4. Therapies for chronic SCI

Many patients with chronic SCI experience little partial recovery with the use of acute phase treatments. When compared to acute SCI treatments, the efficacy of therapies that promote axonal regeneration in chronic models is reduced due to the generalized stability, induced by protective means or restoration promoters not present during the acute phase [165]. Studies indicate that this period of stability is reached in up to 3 months [166], followed by a progressive decline of neurologic functions in rodents that underwent SCI [167, 168].

Treatments for chronic SCI focus on avoiding or improving characteristic pathophysiological mechanisms, such as glial scar formation, demyelination, and astrogliosis. Moreover, it must be emphasized that while strategies for acute SCI are limited to preventing further damage, therapeutic strategies for chronic SCI instead focus on promoting neuronal regeneration and treating accompanying symptoms of chronic complications. Pharmacological and nonpharmacological therapies utilized in the treatment of chronic SCI are summarized in Tables 3 and 4.


Preclinical therapies

Anti-Nogo therapies a) Nogo receptor (NgR)

Clinical therapies Rho-ROCK inhibitor Cethrin/VX-210

Anti-Nogo antibodies

Therapy Mechanism of

neuroprotection ↑ Increase ↓ Decrease () Blocked (+) Activated

Myelin-associated inhibitors

Myelin-associated inhibitors

Table 3. Pharmacological therapies in chronic SCI.

Biocompatible matrices a) Fibrin glue (Tissucol)

b) Alginate

c) Hyaluronic acid

Glial scar removal ↓ or () glial scar (Surgical) Promotes axonal development, although

e) ChABC () ECM molecules Promotes spinal cord plasticity along injured corticospinal tract

Fibrinogen and thrombin compound, potentially adequate biological vehicle

2016.

Vehicle for drug release, cellular encapsulation and cellular transplant

Porous structures that gradually release growth factors, cellular encapsulation,

for cell transplant.

or drugs

surgical removal may lead to a second

Treatment outcome References

http://dx.doi.org/10.5772/intