017 is between 440 and 526 cases per million population, with a mortality rate as high as 22% in both developed and nondeveloped countries [3]. Regarding its incidence, there are 130,000 new cases reported every year [4]. And even though it may not seem like a large group of patients, it accounts for more than approximately a million dollars' worth of treatment for every case reported, thus becoming an important target for research toward finding an effective treatment that can limit symptomatology as well as

SCI pathophysiology encompasses an important number of phenomena that

The understanding of the pathophysiology of acute and chronic SCI is essential to the development of new therapeutic techniques that can effectively stop damag-

Primary lesion is caused by the physical consequences of injury: contusion, compression, or laceration [5]. This leads to demyelization and hemorrhage, which by itself causes ischemia and necrosis affecting nearby cells in the central nervous system. With this process comes edema which develops hours after the insult and continues to expand for several days afterward. Finally in this stage, inflammatory response, cells such as neutrophils and macrophages approach the affected area to

mainly contribute to SC-tissue destruction and/or regeneration inhibition.

#### Chapter 1

## Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury

Tamara D. Frydman and Antonio Ibarra

#### 1. Epidemiology

Spinal cord injury (SCI) continues to be a diagnosis without a straightforward treatment plan, even in today's advanced medical-technological time. This is a problematic pathology not only for the patient but also for the health system since, aside from causing individual disability, it also originates an important economic cost. This is due—in great part—to the age group most affected by this type of injury, which regularly involves an average age of injury of 37.1 years old [1].

Spinal cord injury can lead to fatal consequences when autonomic processes such as respiratory or cardiovascular function are altered by injury. Otherwise, the most common repercussions are those affecting motor and sensitivity skills. This generates a scenario where the patient's clinical prognosis may vary from complete paralysis to an optimum case of injury where the patient could only need physical therapy for rehabilitation [2].

The reported prevalence as of 2017 is between 440 and 526 cases per million population, with a mortality rate as high as 22% in both developed and nondeveloped countries [3]. Regarding its incidence, there are 130,000 new cases reported every year [4]. And even though it may not seem like a large group of patients, it accounts for more than approximately a million dollars' worth of treatment for every case reported, thus becoming an important target for research toward finding an effective treatment that can limit symptomatology as well as complications due to SCI [3].

SCI pathophysiology encompasses an important number of phenomena that mainly contribute to SC-tissue destruction and/or regeneration inhibition.

#### 2. Pathophysiology

The understanding of the pathophysiology of acute and chronic SCI is essential to the development of new therapeutic techniques that can effectively stop damaging mechanisms and promote beneficial effects.

Primary lesion is caused by the physical consequences of injury: contusion, compression, or laceration [5]. This leads to demyelization and hemorrhage, which by itself causes ischemia and necrosis affecting nearby cells in the central nervous system. With this process comes edema which develops hours after the insult and continues to expand for several days afterward. Finally in this stage, inflammatory response, cells such as neutrophils and macrophages approach the affected area to phagocytize the apoptotic and necrotic waste [6].

#### Spinal Cord Injury Therapy

After this immediate response to the injury, there is a second phase with further effects on neural degeneration and tissue restoration:

3. Neuroprotective therapies

DOI: http://dx.doi.org/10.5772/intechopen.86687

as to find suitable possibilities and improve recovery:

preventing inflammation aggravation and edema) [22].

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury

process and stops the spreading of inflammation [25].

it being a risk factor for pneumonia development [27].

As secondary lesion mechanisms are so abundant and have such a long-term effect on the patient's outcome; they have become the main target for SCI therapy. All of these potential treatment options are involved in various research proposals

• Cyclooxygenase inhibitors. COX is a pro-inflammatory enzyme that leads to the production of prostanoids and therefore increased inflammation. This is the basis for the neuroprotective role of cox-inhibitors such as indomethacin (inhibits COX-1/COX-2 and the activity of select leucocytes, thereby

• Immunophilin ligands. These proteins are abundantly found in neural tissue and bind immunosuppressants like cyclosporine A and their analogs which are known as ligands [23]. When these ligands bind to immunophilins, they inhibit rotamase and calcineurin activity. These effects decrease immune responses such as cytokine production and neutrophil motility [24]. Ultimately, cyclosporine A binding to immunophilin slows down the demyelination

• Antioxidants. One of the most damaging pathophysiological mechanisms of SCI is perhaps the increased release of free radicals [26]. Methylprednisolone, currently the primary treatment for acute SCI, is aimed toward inhibiting lipid peroxidation and lactate accumulation. However, there are still concerns about

promotes apoptosis through enzyme degradation of cytoskeletal and membrane proteins. Researchers have found this to be associated with the increased concentration of intracellular calcium following SCI [28]. The two main classes include aldehyde-calpain and oxirane inhibitors, of this last one the primary example is E-64-d. This therapeutic option has demonstrated its neuroprotective effects in SCI models. By blocking calpains, apoptosis could be reduced [29].

• Apoptosis inhibitors. Caspase-3 and caspase-9 are key mediators for apoptosis after acute SCI; by inhibiting these molecules, there has been a proven clinical improvement in previous studies using minocycline. Minocycline is a secondgeneration tetracycline that has demonstrated to have anti-inflammatory and

• Hormones. Steroid hormones such as progesterone and estrogen have proven to be neuroprotective in SCI by showing decreased excitotoxicity, increased

• Na channel blockers. Tetrodotoxin is the most investigated compound of this category; it has proven effects of better recovery by inhibiting fast Na channels and thereby lessening the continuous depolarized state of injured neurons [32].

neuroprotective qualities in experimental studies in SCI, stroke, and neurodegenerative diseases. Talking about its antiapoptotic effects, minocycline decreases caspase 1 and caspase 3 availability, cytochrome c release, mitochondrial calcium uptake, and the release of apoptotic factors. By downsizing apoptosis in SCI, this drug reduces microglial activation [30].

myelination, and enhanced antioxidant properties [31].

5

• Calpain inhibitors. Calpain is a calcium-dependent cysteine protease that


At the moment, there is enough evidence about the deleterious effects exerted by each one of the abovementioned phenomena. That is why, several investigation groups are working on developing therapeutic strategies to induce neuroprotection and subsequently promote SC regeneration.

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.86687

#### 3. Neuroprotective therapies

After this immediate response to the injury, there is a second phase with further

reperfusion phase that contributes to a secondary injury and the release of free

• Oxidative stress. Free radicals have important effects on DNA and proteins by damaging the cell membrane through lipid peroxidation, as well as promoting apoptosis, resulting in a strong inhibition of Na-K ATPase [9, 10]. These are important consequences to keep in mind being that several treatment options

• Excitotoxicity. Glutamate, an important neurotransmitter in the central nervous system, also plays a role in the pathophysiology of SCI, as the extensive release of this molecule allows calcium entrance and the accumulation of intracellular Na and Cl (using its NMDA receptor), which in turn results in cytotoxic edema [12]. Therefore, NMDA receptor blockade becomes a therapeutic option to

• Immune response. As an immune-privileged site, the central nervous system is not known for having a large immune cell presence. Nonetheless, after a SCI, microglia suffers activation, and cytokines are rapidly released. There is an increase in the amount of TNF-α and arachidonic acid metabolites that can be found in cerebral spinal fluid. This, however, is a positive effect since TNF-α has been shown to increase levels of interleukin-10 which counteracts free radicals and stimulates axonal regeneration, making it a target for stimulation

• Activation of Rho pathway. SCI activates Rho pathway, which in turn inhibits the re-growth of axons and causes apoptosis. By inhibiting this activation, recovery improves substantially; however, there is no therapy for this purpose

• Depletion of cAMP. After injury an important reduction of cAMP in neurons

injury represents a barrier to growing axons [17–20]. Additionally, activated astrocytes—the main cells conforming glial scar—express chondroitin sulfate proteoglycans (CSPGs) and extracellular matrix molecules like

phosphocan and neurocan that, when downregulated, have shown to improve axonal regeneration, thereby proving their role in regeneration inhibition

At the moment, there is enough evidence about the deleterious effects exerted by each one of the abovementioned phenomena. That is why, several investigation groups are working on developing therapeutic strategies to induce neuroprotection

occurs; this alteration inhibits neuron regeneration [16].

• Glial scar and astrocyte activation. The formation of a glial scar after

available today such as methylprednisolone are related directly to this

• Vascular changes. These are due—in great part—to the ischemia that takes place, especially in the gray matter structures, and are aggravated by the

hypotensive state of hypovolemia. This could be followed by a

effects on neural degeneration and tissue restoration:

radicals [7, 8].

Spinal Cord Injury Therapy

further explore.

[17, 21].

4

damaging mechanism [6, 11].

as a treatment option [13, 14].

that has been approved yet [15].

and subsequently promote SC regeneration.

As secondary lesion mechanisms are so abundant and have such a long-term effect on the patient's outcome; they have become the main target for SCI therapy. All of these potential treatment options are involved in various research proposals as to find suitable possibilities and improve recovery:


### 4. Regenerative therapies

#### • Pharmacological treatments

◦ Rho pathway antagonists. The Rho family has been associated with several pathways concerning cell proliferation, regeneration, and gene expression [33]. When activated, it leads to neurite growth blockade, especially when implicating Rho kinase (ROCK) [34]. This is why Rho-ROCK inhibitors are now under research as treatment options. These include C3 transferase, which modifies the Rho family thus minimizing its effect, and Y27632 which competes with ROCK for ATP receptors [35].

microenvironment generated after SCI by secreting anti-inflammatory molecules and switching from M1 to M2 macrophage phenotype (protective and restorer phenotype) [45]. They also release neurotrophic factors that

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury

• Combination therapies. As there is a large amount of experimental therapies that target different physiopathological pathways, researchers have found it to be more effective to combine some of these options when it comes to tackling acute and chronic injuries [47]. Some examples of this are the combination of several growth factors and cell transplants, combining chondroitinase ABC and physical rehabilitation and the surgical removal of scar tissue along with

So far, there is no definite treatment course for patients with SCI. This fact remains, although research over the years has developed several options that target the immunologic response that is triggered after an injury and that have both beneficial and damaging consequences as well as other mechanisms such as

lipoperoxidation and cytotoxicity. Hence, there are several circumstances that need to be neutralized before a second strategy can intervene that can initiate remodeling and restoring the damaged tissue. So far, the understanding of pathophysiological mechanisms has been our most powerful tool into deciphering the best therapeutic plan. Neuroprotection is the current target for pharmacological as well as nonpharmacological therapies such as rolipram, MSCs, methylprednisolone, indomethacin, dibutyryl cAMP, and scar removal. The endpoint for all these treatment options is to encourage and enable neuroregeneration, and although as mentioned previously, there have been incredible advancements in this area, the search con-

Centro de Investigación en Ciencias de la Salud, FCS, Universidad Anáhuac México

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

stimulate myelination and reduce apoptosis [46].

immune modulatory therapy [48, 49].

DOI: http://dx.doi.org/10.5772/intechopen.86687

tinues for new alternatives that offer better outcomes.

Author details

7

Campus Norte, Mexico

Tamara D. Frydman and Antonio Ibarra\*

provided the original work is properly cited.

\*Address all correspondence to: jose.ibarra@anahuac.mx


Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.86687

microenvironment generated after SCI by secreting anti-inflammatory molecules and switching from M1 to M2 macrophage phenotype (protective and restorer phenotype) [45]. They also release neurotrophic factors that stimulate myelination and reduce apoptosis [46].

• Combination therapies. As there is a large amount of experimental therapies that target different physiopathological pathways, researchers have found it to be more effective to combine some of these options when it comes to tackling acute and chronic injuries [47]. Some examples of this are the combination of several growth factors and cell transplants, combining chondroitinase ABC and physical rehabilitation and the surgical removal of scar tissue along with immune modulatory therapy [48, 49].

So far, there is no definite treatment course for patients with SCI. This fact remains, although research over the years has developed several options that target the immunologic response that is triggered after an injury and that have both beneficial and damaging consequences as well as other mechanisms such as lipoperoxidation and cytotoxicity. Hence, there are several circumstances that need to be neutralized before a second strategy can intervene that can initiate remodeling and restoring the damaged tissue. So far, the understanding of pathophysiological mechanisms has been our most powerful tool into deciphering the best therapeutic plan. Neuroprotection is the current target for pharmacological as well as nonpharmacological therapies such as rolipram, MSCs, methylprednisolone, indomethacin, dibutyryl cAMP, and scar removal. The endpoint for all these treatment options is to encourage and enable neuroregeneration, and although as mentioned previously, there have been incredible advancements in this area, the search continues for new alternatives that offer better outcomes.

#### Author details

4. Regenerative therapies

Spinal Cord Injury Therapy

• Pharmacological treatments

◦ Rho pathway antagonists. The Rho family has been associated with several pathways concerning cell proliferation, regeneration, and gene expression [33]. When activated, it leads to neurite growth blockade, especially when implicating Rho kinase (ROCK) [34]. This is why Rho-ROCK inhibitors

transferase, which modifies the Rho family thus minimizing its effect, and

are now under research as treatment options. These include C3

◦ Cyclic AMP enhancers. The elevation of cyclic AMP levels is directly associated with a better neuronal response to myelin inhibitors. This has led to research for strategies that elevate cyclic AMP, for instance, the administration of dibutyryl cAMP (activating cAMP-dependent protein kinase) [36] or the inhibition of phosphodiesterase (PDE) using rolipram (a PDE-4 inhibitor that targets SNC tissue more specifically) has shown

◦ Glial scar inhibitors. Being that the scar itself is an inhibiting factor for regeneration, several studies have tried to find a strategy to counteract this effect. Decorin is a proteoglycan molecule that has been linked to a reduction in the expression of inhibitory molecules such as brevican and neurocan as well as to the increased capability for axonal growth across

◦ Hydrogels. This type of material allows for healthy tissue to reconnect and therefore enable axonal growth across the injury. Hydrogels are usually made of hyaluronic acid or poly(2-hydroxyethyl methacrylate-co-methyl

methacrylate); however, other options are being studied for their additional benefits. Some of these new prospects include poly(2 hydroxyethyl methacrylate-co-methyl methacrylate) which has shown improvement in locomotor function [39] and poly[N-(2-hydroxypropyl) methacrylamide] with evidence that it has axonogenic and angiogenic

• Scar removal. Numerous research projects have proven that during chronic stages of injury (>2 weeks), there is a clear benefit when removing the glial scar given that it portrays a barrier both physically and chemically for axonal

• Biocompatible matrices. Tissucol (fibrin glue) is a fibrinogen and thrombin compound that's biocompatible and can therefore be used for cell transplant, as well as promoting growth [42]. Another alternative in this area is alginate, a biocompatible material obtained from bacteria and algae that promotes cell migration and axonal growth [43]. Other options in this category include

• Cell therapies. In chronic stages of SCI, studies have shown that transplanting different cell types has improved recovery. Mesenchymal stem cells (MSCs) are the most promising ones so far, with the capacity to modulate the

Matrigel, polyethylene glycol, and hyaluronic acid [44].

Y27632 which competes with ROCK for ATP receptors [35].

relevant effects on axonal regeneration [37].

myelin-rich environments [38].

properties [40].

regeneration [21, 41].

6

Tamara D. Frydman and Antonio Ibarra\* Centro de Investigación en Ciencias de la Salud, FCS, Universidad Anáhuac México Campus Norte, Mexico

\*Address all correspondence to: jose.ibarra@anahuac.mx

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### References

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Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury

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[30] Barut Ş, Ünlü YA, Karaoğlan A, Tunçdemir M, Dağistanli FK, Öztürk M, et al. The neuroprotective effects of z-DEVD. Fmk, a caspase-3 inhibitor, on traumatic spinal cord injury in rats. Surgical Neurology. 2005;64(3):

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Neurology. 1991;307(2):311-334

[20] Jakovcevski I, Wu J, Karl N, Leshchyns'ka I, Sytnyk V, Chen J, et al. Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury. The Journal of Neuroscience. 2007;

[19] Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Research Bulletin. 1999;49(6):377-391

[21] Li X, Yang B, Xiao Z, Zhao Y, Han S, Yin Y, et al. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Experimental

[22] Takeuchi K, Tanaka A, Hayashi Y, Yokota A. COX inhibition and NSAIDinduced gastric damage—Roles in various pathogenic events. Current Topics in Medicinal Chemistry. 2005;

[23] Steiner JP, Hamilton GS, Ross DT, Valentine HL, Guo H, Connolly MA, et al. Neurotrophic immunophilin ligands stimulate structural and

neurodegenerative animal models. Proceedings of the National Academy of

[24] Ibarra A, Diaz-Ruiz A. Protective effect of cyclosporin-A in spinal cord

Sciences. 1997;94(5):2019-2024

Neurology. 2018;306:132-137

209(2):294-301

27(27):7222-7233

5(5):475-486

9

functional recovery in

[10] Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. The Spine Journal. 2004;4(4):451-464

[11] Saunders RD, Dugan LL, Demediuk P, Means ED, Horrocks LA, Anderson DK. Effects of methylprednisolone and the combination of α-tocopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue. Journal of Neurochemistry. 1987;49(1):24-31

[12] Rungta RL, Choi HB, Tyson JR, Malik A, Dissing-Olesen L, Lin PJC, et al. The cellular mechanisms of neuronal swelling underlying cytotoxic edema. Cell. 2015;161(3):610-621

[13] Chen WF, Chen CH, Chen NF, Sung CS, Wen ZH. Neuroprotective effects of direct intrathecal administration of granulocyte colony-stimulating factor in rats with spinal cord injury. CNS Neuroscience & Therapeutics. 2015; 21(9):698-707

[14] Schwab JM, Zhang Y, Kopp MA, Brommer B, Popovich PG. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Experimental Neurology. 2014; 258:121-129

[15] Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, et al. Nonsteroidal antiinflammatory drugs can lower amyloidogenic Aβ42 by inhibiting rho. Science. 2003;302(5648):1215-1217

[16] Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT, et al. cAMP and Schwann cells promote

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.86687

axonal growth and functional recovery after spinal cord injury. Nature Medicine. 2004;10(6):610

References

Spinal Cord Injury Therapy

92(3):332-338

(Suppl 7):S28

[1] DeVivo MJ, Chen Y. Trends in new injuries, prevalent cases, and aging with spinal cord injury. Archives of Physical Medicine and Rehabilitation. 2011;

Cellular and subcellular oxidative stress parameters following severe spinal cord injury. Redox Biology. 2016;8:59-67

[10] Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. The Spine Journal.

[11] Saunders RD, Dugan LL, Demediuk P, Means ED, Horrocks LA, Anderson DK. Effects of methylprednisolone and the combination of α-tocopherol and

metabolism and lipid peroxidation in traumatized spinal cord tissue. Journal of Neurochemistry. 1987;49(1):24-31

[12] Rungta RL, Choi HB, Tyson JR, Malik A, Dissing-Olesen L, Lin PJC, et al. The cellular mechanisms of neuronal swelling underlying cytotoxic edema. Cell. 2015;161(3):610-621

[13] Chen WF, Chen CH, Chen NF, Sung CS, Wen ZH. Neuroprotective effects of direct intrathecal administration of granulocyte colony-stimulating factor in

rats with spinal cord injury. CNS Neuroscience & Therapeutics. 2015;

[14] Schwab JM, Zhang Y, Kopp MA, Brommer B, Popovich PG. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Experimental Neurology. 2014;

[15] Zhou Y, Su Y, Li B, Liu F, Ryder JW,

amyloidogenic Aβ42 by inhibiting rho. Science. 2003;302(5648):1215-1217

[16] Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT, et al. cAMP and Schwann cells promote

Wu X, et al. Nonsteroidal antiinflammatory drugs can lower

21(9):698-707

258:121-129

selenium on arachidonic acid

2004;4(4):451-464

[2] Hagen EM. Acute complications of spinal cord injuries. World Journal of

[3] Kang Y, Ding H, Zhou H, Wei Z, Liu

L, Pan D, et al. Epidemiology of worldwide spinal cord injury: A literature review. Journal of Neurorestoratology. 2017;6:1-9

[4] Mohit AA. Cellular events and pathophysiology of SCI. Spine. 2016;41

Design. 2016;22(6):720-727

potential of non-steroidal anti-

2002;34(6):A10

8

[5] Morales I-I, Toscano-Tejeida D, Ibarra A. Non pharmacological strategies to promote spinal cord regeneration: A view on some individual or combined approaches. Current Pharmaceutical

[6] Hayta E, Elden H. Acute spinal cord injury: A review of pathophysiology and

inflammatory drugs for pharmacological intervention. Journal of Chemical Neuroanatomy. 2018;87:25-31

[7] Bilenko MV, Khilchenko AV. Free radical inhibitors (FRI) can prevent celigmediated LDL oxidation under ischemia (I) and reperfusion (R) of vascular wall in situ. Journal of Molecular and Cellular Cardiology.

[8] Zhang Y-S, He L, Liu B, Li N-S, Luo X-J, Hu C-P, et al. A novel pathway of NADPH oxidase/vascular peroxidase 1 in mediating oxidative injury following ischemia-reperfusion. Basic Research in

[9] Visavadiya NP, Patel SP, VanRooyen JL, Sullivan PG, Rabchevsky AG.

Cardiology. 2012;107(3):266

Orthopedics. 2015;6(1):17

[17] Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Experimental Neurology. 2008; 209(2):294-301

[18] Jakeman LB, Reier PJ. Axonal projections between fetal spinal cord transplants and the adult rat spinal cord: A neuroanatomical tracing study of local interactions. The Journal of Comparative Neurology. 1991;307(2):311-334

[19] Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Research Bulletin. 1999;49(6):377-391

[20] Jakovcevski I, Wu J, Karl N, Leshchyns'ka I, Sytnyk V, Chen J, et al. Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury. The Journal of Neuroscience. 2007; 27(27):7222-7233

[21] Li X, Yang B, Xiao Z, Zhao Y, Han S, Yin Y, et al. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Experimental Neurology. 2018;306:132-137

[22] Takeuchi K, Tanaka A, Hayashi Y, Yokota A. COX inhibition and NSAIDinduced gastric damage—Roles in various pathogenic events. Current Topics in Medicinal Chemistry. 2005; 5(5):475-486

[23] Steiner JP, Hamilton GS, Ross DT, Valentine HL, Guo H, Connolly MA, et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proceedings of the National Academy of Sciences. 1997;94(5):2019-2024

[24] Ibarra A, Diaz-Ruiz A. Protective effect of cyclosporin-A in spinal cord

injury: An overview. Current Medicinal Chemistry. 2006;13(22):2703-2710

[25] Diaz-Ruiz A, Rios C, Duarte I, Correa D, Guizar-Sahagun G, Grijalva I, et al. Lipid peroxidation inhibition in spinal cord injury: Cyclosporin-A vs methylprednisolone. Neuroreport. 2000;11(8):1765-1767

[26] Hall ED, Springer JE. Neuroprotection and acute spinal cord injury: A reappraisal. NeuroRx. 2004; 1(1):80-100

[27] Martinon S, Ibarra A. Pharmacological neuroprotective therapy for acute spinal cord injury: State of the art. Mini Reviews in Medicinal Chemistry. 2008;8(3): 222-230

[28] Ray SK, Hogan EL, Banik NL. Calpain in the pathophysiology of spinal cord injury: Neuroprotection with calpain inhibitors. Brain Research Reviews. 2003;42(2):169-185

[29] Zhang S-X, Bondada V, Geddes JW. Evaluation of conditions for calpain inhibition in the rat spinal cord: Effective postinjury inhibition with intraspinal MDL28170 microinjection. Journal of Neurotrauma. 2003;20(1): 59-67

[30] Barut Ş, Ünlü YA, Karaoğlan A, Tunçdemir M, Dağistanli FK, Öztürk M, et al. The neuroprotective effects of z-DEVD. Fmk, a caspase-3 inhibitor, on traumatic spinal cord injury in rats. Surgical Neurology. 2005;64(3): 213-220

[31] Gonzalez SL, Labombarda F, Deniselle MCG, Mougel A, Guennoun R, Schumacher M, et al. Progesterone neuroprotection in spinal cord trauma involves up-regulation of brain-derived neurotrophic factor in motoneurons. The Journal of Steroid Biochemistry and Molecular Biology. 2005;94(1-3): 143-149

[32] Rosenberg LJ, Wrathall JR. Time course studies on the effectiveness of tetrodotoxin in reducing consequences of spinal cord contusion. Journal of Neuroscience Research. 2001;66(2): 191-202

[33] Kubo T, Hata K, Yamaguchi A, Yamashita T. Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. Current Pharmaceutical Design. 2007;13(24):2493-2499

[34] McKerracher L, Higuchi H. Targeting rho to stimulate repair after spinal cord injury. Journal of Neurotrauma. 2006;23(3-4):309-317

[35] Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, et al. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. The Journal of Biological Chemistry. 2006;281(1):260-268

[36] Qiu J, Cai D, Dai H, McAtee M, Hoffman PN, Bregman BS, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron. 2002;34(6): 895-903

[37] Griswold DE, Webb EF, Breton J, White JR, Marshall PJ, Torphy TJ. Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. Inflammation. 1993;17(3): 333-344

[38] Minor K, Tang X, Kahrilas G, Archibald SJ, Davies JE, Davies SJ. Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiology of Disease. 2008;32(1):88-95

[39] Tsai EC, Dalton PD, Shoichet MS, Tator CH. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006;27(3):519-533

[40] Woerly S, Petrov P, Sykova E, Roitbak T, Simonova Z, Harvey AR. Neural tissue formation within porous hydrogels implanted in brain and spinal cord lesions: Ultrastructural, immunohistochemical, and diffusion studies. Tissue Engineering. 1999;5(5): 467-488

neuritogenesis. Experimental Neurology. 2006;198(1):54-64

needed for spinal cord injury. Experimental Neurology. 2013;248:

[48] Martiñón S, García-Vences E, Toscano-Tejeida D, Flores-Romero A, Rodriguez-Barrera R, Ferrusquia M, et al. Long-term production of BDNF

immunization after spinal cord injury. BMC Neuroscience. 2016;17(1):42

[49] Martiñon S, García E, Flores N, Gonzalez I, Ortega T, Buenrostro M, et al. Vaccination with a neural-derived

glutathione improves the performance of paraplegic rats. The European Journal of Neuroscience. 2007;26(2):403-412

peptide plus administration of

and NT-3 induced by A91-

309-315

11

[47] Olson L. Combinatory treatments

DOI: http://dx.doi.org/10.5772/intechopen.86687

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury

[41] Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Experimental Neurology. 2007;203(1): 8-21

[42] Liu J, Chen Q , Zhang Z, Zheng Y, Sun X, Cao X, et al. Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury. Cells, Tissues, Organs. 2013; 198(1):35-46

[43] Prang P, Müller R, Eljaouhari A, Heckmann K, Kunz W, Weber T, et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials. 2006;27(19): 3560-3569

[44] Preston M, Sherman LS. Neural stem cell niches: Critical roles for the hyaluronan-based extracellular matrix in neural stem cell proliferation and differentiation. Frontiers in Bioscience. 2012;3:1165

[45] Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, et al. Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. Journal of Neurotrauma. 2012; 29(8):1614-1625

[46] Crigler L, Robey RC,

Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and

Introductory Chapter: Trends in Therapeutic Strategies after Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.86687

neuritogenesis. Experimental Neurology. 2006;198(1):54-64

[32] Rosenberg LJ, Wrathall JR. Time course studies on the effectiveness of tetrodotoxin in reducing consequences of spinal cord contusion. Journal of Neuroscience Research. 2001;66(2):

Spinal Cord Injury Therapy

[40] Woerly S, Petrov P, Sykova E, Roitbak T, Simonova Z, Harvey AR. Neural tissue formation within porous hydrogels implanted in brain and spinal

immunohistochemical, and diffusion studies. Tissue Engineering. 1999;5(5):

[41] Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Experimental Neurology. 2007;203(1):

[42] Liu J, Chen Q , Zhang Z, Zheng Y, Sun X, Cao X, et al. Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury. Cells, Tissues, Organs. 2013;

[43] Prang P, Müller R, Eljaouhari A, Heckmann K, Kunz W, Weber T, et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials. 2006;27(19):

[44] Preston M, Sherman LS. Neural stem cell niches: Critical roles for the hyaluronan-based extracellular matrix in neural stem cell proliferation and differentiation. Frontiers in Bioscience.

[45] Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, et al. Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. Journal of Neurotrauma. 2012;

Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and

cord lesions: Ultrastructural,

467-488

8-21

198(1):35-46

3560-3569

2012;3:1165

29(8):1614-1625

[46] Crigler L, Robey RC,

[33] Kubo T, Hata K, Yamaguchi A, Yamashita T. Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. Current Pharmaceutical Design. 2007;13(24):2493-2499

[34] McKerracher L, Higuchi H. Targeting rho to stimulate repair after

Neurotrauma. 2006;23(3-4):309-317

[36] Qiu J, Cai D, Dai H, McAtee M, Hoffman PN, Bregman BS, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron. 2002;34(6):

[37] Griswold DE, Webb EF, Breton J, White JR, Marshall PJ, Torphy TJ. Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and

cellular phases of inflammatory response. Inflammation. 1993;17(3):

[38] Minor K, Tang X, Kahrilas G, Archibald SJ, Davies JE, Davies SJ. Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiology

of Disease. 2008;32(1):88-95

2006;27(3):519-533

10

[39] Tsai EC, Dalton PD, Shoichet MS, Tator CH. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials.

[35] Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, et al. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. The Journal of Biological Chemistry.

spinal cord injury. Journal of

2006;281(1):260-268

895-903

333-344

191-202

[47] Olson L. Combinatory treatments needed for spinal cord injury. Experimental Neurology. 2013;248: 309-315

[48] Martiñón S, García-Vences E, Toscano-Tejeida D, Flores-Romero A, Rodriguez-Barrera R, Ferrusquia M, et al. Long-term production of BDNF and NT-3 induced by A91 immunization after spinal cord injury. BMC Neuroscience. 2016;17(1):42

[49] Martiñon S, García E, Flores N, Gonzalez I, Ortega T, Buenrostro M, et al. Vaccination with a neural-derived peptide plus administration of glutathione improves the performance of paraplegic rats. The European Journal of Neuroscience. 2007;26(2):403-412

**13**

**Chapter 2**

Injury

**Abstract**

process until years later.

**1. Introduction**

countries [1].

treatments.

Physiopathology of Spinal Cord

Spinal cord injuries have a multifactorial process with diverse evolution over time. An acute injury produces severe pathological and physiological changes in the organism, homeostasis is recovered, and both adverse and favorable reactions occur for the individual. In this chapter, we describe the pathophysiological follow-up to spinal cord injuries, from their acute to chronic presentations. The importance of this knowledge lies in finding solutions to the multiple disorders generated from a spinal cord injury. These will depend on the specific needs of each stage, considering the intensity of the injury, and the time elapsed from the beginning of the

Spinal cord injury represents a devastating impairment in the patient's life that it is also known to include the patient's family. Adapting to the new condition is a challenge for all who are involved, as it is especially expensive from the economic point of view, not only for the patient and his family but also for health services, as it involves expenses of a diverse nature to offer the best quality of life for the patient. In addition, the majority of patients who suffer from it are of a productive age, which implies the need to abandon their sources of income, depending totally on their family, both financially and on their basic survival needs, such as eating, getting dressed, bathing, etc., even needing in-home specialized health care. According to various epidemiological studies, spinal cord injuries affect between 236 and 1298 patients per million inhabitants in different

Spinal cord injury is caused by three experimental mechanisms, contusion, compression, and hemisection, all of these representing clinical lesions for study [2]. All three have different degrees of primary tissue damage; however, the three trigger severe secondary mechanisms that amplify tissue damage, hindering and even preventing the regeneration of damaged tissue. In this review, an approach is made to these destructive mechanisms after a spinal cord injury, with the aim of providing the bases of the pathophysiology of spinal cord injury to aid in decision-making for implementation of clinical and/or experimental

*Susana Martiñón, Juan Armando Reyes-Perez* 

**Keywords:** spinal cord injury, anatomy, physiology, pathophysiology

*and Psyché Calderón-Vargas*

#### **Chapter 2**

## Physiopathology of Spinal Cord Injury

*Susana Martiñón, Juan Armando Reyes-Perez and Psyché Calderón-Vargas*

#### **Abstract**

Spinal cord injuries have a multifactorial process with diverse evolution over time. An acute injury produces severe pathological and physiological changes in the organism, homeostasis is recovered, and both adverse and favorable reactions occur for the individual. In this chapter, we describe the pathophysiological follow-up to spinal cord injuries, from their acute to chronic presentations. The importance of this knowledge lies in finding solutions to the multiple disorders generated from a spinal cord injury. These will depend on the specific needs of each stage, considering the intensity of the injury, and the time elapsed from the beginning of the process until years later.

**Keywords:** spinal cord injury, anatomy, physiology, pathophysiology

#### **1. Introduction**

Spinal cord injury represents a devastating impairment in the patient's life that it is also known to include the patient's family. Adapting to the new condition is a challenge for all who are involved, as it is especially expensive from the economic point of view, not only for the patient and his family but also for health services, as it involves expenses of a diverse nature to offer the best quality of life for the patient. In addition, the majority of patients who suffer from it are of a productive age, which implies the need to abandon their sources of income, depending totally on their family, both financially and on their basic survival needs, such as eating, getting dressed, bathing, etc., even needing in-home specialized health care. According to various epidemiological studies, spinal cord injuries affect between 236 and 1298 patients per million inhabitants in different countries [1].

Spinal cord injury is caused by three experimental mechanisms, contusion, compression, and hemisection, all of these representing clinical lesions for study [2]. All three have different degrees of primary tissue damage; however, the three trigger severe secondary mechanisms that amplify tissue damage, hindering and even preventing the regeneration of damaged tissue. In this review, an approach is made to these destructive mechanisms after a spinal cord injury, with the aim of providing the bases of the pathophysiology of spinal cord injury to aid in decision-making for implementation of clinical and/or experimental treatments.

### **2. Methodology**

A systematic search was conducted in PubMed and Embase with the following MeSH terms and keywords: "spinal cord injury and hemorrhagic," "spinal cord injury and secondary damage," "spinal cord injury and pathophysiology," "spinal cord injury and ischemic effects," "spinal cord injury and ionic dysregulation," "spinal cord injury and free radicals (FR)," "spinal cord injury and excitotoxicity," and "spinal cord injury and electrolyte imbalances." The search results were refined, selecting published articles from renowned journals in the medical and scientific areas that are less than 10 years old. Twenty-six studies were selected.

### **3. Pathophysiology of traumatic injury in the spinal cord**

After a mechanical spinal cord injury (primary lesion), a series of self-destructive mechanisms (secondary lesion) is triggered that cause greater destruction of the spinal cord parenchyma with long-term sequela. Spinal cord injury is associated with mechanical damage, biochemical disorders, and hemodynamic changes [3]. The anatomic point where the primary lesion is exerted is known as the "epicenter," and the secondary mechanisms develop in a centrifugal form around the epicenter, expanding the injured area (**Figure 1**).

#### **Figure 1.**

*Schematic summary of spinal cord injury. The primary lesion is the result of trauma directly on the neural tissue, anatomically called the epicenter of the injury to the point where the spinal cord is affected by the primary lesion; this injury triggers a series of destructive events known as a secondary injury, which will increase the area of injury in a centrifugal way, magnifying the systemic effects; these events can be observed years after the primary lesion.*

**15**

*Physiopathology of Spinal Cord Injury*

**3.1 Loss of ion regulation**

**3.2 Necrosis and apoptosis**

**3.3 Loss of axoplasmic flow**

fibroglial scar in the area of injury [11].

**3.4 Vascular events**

potassium (K<sup>+</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.86234*

ent in which the concentrations of sodium (Na<sup>+</sup>

) and magnesium (Mg<sup>+</sup>

Some of the histological changes that are observed after a TSC are the formation of edema and softening of the tissue, increase in the concentration of water, change in the caliber of the blood vessels, and rupture of the myelin surrounding the axons, in addition to a decrease in axoplasmic flow [4], with loss of ion regulation, in which an intense movement of ions is observed through an electrochemical gradi-

gradient is altered, the electrical conduction ceases immediately, and the formation of edema is stimulated [5]. In addition, the increase in free intracellular Ca2+ triggers cell death by inhibiting mitochondrial function. It decreases the activation of ATP by activation of ATPase, protease, and phospholipases, with the resulting catabolism of proteins and structural lipids and inhibition of axoplasmic transport, because the increase of Ca2+ in the axoplasm triggers the action of neutral proteases activated by this ion and massive proteolysis of neurofilaments, which can lead to progressive collapse and fragmentation of the axon, causing tissue necrosis [6].

Activation of calpains and caspases represents other activation mechanism processes of necrosis and apoptosis by increasing intracellular Ca2+ [7]. The calpains constitute a superfamily of non-lysosomal proteases dependent on Ca2+ with a cysteine in its catalytic site. They are encoded by around 14 independent genes and have been attributed to various functions as the anchor of membrane proteins, signaling cascades, cytoskeleton remodeling, and apoptosis. The importance of caspases is the activation to start the process of programmed cell death; this has

The axonal flow is modified because of axonal breakage. The axoplasmic flow can be retrograde or anterograde, both of which are fundamental for neuronal function. Although the cytoskeleton is composed of microtubules, actin filaments, and intermediate filaments, only microtubules are involved in the transport of materials through axons [9]. The anterograde transport is carried out through proteins associated with the cytoskeleton called kinesins, and it happens at a speed between 50 and 400 mm/day, while retrograde transport is through proteins known as dyneins [10]. The main molecules that are transported through the axons are synaptic precursor vesicles and dense core vesicles, signaling endosomes, BDNF vesicles, endosomes, late lysosomes, autophagosomes, APP, mRNA, neurofilament, and tubulin assembly and cytosolic proteins, in addition to organelles such as mitochondria [9]. Axonal fragmentation resulting from the traumatic spinal cord injury makes it impossible for the neuron to send these in both directions, which generates growth abortion and no axonal regeneration, conjointly with the formation of a

As mentioned earlier, the ischemic process is another mechanism through which secondary damage occurs. One of the achievements of modern vascular neurology

been demonstrated in deficient caspase-3 and caspase-9 mice [8].

) and calcium (Ca2+) increase and

) decrease at the intracellular level. When the

#### **3.1 Loss of ion regulation**

*Spinal Cord Injury Therapy*

A systematic search was conducted in PubMed and Embase with the following MeSH terms and keywords: "spinal cord injury and hemorrhagic," "spinal cord injury and secondary damage," "spinal cord injury and pathophysiology," "spinal cord injury and ischemic effects," "spinal cord injury and ionic dysregulation," "spinal cord injury and free radicals (FR)," "spinal cord injury and excitotoxicity," and "spinal cord injury and electrolyte imbalances." The search results were refined, selecting published articles from renowned journals in the medical and scientific areas that are less than 10 years old. Twenty-six studies

After a mechanical spinal cord injury (primary lesion), a series of self-destructive mechanisms (secondary lesion) is triggered that cause greater destruction of the spinal cord parenchyma with long-term sequela. Spinal cord injury is associated with mechanical damage, biochemical disorders, and hemodynamic changes [3]. The anatomic point where the primary lesion is exerted is known as the "epicenter," and the secondary mechanisms develop in a centrifugal form around the epicenter,

*Schematic summary of spinal cord injury. The primary lesion is the result of trauma directly on the neural tissue, anatomically called the epicenter of the injury to the point where the spinal cord is affected by the primary lesion; this injury triggers a series of destructive events known as a secondary injury, which will increase the area of injury in a centrifugal way, magnifying the systemic effects; these events can be observed* 

**3. Pathophysiology of traumatic injury in the spinal cord**

expanding the injured area (**Figure 1**).

**2. Methodology**

were selected.

**14**

**Figure 1.**

*years after the primary lesion.*

Some of the histological changes that are observed after a TSC are the formation of edema and softening of the tissue, increase in the concentration of water, change in the caliber of the blood vessels, and rupture of the myelin surrounding the axons, in addition to a decrease in axoplasmic flow [4], with loss of ion regulation, in which an intense movement of ions is observed through an electrochemical gradient in which the concentrations of sodium (Na<sup>+</sup> ) and calcium (Ca2+) increase and potassium (K<sup>+</sup> ) and magnesium (Mg+ ) decrease at the intracellular level. When the gradient is altered, the electrical conduction ceases immediately, and the formation of edema is stimulated [5]. In addition, the increase in free intracellular Ca2+ triggers cell death by inhibiting mitochondrial function. It decreases the activation of ATP by activation of ATPase, protease, and phospholipases, with the resulting catabolism of proteins and structural lipids and inhibition of axoplasmic transport, because the increase of Ca2+ in the axoplasm triggers the action of neutral proteases activated by this ion and massive proteolysis of neurofilaments, which can lead to progressive collapse and fragmentation of the axon, causing tissue necrosis [6].

#### **3.2 Necrosis and apoptosis**

Activation of calpains and caspases represents other activation mechanism processes of necrosis and apoptosis by increasing intracellular Ca2+ [7]. The calpains constitute a superfamily of non-lysosomal proteases dependent on Ca2+ with a cysteine in its catalytic site. They are encoded by around 14 independent genes and have been attributed to various functions as the anchor of membrane proteins, signaling cascades, cytoskeleton remodeling, and apoptosis. The importance of caspases is the activation to start the process of programmed cell death; this has been demonstrated in deficient caspase-3 and caspase-9 mice [8].

#### **3.3 Loss of axoplasmic flow**

The axonal flow is modified because of axonal breakage. The axoplasmic flow can be retrograde or anterograde, both of which are fundamental for neuronal function. Although the cytoskeleton is composed of microtubules, actin filaments, and intermediate filaments, only microtubules are involved in the transport of materials through axons [9]. The anterograde transport is carried out through proteins associated with the cytoskeleton called kinesins, and it happens at a speed between 50 and 400 mm/day, while retrograde transport is through proteins known as dyneins [10]. The main molecules that are transported through the axons are synaptic precursor vesicles and dense core vesicles, signaling endosomes, BDNF vesicles, endosomes, late lysosomes, autophagosomes, APP, mRNA, neurofilament, and tubulin assembly and cytosolic proteins, in addition to organelles such as mitochondria [9]. Axonal fragmentation resulting from the traumatic spinal cord injury makes it impossible for the neuron to send these in both directions, which generates growth abortion and no axonal regeneration, conjointly with the formation of a fibroglial scar in the area of injury [11].

#### **3.4 Vascular events**

As mentioned earlier, the ischemic process is another mechanism through which secondary damage occurs. One of the achievements of modern vascular neurology

is the description of the vascular, cellular, and biochemical changes that constitute this process [12]. The primary spinal cord injury generates a spinal cord shock, with the consequent neurogenic shock. According to Popa [13], a systemic vascular response is generated when the following are observed: coronary heart disease, arterial hypotension, and deep vein thrombosis, which may be perpetuated to become chronic processes.

Ischemic damage is constituted by the dynamic interaction between neurons, astrocytes, fibroblasts, smooth muscle, and endothelial cells that interact with the formed elements of the blood leading to cell death [12]. The main biochemical events that occur in this ischemic process are inhibition of protein synthesis, depression of intracellular energy reserves, depolarization of the cell membrane, release of intracellular K+ followed by the release of neurotransmitters, Ca2+ influx to the cell, and cellular metabolic commitment, which leads to lipidic peroxidation that ultimately results in neuronal nuclear destruction and death. At the molecular level, an increase in oxygen extraction increases glucose demand, and lactic acidosis is expressed [14].

#### **3.5 Neurotoxicity by free radicals**

Another mechanism that contributes in a very important way to the increase in damage in the area of injury is the neurotoxicity caused by free radicals. These reactive molecules are powerful oxidizing agents that are in balance with antioxidant systems. They have one or more unpaired electrons due to their loss or gain, which makes them very unstable, and they are responsible for damage to cell structures of biological importance [13, 15]. The free radical species that can be found include superoxide anion (O2 <sup>−</sup>), hydrogen peroxide (H2O2), hydroxyl radical (OH<sup>−</sup>), ozone (Oz), nitric oxide (ON), hypochlorous acid (HOCl), and different metal ions. These ions are generated in the mitochondria during oxidative phosphorylation which is a process whereby ATP is formed as a result of the transfer of electrons from NADH or FADH2 to oxygen through a series of electron transporters [16].

The free radical-mediated tissue injury is the result of abnormal and uncontrolled reactions of these molecules in several cellular compartments. The activity is divided into three stages: initiation, propagation, and termination [17].

The initiation of lipoperoxidation is by extraction of a hydrogen atom from the allylic carbons (〓C▬) of the unsaturated fatty acids of the cell membranes as well as the purine bases and pyrimidine bases of the nucleic acids, resulting in free radical alkyl (R.). Free radicals alkyl rearrange molecularly forming a conjugated diene that will react with molecular oxygen generating peroxyl radicals (ROO˙) [18] which by extraction of one hydrogen atom from another allylic carbon, from another unsaturated fatty acid from the bilayer lipidic biological membranes reacting to hydroperoxides forms (ROOH) involving the process called propagation. Finally, the termination phase occurs by the formation of aldehydes, hydrocarbonaceous gases, and various chemical residues, including malondialdehyde (COH▬CH2▬CHO) which will react with lipids and proteins to form conjugated Schiff bases, insoluble products that accumulate inside the lysosomes and form the pigment known as lipofuscin [19].

As will be seen below, the immune response after spinal cord injury recruits a large number of inflammatory cells, including neutrophils and macrophages, which are producers of nitric oxide. Nitric oxide is a free radical that is very important for vascular physiology since it participates in numerous regulatory events, which include vascular tone and blood pressure. This radical is formed by the reaction of L-arginine and oxygen and cofactors such as NADPH, and this reaction is catalyzed by nitric oxide synthase (NOS). Nitric oxide synthase has three isoforms: nNOS (present in brain neurons), eNOS (in endothelial cells), and iNOS (inducible in the

**17**

*Physiopathology of Spinal Cord Injury*

inflammatory processes [20].

(O2

*DOI: http://dx.doi.org/10.5772/intechopen.86234*

dioxide (NO2), and hydroxyl ion (OH<sup>−</sup>) [16].

ability of the antioxidant defense decreases [22].

ing cell death by excitotoxicity [24].

**3.6 Excitotoxicity**

macrophage); the first two are dependent on high concentrations of Ca2+ and have a physiological function, while the latter is independent of Ca2+ and is important in

Among other consequences, the alteration in the basal levels of NO produces cell death, and, although the mechanisms are not totally clear, it is known that apoptosis can occur from the inhibition of glycolysis, the Krebs cycle, and the synthesis of the DNA; also, when combined with superoxide radical, peroxynitrite is formed

<sup>−</sup> + NO → ONOO<sup>−</sup>), which is a highly reactive species and cytotoxic, as it reacts with proteins, fatty acids of membranes, and nucleic acids and decomposes into

In this regard there are protective systems that prevent the excessive increase of oxidizing species. Among them there are three enzymes that are the most important system of this protection: superoxide dismutase (SOD), which converts the superoxide radical into hydrogen peroxide; the glutathione peroxidase, which using two molecules of glutathione in the reaction converts hydrogen peroxide into two water molecules, while the lipid peroxides are reduced in the presence of glutathione; and finally catalase, which also destroys hydrogen peroxide. However, the activity of these antioxidant enzymes is particularly low in the CNS compared to other tissues [21]. This makes this system particularly sensitive to free radicals. In addition, the CNS is rich in iron, which is the main inducer of the production of free radicals after an injury to the CNS itself. On the other hand, the cellular membrane of tissues is rich in cholesterol and polyunsaturated fatty acids which are targets of oxygen free radicals. Likewise, the CNS has few antioxidant defenses, which causes it to be even more vulnerable; in addition, studies in patients have shown that during the first year after injury, oxidative stress increases and the

Another mechanism of cell damage after spinal cord injury is known as excitotoxicity, caused by excessive release of neurotransmitters. A continuous increase in glutamate concentrations is observed, due to the self-amplification of glutamatergic circuits. These circuits function due to the recycling of glutamate, exocytosis of calcium-dependent synaptic vesicles, and discharge of intracellular glutamate as a result of cell lysis [23]. This abundance of glutamate, especially in a hypoxic environment, overstimulates its ionotropic receptors, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), and kainate, trigger-

Initially, glutamate binds to its receptors and causes depolarization. This activates voltage-dependent sodium channels, causing extensive depolarization and a marked increase in intracellular sodium concentration. The chronicity of this response will lead to the release of NMDA receptors from their blockade by magnesium, leaving them available for activation by glutamate and increasing intracellular sodium. This intracellular imbalance of ions, caused by the flow of sodium, is corrected by a flow of chloride ions. In addition, this attempt to restore the osmotic balance of the cell leads to a flow of water into the intracellular space causing lysis [24]. Alternatively, excitotoxicity can kill neuronal cells by calcium-dependent mechanisms. This means that chronic depolarization leads to an intracellular calcium flux via calcium-dependent channels and the opening of channels of NMDA receptors; this flow is increased by the mobilization of calcium from its intracellular reservoirs and the reverse sodium-calcium exchange operation of the membrane, and activa-

tion of calcium-dependent self-destructive enzymes begins as a result [22].

+

), nitrogen

products with toxic substances that may include nitronium ion (NO2

*Spinal Cord Injury Therapy*

become chronic processes.

**3.5 Neurotoxicity by free radicals**

pigment known as lipofuscin [19].

superoxide anion (O2

cellular K+

is the description of the vascular, cellular, and biochemical changes that constitute this process [12]. The primary spinal cord injury generates a spinal cord shock, with the consequent neurogenic shock. According to Popa [13], a systemic vascular response is generated when the following are observed: coronary heart disease, arterial hypotension, and deep vein thrombosis, which may be perpetuated to

Ischemic damage is constituted by the dynamic interaction between neurons, astrocytes, fibroblasts, smooth muscle, and endothelial cells that interact with the formed elements of the blood leading to cell death [12]. The main biochemical events that occur in this ischemic process are inhibition of protein synthesis, depression of intracellular energy reserves, depolarization of the cell membrane, release of intra-

cellular metabolic commitment, which leads to lipidic peroxidation that ultimately results in neuronal nuclear destruction and death. At the molecular level, an increase in oxygen extraction increases glucose demand, and lactic acidosis is expressed [14].

Another mechanism that contributes in a very important way to the increase in damage in the area of injury is the neurotoxicity caused by free radicals. These reactive molecules are powerful oxidizing agents that are in balance with antioxidant systems. They have one or more unpaired electrons due to their loss or gain, which makes them very unstable, and they are responsible for damage to cell structures of biological importance [13, 15]. The free radical species that can be found include

(Oz), nitric oxide (ON), hypochlorous acid (HOCl), and different metal ions. These ions are generated in the mitochondria during oxidative phosphorylation which is a process whereby ATP is formed as a result of the transfer of electrons from NADH

The free radical-mediated tissue injury is the result of abnormal and uncontrolled reactions of these molecules in several cellular compartments. The activity is

The initiation of lipoperoxidation is by extraction of a hydrogen atom from the allylic carbons (〓C▬) of the unsaturated fatty acids of the cell membranes as well as the purine bases and pyrimidine bases of the nucleic acids, resulting in free radical alkyl (R.). Free radicals alkyl rearrange molecularly forming a conjugated diene that will react with molecular oxygen generating peroxyl radicals (ROO˙) [18] which by extraction of one hydrogen atom from another allylic carbon, from another unsaturated fatty acid from the bilayer lipidic biological membranes reacting to hydroperoxides forms (ROOH) involving the process called propagation. Finally, the termination phase occurs by the formation of aldehydes, hydrocarbonaceous gases, and various chemical residues, including malondialdehyde (COH▬CH2▬CHO) which will react with lipids and proteins to form conjugated Schiff bases, insoluble products that accumulate inside the lysosomes and form the

As will be seen below, the immune response after spinal cord injury recruits a large number of inflammatory cells, including neutrophils and macrophages, which are producers of nitric oxide. Nitric oxide is a free radical that is very important for vascular physiology since it participates in numerous regulatory events, which include vascular tone and blood pressure. This radical is formed by the reaction of L-arginine and oxygen and cofactors such as NADPH, and this reaction is catalyzed by nitric oxide synthase (NOS). Nitric oxide synthase has three isoforms: nNOS (present in brain neurons), eNOS (in endothelial cells), and iNOS (inducible in the

or FADH2 to oxygen through a series of electron transporters [16].

divided into three stages: initiation, propagation, and termination [17].

<sup>−</sup>), hydrogen peroxide (H2O2), hydroxyl radical (OH<sup>−</sup>), ozone

followed by the release of neurotransmitters, Ca2+ influx to the cell, and

**16**

macrophage); the first two are dependent on high concentrations of Ca2+ and have a physiological function, while the latter is independent of Ca2+ and is important in inflammatory processes [20].

Among other consequences, the alteration in the basal levels of NO produces cell death, and, although the mechanisms are not totally clear, it is known that apoptosis can occur from the inhibition of glycolysis, the Krebs cycle, and the synthesis of the DNA; also, when combined with superoxide radical, peroxynitrite is formed (O2 <sup>−</sup> + NO → ONOO<sup>−</sup>), which is a highly reactive species and cytotoxic, as it reacts with proteins, fatty acids of membranes, and nucleic acids and decomposes into products with toxic substances that may include nitronium ion (NO2 + ), nitrogen dioxide (NO2), and hydroxyl ion (OH<sup>−</sup>) [16].

In this regard there are protective systems that prevent the excessive increase of oxidizing species. Among them there are three enzymes that are the most important system of this protection: superoxide dismutase (SOD), which converts the superoxide radical into hydrogen peroxide; the glutathione peroxidase, which using two molecules of glutathione in the reaction converts hydrogen peroxide into two water molecules, while the lipid peroxides are reduced in the presence of glutathione; and finally catalase, which also destroys hydrogen peroxide. However, the activity of these antioxidant enzymes is particularly low in the CNS compared to other tissues [21]. This makes this system particularly sensitive to free radicals. In addition, the CNS is rich in iron, which is the main inducer of the production of free radicals after an injury to the CNS itself. On the other hand, the cellular membrane of tissues is rich in cholesterol and polyunsaturated fatty acids which are targets of oxygen free radicals. Likewise, the CNS has few antioxidant defenses, which causes it to be even more vulnerable; in addition, studies in patients have shown that during the first year after injury, oxidative stress increases and the ability of the antioxidant defense decreases [22].

#### **3.6 Excitotoxicity**

Another mechanism of cell damage after spinal cord injury is known as excitotoxicity, caused by excessive release of neurotransmitters. A continuous increase in glutamate concentrations is observed, due to the self-amplification of glutamatergic circuits. These circuits function due to the recycling of glutamate, exocytosis of calcium-dependent synaptic vesicles, and discharge of intracellular glutamate as a result of cell lysis [23]. This abundance of glutamate, especially in a hypoxic environment, overstimulates its ionotropic receptors, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), and kainate, triggering cell death by excitotoxicity [24].

Initially, glutamate binds to its receptors and causes depolarization. This activates voltage-dependent sodium channels, causing extensive depolarization and a marked increase in intracellular sodium concentration. The chronicity of this response will lead to the release of NMDA receptors from their blockade by magnesium, leaving them available for activation by glutamate and increasing intracellular sodium. This intracellular imbalance of ions, caused by the flow of sodium, is corrected by a flow of chloride ions. In addition, this attempt to restore the osmotic balance of the cell leads to a flow of water into the intracellular space causing lysis [24]. Alternatively, excitotoxicity can kill neuronal cells by calcium-dependent mechanisms. This means that chronic depolarization leads to an intracellular calcium flux via calcium-dependent channels and the opening of channels of NMDA receptors; this flow is increased by the mobilization of calcium from its intracellular reservoirs and the reverse sodium-calcium exchange operation of the membrane, and activation of calcium-dependent self-destructive enzymes begins as a result [22].

Cell death by excitotoxicity is also observed in the glia [24], oligodendrocytes being the most susceptible cells [25]; as these cells do not have NMDA receptors, excitotoxicity is via AMPA, and kainite receptors in oligodendrocytes are more permeable to calcium in neurons, resulting in a more accelerated destabilization of their organelles; in addition, these cells have less efficient calcium buffering systems, which generate cell death in a more hasty manner [25].

#### **3.7 Inflammation and immune response**

After a TSC an intense inflammatory response is triggered that involves the action of chemical mediators, the cytokines IL-2, IL-6, and tumor necrosis factor alpha (TNF-α), and the participation of inflammatory cells such as neutrophils and mast cells. In addition to a large invasion of macrophages to the site of injury, both activated neutrophils and macrophages produce superoxide anion and nitric oxide; the latter can also be produced by platelets, endothelial cells, and microglia (CNS macrophages). Activated macrophages/microglia are important producers of cytotoxic substances, such as the proinflammatory cytokines mentioned above, causing neural damage and preventing tissue regeneration [26]. According to David [2], a flow of monocytes to the spinal cord of mice occurs at 12 hours and again at 4 days after injury. This flow is dependent on MYD88 and IL-4; however, it is not well determined whether it is from proinflammatory monocytes. In rats, researchers have been able to track dendritic cells to the area of injury by immunofluorescence, though it has not been seen in mice.

#### **4. Discussion**

The pathophysiology of spinal cord injury is not sufficiently described, and further research is needed to gain a better understanding of all the processes involved.

However, the mechanisms known so far show us a multifactorial syndrome that requires detailed study of destruction phenomena that are triggered as secondary injury. The understanding of these phenomena will lead to the rational search for solutions for patients with this condition. It is important to emphasize finding therapies that help the patient in both moments of the evolution of the lesion, as well as to provide neuroprotection, so as to favor the regeneration of injured tissue. In this chapter a brief description of the pathophysiology of the spinal cord lesion is offered in order to help the researcher find the best solutions.

There are a large number of studies with different approaches. However, a solution to all the consequences that a spinal cord injury causes has yet to be found, and so the need to find alternative treatments remains.

#### **5. Conclusions**

All the alterations and phenomena that occur at a cellular and molecular level are related to gradual degeneration of both vascular and neural tissue, destroying the anatomical substrate necessary for neurological recovery. These neurodegenerative processes cause the need to use different therapeutic strategies that reduce the damage caused by secondary injury, always looking for alternatives based on an understanding of the pathophysiology of spinal cord injury, which helps generate comprehensive and multivariable treatments that favor the recovery of function, preventing secondary damage and favoring regeneration of the neural tissue.

**19**

provided the original work is properly cited.

Susana Martiñón1,2\*, Juan Armando Reyes-Perez3

2 Anahuac University, Huixquilucan, Mexico State, Mexico

3 National Institute of Cancerology, Mexico City, Mexico

\*Address all correspondence to: susimar2000@yahoo.com

4 Centro de la Conducta S.C., Tijuana, Baja California, Mexico

*Physiopathology of Spinal Cord Injury*

**Acknowledgements**

Anáhuac University.

**Conflict of interest**

of this paper.

**Author details**

*DOI: http://dx.doi.org/10.5772/intechopen.86234*

We thank the National Institute of Psychiatry Ramón de la Fuente Muñiz, especially QFB Ricardo J. Hernández Miramontes, and the Faculty of Health Sciences of

The authors declare that there is no conflict of interest regarding the publication

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico

and Psyché Calderón-Vargas4

### **Acknowledgements**

*Spinal Cord Injury Therapy*

Cell death by excitotoxicity is also observed in the glia [24], oligodendrocytes being the most susceptible cells [25]; as these cells do not have NMDA receptors, excitotoxicity is via AMPA, and kainite receptors in oligodendrocytes are more permeable to calcium in neurons, resulting in a more accelerated destabilization of their organelles; in addition, these cells have less efficient calcium buffering

After a TSC an intense inflammatory response is triggered that involves the action of chemical mediators, the cytokines IL-2, IL-6, and tumor necrosis factor alpha (TNF-α), and the participation of inflammatory cells such as neutrophils and mast cells. In addition to a large invasion of macrophages to the site of injury, both activated neutrophils and macrophages produce superoxide anion and nitric oxide; the latter can also be produced by platelets, endothelial cells, and microglia (CNS macrophages). Activated macrophages/microglia are important producers of cytotoxic substances, such as the proinflammatory cytokines mentioned above, causing neural damage and preventing tissue regeneration [26]. According to David [2], a flow of monocytes to the spinal cord of mice occurs at 12 hours and again at 4 days after injury. This flow is dependent on MYD88 and IL-4; however, it is not well determined whether it is from proinflammatory monocytes. In rats, researchers have been able to track dendritic cells to the area of injury by immunofluorescence,

The pathophysiology of spinal cord injury is not sufficiently described, and further research is needed to gain a better understanding of all the processes involved. However, the mechanisms known so far show us a multifactorial syndrome that requires detailed study of destruction phenomena that are triggered as secondary injury. The understanding of these phenomena will lead to the rational search for solutions for patients with this condition. It is important to emphasize finding therapies that help the patient in both moments of the evolution of the lesion, as well as to provide neuroprotection, so as to favor the regeneration of injured tissue. In this chapter a brief description of the pathophysiology of the spinal cord lesion is

There are a large number of studies with different approaches. However, a solution to all the consequences that a spinal cord injury causes has yet to be found, and

All the alterations and phenomena that occur at a cellular and molecular level are related to gradual degeneration of both vascular and neural tissue, destroying the anatomical substrate necessary for neurological recovery. These neurodegenerative processes cause the need to use different therapeutic strategies that reduce the damage caused by secondary injury, always looking for alternatives based on an understanding of the pathophysiology of spinal cord injury, which helps generate comprehensive and multivariable treatments that favor the

recovery of function, preventing secondary damage and favoring regeneration of

offered in order to help the researcher find the best solutions.

so the need to find alternative treatments remains.

systems, which generate cell death in a more hasty manner [25].

**3.7 Inflammation and immune response**

though it has not been seen in mice.

**4. Discussion**

**5. Conclusions**

the neural tissue.

**18**

We thank the National Institute of Psychiatry Ramón de la Fuente Muñiz, especially QFB Ricardo J. Hernández Miramontes, and the Faculty of Health Sciences of Anáhuac University.

### **Conflict of interest**

The authors declare that there is no conflict of interest regarding the publication of this paper.

### **Author details**

Susana Martiñón1,2\*, Juan Armando Reyes-Perez3 and Psyché Calderón-Vargas4


\*Address all correspondence to: susimar2000@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[4] Chen K, Ye J-C, Cai Z-P, et al. Intraoperative contrast-enhanced ultrasonography for microcirculatory evaluation in rhesus monkey with spinal cord injury. Oncotarget. 2017;**8**:40756-40764

[5] Pappalardo LW, Samad OA, Black JA, et al. Voltage-gated sodium channel Nav1.5 contributes to astrogliosis in an in vitro model of glial injury via reverse Na<sup>+</sup> /Ca2+ exchange. Glia. 2014;**62**:1162-1175

[6] Stirling DP, Cummins K, Wayne Chen SR, et al. Axoplasmic reticulum Ca2+ release causes secondary degeneration of spinal axons. Annals of Neurology. 2014;**75**:220-229

[7] Cerretani D, La Russa R, Santurro A, et al. Diffuse axonal injury and oxidative stress: A comprehensive review. International Journal of Molecular Sciences. 2017;**18**:2600

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[9] Maday S, Twelvetrees AE, Moughamian AJ, et al. Axonal transport: Cargo-specific mechanisms of motility and regulation. Neuron. 2014;**84**:292-309

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[12] Batista CM, Bianqui LLT, Zanon BB, et al. Behavioral improvement and regulation of molecules related to neuroplasticity in ischemic rat spinal cord treated with PEDF. Neural Plasticity. 2014;**2014**:451639. DOI: 10.1155/2014/451639

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[14] Zhu P, Li JX, Fujino M, et al. Development and treatments of inflammatory cells and cytokines in spinal cord ischemia-reperfusion injury. Mediators of Inflammation. 2013;**2013**:701970. DOI: 10.1155/2013/ 701970

[15] Popa C, Popa F, Titus Grigorean V, et al. Vascular dysfunctions following spinal cord injury. Journal of Medicine and Life. 2010;**3**:275-285

[16] Xiao M, Zhong H, Xia L, et al. Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in

**21**

2016;**6**:1-12

apmr.2012.06.021

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Medicine. 2017;**111**:316-327

receptors, neurotoxicity and

Research. 2012;**90**:656-663

10.1124/jpet.117.244806

[19] Scholpa NE, Schnellmann RG. Mitochondrial-based therapeutics for the treatment of spinal cord injury: Mitochondrial biogenesis as a potential pharmacological target. The Journal of Pharmacology and Experimental Therapeutics. 2017;**363**:303-313. DOI:

[20] Palencia G, Medrano JÁN, Ortiz-Plata A, et al. Anti-apoptotic, antioxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/ reperfusion injury in rats. Journal of the Neurological Sciences. 2015;**351**:78-87

[21] Mohamed HRH. Estimation of genomic instability and mitochondrial DNA damage induction by acute oral administration of calcium hydroxide normal- and nano- particles in mice. Toxicology Letters. 2019;**304**:1-12

[22] Bastani NE, Kostovski E, Sakhi AK, et al. Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients. Archives of Physical Medicine and Rehabilitation. 2012;**93**:2223-8.e2. DOI: 10.1016/j.

[23] Fernández-López B, Barreiro-Iglesias A, Rodicio MC. Anatomical recovery of the spinal glutamatergic system following a complete spinal cord injury in lampreys. Scientific Reports.

2010;**460**:525-542

*DOI: http://dx.doi.org/10.5772/intechopen.86234*

[24] Fernández-López B, Valle-Maroto SM, Barreiro-Iglesias A, et al. Neuronal release and successful astrocyte uptake of aminoacidergic neurotransmitters after spinal cord injury in lampreys.

[25] Copani A, Spampinato SF, Sortino MA, et al. Metabotropic glutamate receptors in glial cells: A new potential target for neuroprotection? Frontiers in Molecular Neuroscience. 2018;**11**:1-13

[26] Louw AM, Kolar MK, Novikova LN, et al. Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury. Nanomedicine: Nanotechnology, Biology and Medicine. 2016;**12**:643-653

Glia. 2014;**62**:1254-1269

mitochondria. Free Radical Biology &

[17] Lau A, Tymianski M. Glutamate

neurodegeneration. Pflügers Archiv— European Journal of Physiology.

[18] Garcia E, Silva-Garcia R, Mestre H, et al. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury. Journal of Neuroscience

*Physiopathology of Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.86234*

mitochondria. Free Radical Biology & Medicine. 2017;**111**:316-327

[17] Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflügers Archiv— European Journal of Physiology. 2010;**460**:525-542

[18] Garcia E, Silva-Garcia R, Mestre H, et al. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury. Journal of Neuroscience Research. 2012;**90**:656-663

[19] Scholpa NE, Schnellmann RG. Mitochondrial-based therapeutics for the treatment of spinal cord injury: Mitochondrial biogenesis as a potential pharmacological target. The Journal of Pharmacology and Experimental Therapeutics. 2017;**363**:303-313. DOI: 10.1124/jpet.117.244806

[20] Palencia G, Medrano JÁN, Ortiz-Plata A, et al. Anti-apoptotic, antioxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/ reperfusion injury in rats. Journal of the Neurological Sciences. 2015;**351**:78-87

[21] Mohamed HRH. Estimation of genomic instability and mitochondrial DNA damage induction by acute oral administration of calcium hydroxide normal- and nano- particles in mice. Toxicology Letters. 2019;**304**:1-12

[22] Bastani NE, Kostovski E, Sakhi AK, et al. Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients. Archives of Physical Medicine and Rehabilitation. 2012;**93**:2223-8.e2. DOI: 10.1016/j. apmr.2012.06.021

[23] Fernández-López B, Barreiro-Iglesias A, Rodicio MC. Anatomical recovery of the spinal glutamatergic system following a complete spinal cord injury in lampreys. Scientific Reports. 2016;**6**:1-12

[24] Fernández-López B, Valle-Maroto SM, Barreiro-Iglesias A, et al. Neuronal release and successful astrocyte uptake of aminoacidergic neurotransmitters after spinal cord injury in lampreys. Glia. 2014;**62**:1254-1269

[25] Copani A, Spampinato SF, Sortino MA, et al. Metabotropic glutamate receptors in glial cells: A new potential target for neuroprotection? Frontiers in Molecular Neuroscience. 2018;**11**:1-13

[26] Louw AM, Kolar MK, Novikova LN, et al. Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury. Nanomedicine: Nanotechnology, Biology and Medicine. 2016;**12**:643-653

**20**

2010;**116**:3445-3455

*Spinal Cord Injury Therapy*

2019:1-17

**References**

[1] Khorasanizadeh M, Yousefifard M, Eskian M, et al. Neurological recovery following traumatic spinal cord injury: A systematic review and meta-analysis. Journal of Neurosurgery. Spine. 15 Feb

[9] Maday S, Twelvetrees AE, Moughamian AJ, et al. Axonal

2014;**84**:292-309

2018;**301**:59-69

2011;**331**:928-931

10.1155/2014/451639

701970

transport: Cargo-specific mechanisms of motility and regulation. Neuron.

[10] Brock JH, Rosenzweig ES, Yang H, et al. Enhanced axonal transport: A novel form of "plasticity" after primate and rodent spinal cord injury. Experimental Neurology.

[11] Flynn KC, Bradke F, Bixby J, et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science.

[12] Batista CM, Bianqui LLT, Zanon BB, et al. Behavioral improvement and regulation of molecules related to neuroplasticity in ischemic rat spinal cord treated with PEDF. Neural Plasticity. 2014;**2014**:451639. DOI:

[13] Sinescu C, Popa F, Grigorean VT, Onose G, Sandu AM, Popescu M, et al. Molecular basis of vascular events following spinal cord injury. Journal of Medicine and Life. 2010;**3**:254-261

[14] Zhu P, Li JX, Fujino M, et al. Development and treatments of inflammatory cells and cytokines in spinal cord ischemia-reperfusion injury. Mediators of Inflammation. 2013;**2013**:701970. DOI: 10.1155/2013/

[15] Popa C, Popa F, Titus Grigorean V, et al. Vascular dysfunctions following spinal cord injury. Journal of Medicine

[16] Xiao M, Zhong H, Xia L, et al. Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in

and Life. 2010;**3**:275-285

[2] David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nature Reviews.

[3] Khaing ZZ, Cates LN, DeWees DM, et al. Contrast-enhanced ultrasound to visualize hemodynamic changes after rodent spinal cord injury. Journal of Neurosurgery. Spine. 2018;**29**:306-313

Neuroscience. 2011;**12**:388-399

[4] Chen K, Ye J-C, Cai Z-P, et al. Intraoperative contrast-enhanced ultrasonography for microcirculatory evaluation in rhesus monkey with spinal cord injury. Oncotarget.

[5] Pappalardo LW, Samad OA, Black JA, et al. Voltage-gated sodium channel Nav1.5 contributes to astrogliosis in an in vitro model of glial injury

[6] Stirling DP, Cummins K, Wayne Chen SR, et al. Axoplasmic reticulum

degeneration of spinal axons. Annals of

[7] Cerretani D, La Russa R, Santurro A,

Ca2+ release causes secondary

Neurology. 2014;**75**:220-229

et al. Diffuse axonal injury and oxidative stress: A comprehensive review. International Journal of Molecular Sciences. 2017;**18**:2600

[8] Auner HW, Beham-Schmid C, Dillon N, et al. The life span of shortlived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress. Blood.

/Ca2+ exchange. Glia.

2017;**8**:40756-40764

via reverse Na<sup>+</sup>

2014;**62**:1162-1175

**23**

**Chapter 3**

**Abstract**

Molecules

*and Soraya Mehrabi*

treatment strategies for SCI.

**1. Introduction**

Reactive Astrocyte Gliosis:

Production of Inhibitory

*Mohammad Taghi Joghataei, Fereshteh Azedi*

**Keywords:** astrogliosis, reactive astrocyte, inhibitory molecule

Astrocytes are the most numerous glial cells in the CNS, which are pivotal for various structural and physiological functions [1]. SCI triggers astrocytes to become reactive and initiate astrogliosis. Reactive astrogliosis is characterized by the proliferation and hypertrophy of astrocytes, which eventually leads to scar formation via the activation of signaling pathways such as Gp-130/activator of transcription 3 (STAT3) and transforming growth factors-beta (TGF-β/Smad) [2]. With the onset of injury, changes occur in the phenotype and morphology of astrocytes. These changes include increasing in their expression of intermediate filaments such as nestin, glial fibrillary acidic proteins (GFAP), and vimentin. Reactive astrocytes also related to the release of pro-inflammatory and anti-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), TGF-β, interferon-gamma (IFN-γ),

The astrocytic cell responses to injury have been extensively studied in a variety of experimental models, and the term "astrogliosis" is often used to describe the astrocyte reactions to injury. Cells responding in these ways to injury are often referred to as "reactive astrocytes." Glial scarring appears to be a critical feature of wound healing in the central nervous system (CNS), since elimination of the mitotically active contingent of reactive astrocytes leads to increase in the size of the wound. Reactive astrogliosis is a term coined for the morphological and functional events seen in astrocytes responding to CNS injury. The concept of reactive astrogliosis and its molecular and cellular definition in spinal cord injury (SCI) is still incomplete. Producing several inhibitory molecules discourages regeneration of axons in the injured spinal cord. This inhibition is compounded by the poor regenerative ability of most CNS axons. This is probably a more achievable therapeutic target than axon regeneration, and an effective treatment would be of assistance to the majority of patients with partial cord injuries. Of course, understanding about astrogliosis and producing mediators and inhibitory molecules such as signaling pathways help us to develop new

#### **Chapter 3**

## Reactive Astrocyte Gliosis: Production of Inhibitory Molecules

*Mohammad Taghi Joghataei, Fereshteh Azedi and Soraya Mehrabi*

#### **Abstract**

The astrocytic cell responses to injury have been extensively studied in a variety of experimental models, and the term "astrogliosis" is often used to describe the astrocyte reactions to injury. Cells responding in these ways to injury are often referred to as "reactive astrocytes." Glial scarring appears to be a critical feature of wound healing in the central nervous system (CNS), since elimination of the mitotically active contingent of reactive astrocytes leads to increase in the size of the wound. Reactive astrogliosis is a term coined for the morphological and functional events seen in astrocytes responding to CNS injury. The concept of reactive astrogliosis and its molecular and cellular definition in spinal cord injury (SCI) is still incomplete. Producing several inhibitory molecules discourages regeneration of axons in the injured spinal cord. This inhibition is compounded by the poor regenerative ability of most CNS axons. This is probably a more achievable therapeutic target than axon regeneration, and an effective treatment would be of assistance to the majority of patients with partial cord injuries. Of course, understanding about astrogliosis and producing mediators and inhibitory molecules such as signaling pathways help us to develop new treatment strategies for SCI.

**Keywords:** astrogliosis, reactive astrocyte, inhibitory molecule

#### **1. Introduction**

Astrocytes are the most numerous glial cells in the CNS, which are pivotal for various structural and physiological functions [1]. SCI triggers astrocytes to become reactive and initiate astrogliosis. Reactive astrogliosis is characterized by the proliferation and hypertrophy of astrocytes, which eventually leads to scar formation via the activation of signaling pathways such as Gp-130/activator of transcription 3 (STAT3) and transforming growth factors-beta (TGF-β/Smad) [2]. With the onset of injury, changes occur in the phenotype and morphology of astrocytes. These changes include increasing in their expression of intermediate filaments such as nestin, glial fibrillary acidic proteins (GFAP), and vimentin. Reactive astrocytes also related to the release of pro-inflammatory and anti-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), TGF-β, interferon-gamma (IFN-γ),

and interleukins (IL-1 and IL-6). It is well established that these cytokines can modulate inflammation and also secondary injury [3].

When astrocytes are activated, they change the composition of extracellular matrix (ECM) dramatically. Several ECM components including chondroitin sulfate proteoglycans (CSPGs) and tenascins are markedly upregulated in astrocytes. In addition to these phenotypic changes, astrocytes increase in number and migrate to the site of injury [4].

Therefore, astrocyte reactivity is considered as a part of endogenous mechanisms to restrict the initial tissue injury to the spinal cord and prevent extension of damage into adjacent segments. The pivotal role of reactive astrocytes particularly at first stages of SCI is indicated by recent findings. Ablation of reactive astrocytes or altering with their activation at the time of SCI injury can intensify the damage by elevating tissue degeneration and disrupt to reconstruct blood-spinal barrier (BSB) [5]. However, over time after injury, inhibitory features of reactive astrocytes overcome their constructive properties. This is mostly contributed to the upregulation of inhibitory molecules such as CSPGs that extremely prevent neuroregeneration and neural repair [6].

Astrogliosis may be heterogeneous. Not all astrocytes with the morphological characteristics of reactive astrocytes (i.e., increased GFAP) are present in areas with increased levels of ECM. Perhaps not all astrocytes that react to injury play a role in the failure of CNS regeneration, and that only those astrocytes associated with inhibitory molecules are detrimental to axon growth while those further away from the lesion may be more conducive to neurite sprouting, functional plasticity, and long-distance regeneration [7].

#### **2. Functions of astrocytes in a healthy brain**

Based on previous studies, astrocytes were for decades considered to be assisting and nurturing neurons. Regarding several studies, the protoplasmic astrocytes divide the whole gray matter of the brain and spinal cord into distinct domains, with blood vessels, neurons, and synapses contained within these domains [8], and the fibrous astrocytes are in the white matter and are in physical contact with oligodendrocytes and have an important role in myelinization; however, astrocyte functions go far beyond assistance and support [9, 10].

During development, they are considered in key developmental and postnatal traces in the CNS. Astrocytes release neurotrophic factors that regulate neuronal development, cell migration, and differentiation [11]. Developing astrocytes guide postmitotic neurons from the ventricular zone to their target destination in developing CNS. Radial glial cells, a subtype of astrocytes, guide new neurons for accurate migration [12]. Astrocytes secrete vascular endothelial growth factor that is necessary for the generation of new blood vessels in rostral migratory stream (RMS) [13]. Besides, astrocytes have connection with blood vessels through their end-feet. They can produce important mediators which contributed to vasoconstriction or vasodilation such as arachidonic acid, nitric oxide (NO), or prostaglandins [14]. Astrocytes play a critical role in the coupling of neuronal organization to signaling circuits. They are involved in hemodynamic responses with neurons through blood flow.

Astrocytes significantly contribute to the establishment and maintenance of blood-brain barrier (BBB) and BSB in the CNS [15]. Astrocytes also clear neurotransmitters such as gamma-aminobutyric acid (GABA), glycine, and glutamate from the synaptic clefts and facilitate normal synaptic transmission [16]. Astrocytes have an important function in regulation of pH in CNS. They set up

**25**

on this process [28].

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules*

proton shuttling through different proteins such as Na<sup>+</sup>

transporters acting in a sodium-dependent/independent mode, monocarboxylic acid transporters, carbonic anhydrase in both intra-and extracellular spaces, and

Astrocytes are actively involved in the synthesis and maintenance of the ECM in the CNS. They produce a number of ECM components with both growth-promoting and inhibitory properties [18]. Astrocytes also express tenascin-C and different CSPGs with growth inhibitory properties [19]. When neuronal maturation begins in the normal CNS, CSPGs are concentrated strongly in the perineuronal nets where they are critical for stabilizing synapses and limiting undesirable plasticity [20].

After SCI, astrocytes undergo significant cellular, molecular, and functional changes along with profound alterations in their gene expression. The reactions of astrocytes to the injury include hypertrophy of processes and soma and increasing in proliferation and upregulation of intermediate filaments such as GFAP, vimentin, and nestin. These alterations are the important markers of a phenomenon known as

Reactive astrogliosis is also indicated by high production of CSPGs, several cytokines, and chemokines such as IL-1β, IL-6, TGF-β, ciliary neurotrophic factor (CNTF), adhesion molecules, and proteins such as cyclooxygenase2, inducible NO synthase (iNOS), and calcium-binding protein S100β. These factors are considered as the functional markers of astrocyte reactivity whose levels are upregulated fol-

Astrogliosis can be categorized from moderate changes in astrocytes to high reactivity related to scar formation [22]. In initial stages, there is aberrant hypertrophy of astrocytes and low upregulation of GFAP levels; however, no important proliferative activities usually occur in mild astrogliosis [23]. Mild astrogliosis or "isomorphic gliosis" is seen in the cases of axotomy, chemical lesions, or mild injury where astrocytes are distal to the site of lesion [24]. These alterations can be turned by reducing the triggering effects of upstream signaling molecules. Over time, reactive astrocytes express GFAP highly and show substantial hypertrophy, and some degree of proliferation. These remarkable expansions lead to disruption of particular regions of astrocytes and cause tissue distortion [3]. In intensive injuries, astrocytic processes overlap and become densely packed. At this stage, a glial scar encircles the epicenter of spinal cord lesion. Glial scar that is formed after local disruption of spine parenchyma is invariable and is nominated as

Although astrogliosis is an early important marker of SCI in rodents, in human SCI, astrocyte reactivity is not a prominent property at acute or subacute phases, and astrogliosis seems to evolve over the time and become more evident at intermediate and chronic phases of SCI [26]. The presence of dense astrogliosis at 11 days after SCI that was still evident after 1 year post-SCI has been reported in some evidences [27]. Further investigations for astrogliosis in human SCI are necessary to examine the impact and timing. This is particularly important when translating therapeutic strategies that target astrogliosis from rodent models to human SCI. Meningeal fibroblasts also contribute to scar formation. In fact, the glial scar formation is adjusted by a cell-cell contact mechanism between reactive astrocytes and meningeal fibroblasts at the spinal cord lesion. Signaling between ephrin-B2 on reactive astrocytes and EphB2 receptors on meningeal fibroblasts appears to carry

/H+

exchanger, bicarbonate

*DOI: http://dx.doi.org/10.5772/intechopen.85570*

the vacuolar-type proton ATPase [17].

**3. Reactive astrogliosis in SCI**

reactive astrogliosis [7].

lowing CNS injuries [21].

"anisomorphic gliosis" [25].

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules DOI: http://dx.doi.org/10.5772/intechopen.85570*

proton shuttling through different proteins such as Na<sup>+</sup> /H+ exchanger, bicarbonate transporters acting in a sodium-dependent/independent mode, monocarboxylic acid transporters, carbonic anhydrase in both intra-and extracellular spaces, and the vacuolar-type proton ATPase [17].

Astrocytes are actively involved in the synthesis and maintenance of the ECM in the CNS. They produce a number of ECM components with both growth-promoting and inhibitory properties [18]. Astrocytes also express tenascin-C and different CSPGs with growth inhibitory properties [19]. When neuronal maturation begins in the normal CNS, CSPGs are concentrated strongly in the perineuronal nets where they are critical for stabilizing synapses and limiting undesirable plasticity [20].

#### **3. Reactive astrogliosis in SCI**

*Spinal Cord Injury Therapy*

to the site of injury [4].

tion and neural repair [6].

long-distance regeneration [7].

**2. Functions of astrocytes in a healthy brain**

functions go far beyond assistance and support [9, 10].

and interleukins (IL-1 and IL-6). It is well established that these cytokines can

When astrocytes are activated, they change the composition of extracellular matrix (ECM) dramatically. Several ECM components including chondroitin sulfate proteoglycans (CSPGs) and tenascins are markedly upregulated in astrocytes. In addition to these phenotypic changes, astrocytes increase in number and migrate

Therefore, astrocyte reactivity is considered as a part of endogenous mechanisms to restrict the initial tissue injury to the spinal cord and prevent extension of damage into adjacent segments. The pivotal role of reactive astrocytes particularly at first stages of SCI is indicated by recent findings. Ablation of reactive astrocytes or altering with their activation at the time of SCI injury can intensify the damage by elevating tissue degeneration and disrupt to reconstruct blood-spinal barrier (BSB) [5]. However, over time after injury, inhibitory features of reactive astrocytes overcome their constructive properties. This is mostly contributed to the upregulation of inhibitory molecules such as CSPGs that extremely prevent neuroregenera-

Astrogliosis may be heterogeneous. Not all astrocytes with the morphological characteristics of reactive astrocytes (i.e., increased GFAP) are present in areas with increased levels of ECM. Perhaps not all astrocytes that react to injury play a role in the failure of CNS regeneration, and that only those astrocytes associated with inhibitory molecules are detrimental to axon growth while those further away from the lesion may be more conducive to neurite sprouting, functional plasticity, and

Based on previous studies, astrocytes were for decades considered to be assisting and nurturing neurons. Regarding several studies, the protoplasmic astrocytes divide the whole gray matter of the brain and spinal cord into distinct domains, with blood vessels, neurons, and synapses contained within these domains [8], and the fibrous astrocytes are in the white matter and are in physical contact with oligodendrocytes and have an important role in myelinization; however, astrocyte

During development, they are considered in key developmental and postnatal traces in the CNS. Astrocytes release neurotrophic factors that regulate neuronal development, cell migration, and differentiation [11]. Developing astrocytes guide postmitotic neurons from the ventricular zone to their target destination in developing CNS. Radial glial cells, a subtype of astrocytes, guide new neurons for accurate migration [12]. Astrocytes secrete vascular endothelial growth factor that is necessary for the generation of new blood vessels in rostral migratory stream (RMS) [13]. Besides, astrocytes have connection with blood vessels through their end-feet. They can produce important mediators which contributed to vasoconstriction or vasodilation such as arachidonic acid, nitric oxide (NO), or prostaglandins [14]. Astrocytes play a critical role in the coupling of neuronal organization to signaling circuits. They are involved in hemodynamic responses with neurons

Astrocytes significantly contribute to the establishment and maintenance of blood-brain barrier (BBB) and BSB in the CNS [15]. Astrocytes also clear neurotransmitters such as gamma-aminobutyric acid (GABA), glycine, and glutamate from the synaptic clefts and facilitate normal synaptic transmission [16]. Astrocytes have an important function in regulation of pH in CNS. They set up

modulate inflammation and also secondary injury [3].

**24**

through blood flow.

After SCI, astrocytes undergo significant cellular, molecular, and functional changes along with profound alterations in their gene expression. The reactions of astrocytes to the injury include hypertrophy of processes and soma and increasing in proliferation and upregulation of intermediate filaments such as GFAP, vimentin, and nestin. These alterations are the important markers of a phenomenon known as reactive astrogliosis [7].

Reactive astrogliosis is also indicated by high production of CSPGs, several cytokines, and chemokines such as IL-1β, IL-6, TGF-β, ciliary neurotrophic factor (CNTF), adhesion molecules, and proteins such as cyclooxygenase2, inducible NO synthase (iNOS), and calcium-binding protein S100β. These factors are considered as the functional markers of astrocyte reactivity whose levels are upregulated following CNS injuries [21].

Astrogliosis can be categorized from moderate changes in astrocytes to high reactivity related to scar formation [22]. In initial stages, there is aberrant hypertrophy of astrocytes and low upregulation of GFAP levels; however, no important proliferative activities usually occur in mild astrogliosis [23]. Mild astrogliosis or "isomorphic gliosis" is seen in the cases of axotomy, chemical lesions, or mild injury where astrocytes are distal to the site of lesion [24]. These alterations can be turned by reducing the triggering effects of upstream signaling molecules. Over time, reactive astrocytes express GFAP highly and show substantial hypertrophy, and some degree of proliferation. These remarkable expansions lead to disruption of particular regions of astrocytes and cause tissue distortion [3]. In intensive injuries, astrocytic processes overlap and become densely packed. At this stage, a glial scar encircles the epicenter of spinal cord lesion. Glial scar that is formed after local disruption of spine parenchyma is invariable and is nominated as "anisomorphic gliosis" [25].

Although astrogliosis is an early important marker of SCI in rodents, in human SCI, astrocyte reactivity is not a prominent property at acute or subacute phases, and astrogliosis seems to evolve over the time and become more evident at intermediate and chronic phases of SCI [26]. The presence of dense astrogliosis at 11 days after SCI that was still evident after 1 year post-SCI has been reported in some evidences [27]. Further investigations for astrogliosis in human SCI are necessary to examine the impact and timing. This is particularly important when translating therapeutic strategies that target astrogliosis from rodent models to human SCI.

Meningeal fibroblasts also contribute to scar formation. In fact, the glial scar formation is adjusted by a cell-cell contact mechanism between reactive astrocytes and meningeal fibroblasts at the spinal cord lesion. Signaling between ephrin-B2 on reactive astrocytes and EphB2 receptors on meningeal fibroblasts appears to carry on this process [28].

#### **Figure 1.**

*Reactive astrogliosis is a response of activated astrocytes seen in spinal cord injury and can be triggered through various signaling pathways such as signal transducers and activators of transcription (STAT) and TGF-β/ Smad. In most situations, it can be viewed as a defensive reaction counteracting acute stress, restoring the CNS homeostasis, and limiting the tissue damage; however, persisting reactive astrogliosis can be lead to inhibition of neural plasticity and other regenerative responses.*

Reactive astrogliosis can be triggered through several signaling pathways such as signal transducers and activators of transcription (STAT) and TGF-β/Smad (**Figure 1**) [29]. Both beneficial and detrimental effects of SCI can be dependent to which signaling pathways and timing after SCI are involved. Understanding the beneficial and detrimental role of reactive astrocytes will allow us to plan therapeutic approaches.

#### **4. Beneficial effects of reactive astrogliosis in SCI**

Previously, astrocytes were known to be solely harmful in SCI, and their inhibition or ablation was considered as a therapeutic strategy. Recent studies have provided strong evidence that reactive astrocytes play pivotal roles in SCI repair with protective features [30, 31]. Repair responding by reconstructing the damaged BSB and limiting the infiltration of peripheral leukocytes and activation of resident microglia [32], modulating blood flow by the release of vasoconstrictors and regulating blood vessels diameter [33], uptaking excess glutamate, protecting neurons and oligodendrocytes from glutamate excitotoxicity, and producing antioxidants such as glutathione and defending against oxidative stress [34] are inconsiderable parts of beneficial roles of astrocytes. Reactive astrocytes upregulate the expression of intermediate filaments, GFAP, vimentin, and nestin. Interestingly, in hemisection model of SCI, double GFAP and vimentin knockout mice showed beneficial outcomes [35].

Besides, astrocytes are known to become reactive through STAT3 and suppressor of cytokine signaling 3 (SOCS3) pathways. Some evidences indicated that knockout of SOCS3 or STAT3 in GFAP-Cre or nestin-Cre transgenic models caused limited migration of astrocytes to the site of lesion and interfered with the formation of glial scar. Failure of scar formation in these animals resulted in widespread lesion [36]. Also, astrocytes can promote tissue repair and regeneration as they upregulate their expression of fibroblast growth factor-2 (FGF-2) and S100β in the injured spinal cord [37]. Furthermore, astrocyte polarity and directional migration play an important role in astrocyte ability to react to injury. Recent findings

**27**

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules*

**5. Detrimental roles of reactive astrocytes after SCI**

demonstrated that astrocytes depleted of the small RhoGTPase Cdc42, which is a key regulator of cell polarization, display impaired recruitment to the stab wound lesion, despite their upregulation of GFAP and hypertrophic response [38].

Glial scar is a major detriment to regeneration of severed axons by upregulating a great number of molecules around the lesion and preventing regrowth of injured axons at the lesion area, including CSPGs, tenascin, semaphorin 3A, keratan sulfate proteoglycans (KSPGs), myelin-associated inhibitors, and ephrins/Eph receptors [6]. Reactive astrocytes and the ECM components generate a dense glial scar around the SCI lesion and create physical and chemical barriers on axonal regeneration. In fact, as axons come in close contact with the glial scar, they form dystrophic endbulbs and retract without any regeneration [39]. ECM components such as CSPGs [40], tenascins [41], and collagen [42] can be act as main inhibitory factors in axonal regeneration. They could upregulate in the glial scar after SCI and obstruct

STAT3 is a member of the Janus kinase STAT family and a transducer of signals for many cytokines and growth factors, such as IL-6, leukemia inhibitory factor (LIF), and CNTF [44]. The effect on astrocyte activation may be mediated via the STAT3 signaling pathway, phosphorylation, and nuclear translocation of STAT3 in astrocytes as well as indirectly through the effects of these molecules on other cell types such as microglia, neurons, or endothelial cells [45]. One of the key mediators of astrocytic scar formation after SCI is STAT3 signaling. STAT3 conditional knockout mice failed to create a glial scar that led to a widespread lesion and poor recovery of function after SCI. Lack of STAT3 activation especially led to the inability of astrocytes to move and migrate to the lesion site. This resulted in exacerbated infiltration of inflammatory cells at the site of SCI. This finding emphasized the importance of STAT3 activation in astrocytes and the impact of reactive astrogliosis in restraining leukocyte infiltration and reducing the initial insult after SCI [36].

Erythropoietin-producing human hepatocellular (Eph) receptors and ephrin ligands have attracted considerable attention since their discovery, due to their extensive distribution and unique bidirectional signaling between astrocytes and neurons [46]. Eph/ephrin signaling is involved in the glial scar formation in CNS disorders. It has been demonstrated in a model of spinal cord injury that the development of glial scars and the exclusion of meningeal fibroblasts from the site of damage are a result of cell contact-mediated bidirectional signaling cascades, which is stimulated by the interaction of ephrin-B2 and EphB2 with reactive astrocytes and meningeal fibroblasts, respectively [28]. Another previous study demonstrated that ephrin B2 (−/−) mice exhibited a reduction in astrogliosis and an accelerated regeneration of injured corticospinal axons, which resulted in the recovery of murine motor function following spinal cord injury (SCI) [47].

*DOI: http://dx.doi.org/10.5772/intechopen.85570*

axonal elongation and sprouting [43].

**6.2 Ephrins/Eph receptors**

**6.1 STAT3**

**6. Molecular mediators of reactive astrogliosis**

demonstrated that astrocytes depleted of the small RhoGTPase Cdc42, which is a key regulator of cell polarization, display impaired recruitment to the stab wound lesion, despite their upregulation of GFAP and hypertrophic response [38].

#### **5. Detrimental roles of reactive astrocytes after SCI**

Glial scar is a major detriment to regeneration of severed axons by upregulating a great number of molecules around the lesion and preventing regrowth of injured axons at the lesion area, including CSPGs, tenascin, semaphorin 3A, keratan sulfate proteoglycans (KSPGs), myelin-associated inhibitors, and ephrins/Eph receptors [6]. Reactive astrocytes and the ECM components generate a dense glial scar around the SCI lesion and create physical and chemical barriers on axonal regeneration. In fact, as axons come in close contact with the glial scar, they form dystrophic endbulbs and retract without any regeneration [39]. ECM components such as CSPGs [40], tenascins [41], and collagen [42] can be act as main inhibitory factors in axonal regeneration. They could upregulate in the glial scar after SCI and obstruct axonal elongation and sprouting [43].

#### **6. Molecular mediators of reactive astrogliosis**

#### **6.1 STAT3**

*Spinal Cord Injury Therapy*

peutic approaches.

*neural plasticity and other regenerative responses.*

**Figure 1.**

Reactive astrogliosis can be triggered through several signaling pathways such as signal transducers and activators of transcription (STAT) and TGF-β/Smad (**Figure 1**) [29]. Both beneficial and detrimental effects of SCI can be dependent to which signaling pathways and timing after SCI are involved. Understanding the beneficial and detrimental role of reactive astrocytes will allow us to plan thera-

*Reactive astrogliosis is a response of activated astrocytes seen in spinal cord injury and can be triggered through various signaling pathways such as signal transducers and activators of transcription (STAT) and TGF-β/ Smad. In most situations, it can be viewed as a defensive reaction counteracting acute stress, restoring the CNS homeostasis, and limiting the tissue damage; however, persisting reactive astrogliosis can be lead to inhibition of* 

Previously, astrocytes were known to be solely harmful in SCI, and their inhibition or ablation was considered as a therapeutic strategy. Recent studies have provided strong evidence that reactive astrocytes play pivotal roles in SCI repair with protective features [30, 31]. Repair responding by reconstructing the damaged BSB and limiting the infiltration of peripheral leukocytes and activation of resident microglia [32], modulating blood flow by the release of vasoconstrictors and regulating blood vessels diameter [33], uptaking excess glutamate, protecting neurons and oligodendrocytes from glutamate excitotoxicity, and producing antioxidants such as glutathione and defending against oxidative stress [34] are inconsiderable parts of beneficial roles of astrocytes. Reactive astrocytes upregulate the expression of intermediate filaments, GFAP, vimentin, and nestin. Interestingly, in hemisection model of SCI, double GFAP and vimentin knockout

Besides, astrocytes are known to become reactive through STAT3 and suppressor of cytokine signaling 3 (SOCS3) pathways. Some evidences indicated that knockout of SOCS3 or STAT3 in GFAP-Cre or nestin-Cre transgenic models caused limited migration of astrocytes to the site of lesion and interfered with the formation of glial scar. Failure of scar formation in these animals resulted in widespread lesion [36]. Also, astrocytes can promote tissue repair and regeneration as they upregulate their expression of fibroblast growth factor-2 (FGF-2) and S100β in the injured spinal cord [37]. Furthermore, astrocyte polarity and directional migration play an important role in astrocyte ability to react to injury. Recent findings

**4. Beneficial effects of reactive astrogliosis in SCI**

mice showed beneficial outcomes [35].

**26**

STAT3 is a member of the Janus kinase STAT family and a transducer of signals for many cytokines and growth factors, such as IL-6, leukemia inhibitory factor (LIF), and CNTF [44]. The effect on astrocyte activation may be mediated via the STAT3 signaling pathway, phosphorylation, and nuclear translocation of STAT3 in astrocytes as well as indirectly through the effects of these molecules on other cell types such as microglia, neurons, or endothelial cells [45]. One of the key mediators of astrocytic scar formation after SCI is STAT3 signaling. STAT3 conditional knockout mice failed to create a glial scar that led to a widespread lesion and poor recovery of function after SCI. Lack of STAT3 activation especially led to the inability of astrocytes to move and migrate to the lesion site. This resulted in exacerbated infiltration of inflammatory cells at the site of SCI. This finding emphasized the importance of STAT3 activation in astrocytes and the impact of reactive astrogliosis in restraining leukocyte infiltration and reducing the initial insult after SCI [36].

#### **6.2 Ephrins/Eph receptors**

Erythropoietin-producing human hepatocellular (Eph) receptors and ephrin ligands have attracted considerable attention since their discovery, due to their extensive distribution and unique bidirectional signaling between astrocytes and neurons [46]. Eph/ephrin signaling is involved in the glial scar formation in CNS disorders. It has been demonstrated in a model of spinal cord injury that the development of glial scars and the exclusion of meningeal fibroblasts from the site of damage are a result of cell contact-mediated bidirectional signaling cascades, which is stimulated by the interaction of ephrin-B2 and EphB2 with reactive astrocytes and meningeal fibroblasts, respectively [28]. Another previous study demonstrated that ephrin B2 (−/−) mice exhibited a reduction in astrogliosis and an accelerated regeneration of injured corticospinal axons, which resulted in the recovery of murine motor function following spinal cord injury (SCI) [47].

#### **6.3 TGF-β**

TGF-β signaling is one of the mediators of reactive astrogliosis in SCI. TGF-β has been identified as a key trigger of CSPGs formation in the glial scar [48]. In experimental models of SCI, blockade of TGF-β signaling is shown to attenuate scar formation [49]. Interestingly, blood fibrinogen is a factor that activates TGF-β signaling after CNS injury. After vascular disruption and hemorrhage, blood fibrinogen is released into the CNS tissue, and reactive astrogliosis and CSPGs formation through the activation of TGF-β Smad2 pathway can be activated [50].

#### **6.4 Nuclear factor-κB (NF-κB)**

Activation of NF-κB transcription factor has been implicated in astrogliosis, although with some sophisticated evidence. In SCI, one study indicated that increased level of NF-κB was found in microglia/macrophages and endothelial cells but not in astrocytes [51]. However, in another study, reactive astrocytes were displayed to express NF-κB. Notably, studies in transgenic mice expressing IkBα, an inhibitor of NF-κB, under hGFAP promoter demonstrated that inactivation of astroglial NF-κB reduced the expression of TGF-β2 and CSPGs as well as other chemokines involved in glial scar formation such as C-X-C motif chemokine 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2). Moreover, blockade of NF-κB activation in astrocytes has resulted in white matter sparing and improved functional recovery after SCI [52].

#### **6.5 Endothelins (ET)**

ETs are peptides with vasoactive property. They can modulate reactive astrogliosis in various CNS diseases. ET-1 and its receptors are particularly increased in astrocytes after damage and seem to be one fundamental cause of astrogliosis [53]. In a stab wound injury, ET-1 receptor antagonist BQ788 decreased the activation and proliferation of astrocytes. ET-1 stimulates astrocyte proliferation via the activation of JNK/c-Jun signaling pathway in vitro [54].

#### **6.6 Mitogen-activated protein kinase (MAPK)**

MAPK and its downstream cascades mediate astrogliosis. It is indicated that c-mos proto-oncogene, which triggers the activation of MAPK signaling, stimulates astrogliosis. Several studies implicated the phosphorylation of extracellular signalregulated kinase/MAPK in reactive astrocytes in mice and humans [55].

#### **6.7 Semaphorin 3A**

Semaphorin 3A (Sema3A) is an important secreted repulsive guidance factor for many developing neurons [56]. Sema3A may be secreted from non-neuronal cells such as astrocytes. Sema3A continues to be expressed in adulthood, and expression of its receptor, neuropilin-1 (Nrp-1), can be altered by nerve injury [57]. Sema3As are regarded as one of the major classes of axon repulsive molecules that lead to the failure of axons to regenerate through the neural scar. Thus, interfering with Sema3A signaling can be beneficial for axonal regrowth [58].

#### **6.8 Aquaporins**

Aquaporins may play a role in the activities of astrocytes after SCI. In particular, recent studies showed that Aquaporin-4 is critical in glial scar formation [59].

**29**

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules*

the impact of Aquaporin-4 in scar formation after SCI [60].

In a cortical brain injury, Aquaporin-4 null mice displayed decreased migration of astroglia as a contribution to the injury site and less glial scarring. However, findings from rat SCI indicated biphasic changes in astrocytic Aquaporin-4 levels with preliminary downregulation after SCI and a following long-lasting upregulation in subacute and chronic stages of damage. Further elucidation is needed to understand

The ECM comprises the molecules that form the structure of the matrix. There is a huge range of molecules that have been shed from the cell surface or secreted by neurons and glia [22]. Most of these shed or secreted molecules bind to the matrix to some extent, mainly to the negatively charged glycosaminoglycan (GAG) chains of the CSPGs and heparan sulfate proteoglycans (HSPGs). There are two families of cell surface-attached HSPGs, the transmembrane syndecans and the GPI-linked glypicans. Various matrix components, particularly tenascin-C and CSPGs, are

Tenascins are abundant in the ECM of developing vertebrate embryos. There are four members of the tenascin gene family: tenascin-C, tenascin-R, tenascin-X, and tenascin-W. Tenascin-C is the most intensely studied member of the family [61]. Tenascin-C is anti-adhesive to many forms of neuron in vitro and inhibits axon growth from many neurons, although it promotes axon growth from some embryonic neuronal types [62]. These dual properties have been assigned to different splice variants of tenascin-C and molecular epitopes within those splice

The levels of CSPGs increase dramatically following various CNS injuries, including lesions in the spinal cord, cortex, fornix, and nigrostriatal area [20]. CSPGs are primarily generated by reactive astrocytes and to a lesser extent by oligodendrocytes and monocytes. CSPGs are a family of molecules characterized by a core protein to which the large and highly sulfated GAG chains are attached. The major CSPGs found in the CNS include lecticans (neurocan, versican, aggrecan,

KSPGs are another class of inhibitory ECM molecule, which are associated with spinal cord lesions [65]. Mice lacking GlcNAc6ST-1, an enzyme critical for keratan sulfate (KS) biosynthesis, have enhanced plasticity and functional recovery after SCI [66]. Recent findings show that using KS-specific degradative enzyme, keratanase II (K-II), degrade KSPGs and allow substantial motor recovery in acute phase

Beneficial and detrimental effects of astrogliosis have been reported by various researches. It depends on mediators and inhibitory molecules and also signaling pathways involved in SCI. Of course, more studies about astrogliosis as a complex and multifactorial phenomenon in SCI are essential. New strategies are required to minimize the detrimental effects of reactive astrocytes for increasing their benefi-

Limiting the amount of secondary damage done by inflammation to reduce cavitation, encouraging the production of molecules supportive of regeneration, and decreasing factors inhibiting axon growth will tip the delicate balance of growth-promoting and growth-inhibiting factors to a net environment that sup-

and brevican), phosphacan (6B4 proteoglycan), and NG2 [64].

cial effects and improve repair and regeneration.

ports functional regrowth after CNS injury.

*DOI: http://dx.doi.org/10.5772/intechopen.85570*

upregulated in regions of CNS damage.

**6.9 Components of ECM**

variants [63].

of SCI [67].

**7. Conclusion**

In a cortical brain injury, Aquaporin-4 null mice displayed decreased migration of astroglia as a contribution to the injury site and less glial scarring. However, findings from rat SCI indicated biphasic changes in astrocytic Aquaporin-4 levels with preliminary downregulation after SCI and a following long-lasting upregulation in subacute and chronic stages of damage. Further elucidation is needed to understand the impact of Aquaporin-4 in scar formation after SCI [60].

#### **6.9 Components of ECM**

*Spinal Cord Injury Therapy*

**6.4 Nuclear factor-κB (NF-κB)**

**6.5 Endothelins (ET)**

**6.7 Semaphorin 3A**

**6.8 Aquaporins**

TGF-β signaling is one of the mediators of reactive astrogliosis in SCI. TGF-β has been identified as a key trigger of CSPGs formation in the glial scar [48]. In experimental models of SCI, blockade of TGF-β signaling is shown to attenuate scar formation [49]. Interestingly, blood fibrinogen is a factor that activates TGF-β signaling after CNS injury. After vascular disruption and hemorrhage, blood fibrinogen is released into the CNS tissue, and reactive astrogliosis and CSPGs formation through the activation of TGF-β Smad2 pathway can be activated [50].

Activation of NF-κB transcription factor has been implicated in astrogliosis, although with some sophisticated evidence. In SCI, one study indicated that increased level of NF-κB was found in microglia/macrophages and endothelial cells but not in astrocytes [51]. However, in another study, reactive astrocytes were displayed to express NF-κB. Notably, studies in transgenic mice expressing IkBα, an inhibitor of NF-κB, under hGFAP promoter demonstrated that inactivation of astroglial NF-κB reduced the expression of TGF-β2 and CSPGs as well as other chemokines involved in glial scar formation such as C-X-C motif chemokine 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2). Moreover, blockade of NF-κB activation in astrocytes has resulted in white matter sparing and improved functional recovery after SCI [52].

ETs are peptides with vasoactive property. They can modulate reactive astrogliosis in various CNS diseases. ET-1 and its receptors are particularly increased in astrocytes after damage and seem to be one fundamental cause of astrogliosis [53]. In a stab wound injury, ET-1 receptor antagonist BQ788 decreased the activation and proliferation of astrocytes. ET-1 stimulates astrocyte proliferation via the

MAPK and its downstream cascades mediate astrogliosis. It is indicated that c-mos proto-oncogene, which triggers the activation of MAPK signaling, stimulates astrogliosis. Several studies implicated the phosphorylation of extracellular signal-

Semaphorin 3A (Sema3A) is an important secreted repulsive guidance factor for many developing neurons [56]. Sema3A may be secreted from non-neuronal cells such as astrocytes. Sema3A continues to be expressed in adulthood, and expression of its receptor, neuropilin-1 (Nrp-1), can be altered by nerve injury [57]. Sema3As are regarded as one of the major classes of axon repulsive molecules that lead to the failure of axons to regenerate through the neural scar. Thus, interfering with

Aquaporins may play a role in the activities of astrocytes after SCI. In particular,

recent studies showed that Aquaporin-4 is critical in glial scar formation [59].

regulated kinase/MAPK in reactive astrocytes in mice and humans [55].

Sema3A signaling can be beneficial for axonal regrowth [58].

activation of JNK/c-Jun signaling pathway in vitro [54].

**6.6 Mitogen-activated protein kinase (MAPK)**

**6.3 TGF-β**

**28**

The ECM comprises the molecules that form the structure of the matrix. There is a huge range of molecules that have been shed from the cell surface or secreted by neurons and glia [22]. Most of these shed or secreted molecules bind to the matrix to some extent, mainly to the negatively charged glycosaminoglycan (GAG) chains of the CSPGs and heparan sulfate proteoglycans (HSPGs). There are two families of cell surface-attached HSPGs, the transmembrane syndecans and the GPI-linked glypicans. Various matrix components, particularly tenascin-C and CSPGs, are upregulated in regions of CNS damage.

Tenascins are abundant in the ECM of developing vertebrate embryos. There are four members of the tenascin gene family: tenascin-C, tenascin-R, tenascin-X, and tenascin-W. Tenascin-C is the most intensely studied member of the family [61]. Tenascin-C is anti-adhesive to many forms of neuron in vitro and inhibits axon growth from many neurons, although it promotes axon growth from some embryonic neuronal types [62]. These dual properties have been assigned to different splice variants of tenascin-C and molecular epitopes within those splice variants [63].

The levels of CSPGs increase dramatically following various CNS injuries, including lesions in the spinal cord, cortex, fornix, and nigrostriatal area [20]. CSPGs are primarily generated by reactive astrocytes and to a lesser extent by oligodendrocytes and monocytes. CSPGs are a family of molecules characterized by a core protein to which the large and highly sulfated GAG chains are attached. The major CSPGs found in the CNS include lecticans (neurocan, versican, aggrecan, and brevican), phosphacan (6B4 proteoglycan), and NG2 [64].

KSPGs are another class of inhibitory ECM molecule, which are associated with spinal cord lesions [65]. Mice lacking GlcNAc6ST-1, an enzyme critical for keratan sulfate (KS) biosynthesis, have enhanced plasticity and functional recovery after SCI [66]. Recent findings show that using KS-specific degradative enzyme, keratanase II (K-II), degrade KSPGs and allow substantial motor recovery in acute phase of SCI [67].

#### **7. Conclusion**

Beneficial and detrimental effects of astrogliosis have been reported by various researches. It depends on mediators and inhibitory molecules and also signaling pathways involved in SCI. Of course, more studies about astrogliosis as a complex and multifactorial phenomenon in SCI are essential. New strategies are required to minimize the detrimental effects of reactive astrocytes for increasing their beneficial effects and improve repair and regeneration.

Limiting the amount of secondary damage done by inflammation to reduce cavitation, encouraging the production of molecules supportive of regeneration, and decreasing factors inhibiting axon growth will tip the delicate balance of growth-promoting and growth-inhibiting factors to a net environment that supports functional regrowth after CNS injury.

*Spinal Cord Injury Therapy*

### **Conflict of interest**

The authors declare that there are no conflicts of interest.

#### **Author details**

Mohammad Taghi Joghataei1,2\*, Fereshteh Azedi1 and Soraya Mehrabi3

1 Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

3 Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: mt.joghataei@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**31**

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules*

Pathophysiology. Hoboken, NJ: Wiley;

[10] Lundgaard I, Osório M, Kress B, Sanggaard S, Nedergaard M. White matter astrocytes in health and disease. Neuroscience. 2014;**12**(276)161-173. DOI: 10.1016/j.neuroscience.2013.10.050

[11] Cahoy J, Emery B, Kaushal A, Foo L, Zamanian J, Christopherson K, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. The Journal of Neuroscience. 2008;**28**:264-278

[12] Than-Trong E, Bally-Cuif L. Radial glia and neural progenitors in the adult zebrafish central nervous system. Glia.

[13] Schwarz J, Bilbo S. Sex, glia, and development: Interactions in health and disease. Hormones and Behavior.

[14] Schummers J, Yu H, Sur M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science.

[15] Liebner S, Czupalla C, Wolburg H. Current concepts of blood-brain barrier development. The International Journal of Developmental Biology.

[16] Halassa M, Fellin T, Takano H, Dong J, Haydon P. Synaptic islands defined by the territory of a single astrocyte. Neuroscience Bulletin.

[17] Obara M, Szeliga M, Albrecht J. Regulation of pH in the mammalian central nervous system under normal and pathological conditions: Facts and hypotheses. Neurochemistry International. 2008;**52**:905-919

2015;**63**(8):1406-1428

2012;**62**:243-253

2008;**320**:1638-1643

2011;**55**:467-476

2007;**27**:6473-6477

2013. pp. 381-433

*DOI: http://dx.doi.org/10.5772/intechopen.85570*

reactivity and reactive astrogliosis: Costs and benefits. Physiological Reviews.

[2] Okada S, Hara M, Kobayakawa K, Matsumoto Y, Nakashima Y. Astrocyte reactivity and astrogliosis after spinal cord injury. Neuroscience Research.

[3] Sofroniew M. Molecular dissection of reactive astrogliosis and glial scar formation. Trends in Neurosciences.

[4] Raspa A, Bolla E, Cuscona C, Gelain F. Feasible stabilization of chondroitinase abc enables reduced astrogliosis in a chronic model of spinal cord injury. CNS Neuroscience & Therapeutics. 2018;**25**(1):86-100

[5] Faulkner J, Herrmann J, Woo M, Tansey K, Doan N. Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience. 2004;**24**:2143-2155

[6] Ohtake Y, Li S. Molecular mechanisms of scar-sourced axon growth inhibitors. Brain Research.

[7] Beckerman SR, Jimenez JE, Shi Y, Al-Ali H, Bixby JL, Lemmon VP. Phenotypic assays to identify agents that induce reactive gliosis: A counter-screen to prioritize compounds for preclinical animal studies. Assay and Drug Development Technologies.

2014;**1619**:22-35

2015;**13**(7):377-388

2003;**26**:523-530

[8] Nedergaard M, Ransom B, Goldman S. New roles for astrocytes: Redefining the functional architecture of the brain. Trends in Neurosciences.

[9] Verkhratsky A, Butt A. Peripheral glial cells. In: Glial Physiology and

[1] Pekny M, Pekna M. Astrocyte

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2009;**32**:638-647

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules DOI: http://dx.doi.org/10.5772/intechopen.85570*

#### **References**

*Spinal Cord Injury Therapy*

**Conflict of interest**

The authors declare that there are no conflicts of interest.

**30**

**Author details**

Tehran, Iran

Sciences, Tehran, Iran

provided the original work is properly cited.

Mohammad Taghi Joghataei1,2\*, Fereshteh Azedi1

\*Address all correspondence to: mt.joghataei@yahoo.com

University of Medical Sciences, Tehran, Iran

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran

2 Cellular and Molecular Research Center, Iran University of Medical Sciences,

3 Department of Physiology, Faculty of Medicine, Iran University of Medical

and Soraya Mehrabi3

[1] Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: Costs and benefits. Physiological Reviews. 2014;**94**:1077-1098

[2] Okada S, Hara M, Kobayakawa K, Matsumoto Y, Nakashima Y. Astrocyte reactivity and astrogliosis after spinal cord injury. Neuroscience Research. 2017;**126**:39-43

[3] Sofroniew M. Molecular dissection of reactive astrogliosis and glial scar formation. Trends in Neurosciences. 2009;**32**:638-647

[4] Raspa A, Bolla E, Cuscona C, Gelain F. Feasible stabilization of chondroitinase abc enables reduced astrogliosis in a chronic model of spinal cord injury. CNS Neuroscience & Therapeutics. 2018;**25**(1):86-100

[5] Faulkner J, Herrmann J, Woo M, Tansey K, Doan N. Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience. 2004;**24**:2143-2155

[6] Ohtake Y, Li S. Molecular mechanisms of scar-sourced axon growth inhibitors. Brain Research. 2014;**1619**:22-35

[7] Beckerman SR, Jimenez JE, Shi Y, Al-Ali H, Bixby JL, Lemmon VP. Phenotypic assays to identify agents that induce reactive gliosis: A counter-screen to prioritize compounds for preclinical animal studies. Assay and Drug Development Technologies. 2015;**13**(7):377-388

[8] Nedergaard M, Ransom B, Goldman S. New roles for astrocytes: Redefining the functional architecture of the brain. Trends in Neurosciences. 2003;**26**:523-530

[9] Verkhratsky A, Butt A. Peripheral glial cells. In: Glial Physiology and

Pathophysiology. Hoboken, NJ: Wiley; 2013. pp. 381-433

[10] Lundgaard I, Osório M, Kress B, Sanggaard S, Nedergaard M. White matter astrocytes in health and disease. Neuroscience. 2014;**12**(276)161-173. DOI: 10.1016/j.neuroscience.2013.10.050

[11] Cahoy J, Emery B, Kaushal A, Foo L, Zamanian J, Christopherson K, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. The Journal of Neuroscience. 2008;**28**:264-278

[12] Than-Trong E, Bally-Cuif L. Radial glia and neural progenitors in the adult zebrafish central nervous system. Glia. 2015;**63**(8):1406-1428

[13] Schwarz J, Bilbo S. Sex, glia, and development: Interactions in health and disease. Hormones and Behavior. 2012;**62**:243-253

[14] Schummers J, Yu H, Sur M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science. 2008;**320**:1638-1643

[15] Liebner S, Czupalla C, Wolburg H. Current concepts of blood-brain barrier development. The International Journal of Developmental Biology. 2011;**55**:467-476

[16] Halassa M, Fellin T, Takano H, Dong J, Haydon P. Synaptic islands defined by the territory of a single astrocyte. Neuroscience Bulletin. 2007;**27**:6473-6477

[17] Obara M, Szeliga M, Albrecht J. Regulation of pH in the mammalian central nervous system under normal and pathological conditions: Facts and hypotheses. Neurochemistry International. 2008;**52**:905-919

[18] Tom V, Doller C, Malouf A, Silver J. Astrocyte associated fibronectin is critical for axonal regeneration in adult white matter. The Journal of Neuroscience. 2004;**24**:9282-9290

[19] McKeon RJ, Schreiber RC, Rudge JS, Silver J. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. The Journal of Neuroscience. 1991;**11**(11):3398-3411

[20] Andrews EM, Richards RJ, Yin FQ, Viapiano MS, Jakeman LB. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. Experimental Neurology. 2011;**235**(1):174-187

[21] John G, Lee S, Brosnan C. Cytokines: Powerful regulators of glial cell activation. The Neuroscientist. 2003;**9**:10-22

[22] McGraw J, Hiebert GW, Steeves JD. Modulating astrogliosis after neurotrauma. Journal of Neuroscience Research. 2001;**63**(2):109-115

[23] Laywell ED, Steindler DA. Boundaries and wounds, glia and glycoconjugates. Cellular and molecular analyses of developmental partitions and adult brain lesions. Annals of the New York Academy of Sciences. 1991;**633**:122-141

[24] Ridet J, Malhotra S, Privat A, Gage F. Reactive astrocytes: Cellular and molecular cues to biological function. Trends in Neurosciences. 1997;**20**:570-577

[25] Kang W, Hebert J. Signaling pathways in reactive astrocytes, a genetic perspective. Molecular Neurobiology. 2011;**43**:147-154

[26] Norenberg M, Smith J, Marcillo A. The pathology of human spinal cord injury: Defining the problems. Journal of Neurotrauma. 2004;**21**:429-440

[27] Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, et al. Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury. BMC Neurology. 2007;**7**:17

[28] Bundesen L, Scheel T, Bregman B, Kromer L. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. The Journal of Neuroscience. 2003;**23**:7789-7800

[29] Gris P, Tighe A, Levin D, Sharma R, Brown A. Transcriptional regulation of scar gene expression in primary astrocytes. Glia. 2007;**55**:1145-1155

[30] Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nature Reviews Neuroscience. 2009;**10**:235-241

[31] Renault-Mihara F, Okada S, Shibata S, Nakamura M, Toyama Y, Okano H. Spinal cord injury: Emerging beneficial role of reactive astrocytes' migration. The International Journal of Biochemistry & Cell Biology. 2008;**40**:1649-1653

[32] Sofroniew M. Reactive astrocytes in neural repair and protection. The Neuroscientist. 2005;**11**:400-407

[33] Mulligan S, MacVicar B. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004;**431**:195-199

[34] Vermeiren C, Najimi M, Vanhoutte N, Tilleux S, de Hemptinne I. Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes. Journal of Neurochemistry. 2005;**94**:405-416

**33**

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules*

[42] Stichel C, Hermanns S, Luhmann H, Lausberg F, Niermann H. Inhibition of collagen IV deposition promotes regeneration of injured CNS axons. The European Journal of Neuroscience.

[44] Sriram K, Benkovic S, Hebert M, Miller D, O'Callaghan J. Induction of gp130- related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes upregulation of glial fibrillary acidic protein in the 1-methyl-4 phenyl-1,2,3,6 tetrahydropyridine model of neurodegeneration: Key signaling pathway for astrogliosis in vivo? The Journal of Biological Chemistry. 2004;**279**:19936-19947

[45] Herrmann J, Imura T, Song B, Qi J, Ao Y. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of Neuroscience. 2008;**28**:7231-7243

[46] Suetterlin P, Marler K, Drescher U. Axonal ephrinA/EphA interactions,

[47] Ren Z, Chen X, Yang J, Kress B, Tong J, Liu H, et al. Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter. Neuroscience. 2013;**241**:89-99

[48] Mittaud P, Labourdette G, Zingg H, Guenot-Di Scala D. Neurons modulate oxytocin receptor expression in rat cultured astrocytes: Involvement of

and the emergence of order in topographic projections. Seminars in Cell & Developmental Biology.

2012;**32**:1-6

1999;**11**:632-646

[43] Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings M. Synergistic effects of transplanted adult neural stem/ progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. The Journal of Neuroscience. 2010;**30**:1657-1676

*DOI: http://dx.doi.org/10.5772/intechopen.85570*

plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proceedings of the National Academy of Sciences of the United States of America.

[36] Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Medicine.

[37] do Carmo Cunha J, de Freitas Azevedo Levy B, de Luca B, de Andrade M, Gomide V. Responses of reactive astrocytes containing S100beta protein and fibroblast growth factor-2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: Implications for wound repair and neuroregeneration. Wound Repair and Regeneration.

[38] Robel S, Bardehle S, Lepier A, Brakebusch C, Gotz M. Genetic deletion of cdc42 reveals a crucial role for astrocyte recruitment to the injury site in vitro and in vivo. Journal of Neuroscience. 2011;**31**:12471-12482

[39] Busch S, Silver J. The role of extracellular matrix in CNS regeneration. Current Opinion in Neurobiology. 2007;**17**:120-127

[40] Mizuno H, Warita H, Aoki M, Itoyama Y. Accumulation of chondroitin sulfate proteoglycans in the microenvironment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats. Journal of Neuroscience

Research. 2008;**86**:2512-2523

[41] Gutowski NJ, Newcombe J, Cuzner ML. Tenascin-R and C in multiple sclerosis lesions: Relevance to extracellular matrix remodelling. Neuropathology and Applied Neurobiology. 1999;**25**(3):207-214

2003;**100**:8999-9004

2006;**12**:829-834

2007;**15**:134-146

[35] Menet V, Prieto M, Privat A, Gimenez Y, Ribotta M. Axonal

#### *Reactive Astrocyte Gliosis: Production of Inhibitory Molecules DOI: http://dx.doi.org/10.5772/intechopen.85570*

plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proceedings of the National Academy of Sciences of the United States of America. 2003;**100**:8999-9004

*Spinal Cord Injury Therapy*

[18] Tom V, Doller C, Malouf A, Silver J. Astrocyte associated fibronectin is critical for axonal regeneration in adult white matter. The Journal of Neuroscience. 2004;**24**:9282-9290

injury: Defining the problems. Journal of Neurotrauma. 2004;**21**:429-440

[27] Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, et al. Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury.

[28] Bundesen L, Scheel T, Bregman B, Kromer L. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. The Journal of Neuroscience.

[29] Gris P, Tighe A, Levin D, Sharma R, Brown A. Transcriptional regulation of scar gene expression in primary astrocytes. Glia. 2007;**55**:1145-1155

[30] Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nature Reviews Neuroscience. 2009;**10**:235-241

[31] Renault-Mihara F, Okada S, Shibata S, Nakamura M, Toyama Y, Okano H. Spinal cord injury: Emerging beneficial role of reactive astrocytes' migration. The International Journal of Biochemistry & Cell Biology.

[32] Sofroniew M. Reactive astrocytes in neural repair and protection. The Neuroscientist. 2005;**11**:400-407

[33] Mulligan S, MacVicar B. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature.

[34] Vermeiren C, Najimi M, Vanhoutte N, Tilleux S, de Hemptinne I. Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes. Journal of Neurochemistry.

[35] Menet V, Prieto M, Privat A, Gimenez Y, Ribotta M. Axonal

BMC Neurology. 2007;**7**:17

2003;**23**:7789-7800

2008;**40**:1649-1653

2004;**431**:195-199

2005;**94**:405-416

[19] McKeon RJ, Schreiber RC, Rudge JS, Silver J. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. The Journal of Neuroscience. 1991;**11**(11):3398-3411

[20] Andrews EM, Richards RJ, Yin FQ, Viapiano MS, Jakeman LB. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. Experimental Neurology.

[21] John G, Lee S, Brosnan C. Cytokines:

Powerful regulators of glial cell activation. The Neuroscientist.

[22] McGraw J, Hiebert GW, Steeves JD. Modulating astrogliosis after neurotrauma. Journal of Neuroscience

DA. Boundaries and wounds, glia and glycoconjugates. Cellular and molecular analyses of developmental partitions and adult brain lesions. Annals of the New York Academy of Sciences.

[24] Ridet J, Malhotra S, Privat A, Gage F. Reactive astrocytes: Cellular and molecular cues to biological function. Trends in Neurosciences.

[25] Kang W, Hebert J. Signaling pathways in reactive astrocytes, a genetic perspective. Molecular Neurobiology. 2011;**43**:147-154

[26] Norenberg M, Smith J, Marcillo A. The pathology of human spinal cord

Research. 2001;**63**(2):109-115

[23] Laywell ED, Steindler

1991;**633**:122-141

1997;**20**:570-577

2011;**235**(1):174-187

2003;**9**:10-22

**32**

[36] Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Medicine. 2006;**12**:829-834

[37] do Carmo Cunha J, de Freitas Azevedo Levy B, de Luca B, de Andrade M, Gomide V. Responses of reactive astrocytes containing S100beta protein and fibroblast growth factor-2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: Implications for wound repair and neuroregeneration. Wound Repair and Regeneration. 2007;**15**:134-146

[38] Robel S, Bardehle S, Lepier A, Brakebusch C, Gotz M. Genetic deletion of cdc42 reveals a crucial role for astrocyte recruitment to the injury site in vitro and in vivo. Journal of Neuroscience. 2011;**31**:12471-12482

[39] Busch S, Silver J. The role of extracellular matrix in CNS regeneration. Current Opinion in Neurobiology. 2007;**17**:120-127

[40] Mizuno H, Warita H, Aoki M, Itoyama Y. Accumulation of chondroitin sulfate proteoglycans in the microenvironment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats. Journal of Neuroscience Research. 2008;**86**:2512-2523

[41] Gutowski NJ, Newcombe J, Cuzner ML. Tenascin-R and C in multiple sclerosis lesions: Relevance to extracellular matrix remodelling. Neuropathology and Applied Neurobiology. 1999;**25**(3):207-214

[42] Stichel C, Hermanns S, Luhmann H, Lausberg F, Niermann H. Inhibition of collagen IV deposition promotes regeneration of injured CNS axons. The European Journal of Neuroscience. 1999;**11**:632-646

[43] Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings M. Synergistic effects of transplanted adult neural stem/ progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. The Journal of Neuroscience. 2010;**30**:1657-1676

[44] Sriram K, Benkovic S, Hebert M, Miller D, O'Callaghan J. Induction of gp130- related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes upregulation of glial fibrillary acidic protein in the 1-methyl-4 phenyl-1,2,3,6 tetrahydropyridine model of neurodegeneration: Key signaling pathway for astrogliosis in vivo? The Journal of Biological Chemistry. 2004;**279**:19936-19947

[45] Herrmann J, Imura T, Song B, Qi J, Ao Y. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of Neuroscience. 2008;**28**:7231-7243

[46] Suetterlin P, Marler K, Drescher U. Axonal ephrinA/EphA interactions, and the emergence of order in topographic projections. Seminars in Cell & Developmental Biology. 2012;**32**:1-6

[47] Ren Z, Chen X, Yang J, Kress B, Tong J, Liu H, et al. Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter. Neuroscience. 2013;**241**:89-99

[48] Mittaud P, Labourdette G, Zingg H, Guenot-Di Scala D. Neurons modulate oxytocin receptor expression in rat cultured astrocytes: Involvement of

TGF-beta and membrane components. Glia. 2002;**37**:169-177

[49] Davies J, Tang X, Denning J, Archibald S, Davies S. Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. The European Journal of Neuroscience. 2004;**19**:1226-1242

[50] Schachtrup C, Ryu J, Helmrick M, Vagena E, Galanakis D. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. The Journal of Neuroscience. 2010;**30**:5843-5854

[51] Bethea J, Castro M, Keane R, Lee T, Dietrich W. Traumatic spinal cord injury induces nuclear factor-kappaB activation. The Journal of Neuroscience. 1998;**18**:3251-3260

[52] Brambilla R, Bracchi-Ricard V, Hu W, Frydel B, Bramwell A. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. The Journal of Experimental Medicine. 2005;**202**:145-156

[53] Rogers S, Peters C, Pomonis J, Hagiwara H, Ghilardi J. Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia. 2003;**41**:180-190

[54] Koyama Y, Takemura M, Fujiki K, Ishikawa N, Shigenaga Y. BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury-induced reactive astrocytes in rat brain. Glia. 1999;**26**:268-271

[55] Carbonell W, Mandell J. Transient neuronal but persistent astroglial activation of ERK/MAP kinase after focal brain injury in mice. Journal of Neurotrauma. 2003;**20**:327-336

[56] Goshima Y, Yamashita N, Nakamura F, Sasaki Y. Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling. Cell Adhesion & Migration. 2016;**10**(6):627-640

[57] Sharma A, Verhaagen J, Harvey A. Receptor complexes for each of the class 3 semaphorins. Frontiers in Cellular Neuroscience. 2012;**6**:28

[58] Yamashita N, Yamane M, Suto F, Goshima Y. TrkA mediates retrograde semaphorin3A signaling through PlexinA4 to regulate dendritic branching. Journal of Cell Science. 2016;**129**(9):1802-1814

[59] Saadoun S, Papadopoulos M, Watanabe H, Yan D, Manley G. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. Journal of Cell Science. 2005;**118**:5691-5698

[60] Nesic O, Lee J, Ye Z, Unabia G, Rafati D. Acute and chronic changes in aquaporin 4 expression after spinal cord injury. Neuroscience. 2006;**143**:779-792

[61] Jones F, Jones P. The tenascin family of ECM glycoproteins: Structure, function, and regulation during embryonic development and tissue remodeling. Developmental Dynamics. 2000;**218**:235-259

[62] Brenneke F, Bukalo O, Dityatev A, Lie AA. Mice deficient for the extracellular matrix glycoprotein tenascin-r show physiological and structural hallmarks of increased hippocampal excitability, but no increased susceptibility to seizures in the pilocarpine model of epilepsy. Neuroscience. 2004;**124**(4):841-855

[63] Meiners S, Mercado M, Nure-Kamal M, Geller H. Tenascin-C contains domains that independently regulate neurite outgrowth and neurite

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guidance. The Journal of Neuroscience.

[64] Harris NG, Carmichael ST, Hovda DA, Sutton RL. Traumatic brain injury results in disparate regions of chondroitin sulfate proteoglycan expression that are temporally limited. Journal of Neuroscience Research.

[65] Hilton B, Lang B, Cregg J. Keratan sulfate proteoglycans in plasticity and recovery after spinal cord injury. The Journal of Neuroscience.

[66] Ito Z, Sakamoto K, Imagama S, Matsuyama Y, Zhang H, Hirano K, et al. N-acetylglucosamine

6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury. The Journal of Neuroscience. 2010;**30**:5937-5947

[67] Imagama S, Sakamoto K, Tauchi R, Shinjo R, Ohgomori T, Ito Z, et al. Keratan sulfate restricts neural plasticity after spinal cord injury. The Journal of Neuroscience. 2011;**31**:17091-17102

1999;**19**:8443-8453

2009;**87**(13):2937-2950

2012;**32**(13):4331-4333

*Reactive Astrocyte Gliosis: Production of Inhibitory Molecules DOI: http://dx.doi.org/10.5772/intechopen.85570*

guidance. The Journal of Neuroscience. 1999;**19**:8443-8453

*Spinal Cord Injury Therapy*

Glia. 2002;**37**:169-177

2004;**19**:1226-1242

2010;**30**:5843-5854

1998;**18**:3251-3260

2005;**202**:145-156

2003;**41**:180-190

1999;**26**:268-271

TGF-beta and membrane components.

[56] Goshima Y, Yamashita N, Nakamura F, Sasaki Y. Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling. Cell Adhesion & Migration.

[57] Sharma A, Verhaagen J, Harvey A. Receptor complexes for each of the class 3 semaphorins. Frontiers in Cellular Neuroscience. 2012;**6**:28

[58] Yamashita N, Yamane M, Suto F, Goshima Y. TrkA mediates retrograde semaphorin3A signaling through PlexinA4 to regulate dendritic branching. Journal of Cell Science.

2016;**10**(6):627-640

2016;**129**(9):1802-1814

2005;**118**:5691-5698

2000;**218**:235-259

the pilocarpine model of epilepsy. Neuroscience. 2004;**124**(4):841-855

[63] Meiners S, Mercado M, Nure-Kamal M, Geller H. Tenascin-C contains domains that independently regulate neurite outgrowth and neurite

[59] Saadoun S, Papadopoulos M, Watanabe H, Yan D, Manley G. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. Journal of Cell Science.

[60] Nesic O, Lee J, Ye Z, Unabia G, Rafati D. Acute and chronic changes in aquaporin 4 expression after spinal cord injury. Neuroscience. 2006;**143**:779-792

[61] Jones F, Jones P. The tenascin family of ECM glycoproteins: Structure, function, and regulation during embryonic development and tissue remodeling. Developmental Dynamics.

[62] Brenneke F, Bukalo O, Dityatev A, Lie AA. Mice deficient for the extracellular matrix glycoprotein tenascin-r show physiological and structural hallmarks of increased hippocampal excitability, but no increased susceptibility to seizures in

[50] Schachtrup C, Ryu J, Helmrick M, Vagena E, Galanakis D. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. The Journal of Neuroscience.

[51] Bethea J, Castro M, Keane R, Lee T, Dietrich W. Traumatic spinal cord injury induces nuclear factor-kappaB activation. The Journal of Neuroscience.

[52] Brambilla R, Bracchi-Ricard V, Hu W, Frydel B, Bramwell A. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. The Journal of Experimental Medicine.

[53] Rogers S, Peters C, Pomonis J, Hagiwara H, Ghilardi J. Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia.

[54] Koyama Y, Takemura M, Fujiki K, Ishikawa N, Shigenaga Y. BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury-induced reactive astrocytes in rat brain. Glia.

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[49] Davies J, Tang X, Denning J, Archibald S, Davies S. Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. The European Journal of Neuroscience.

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Section 2

Pharmacological

Therapies

Section 2
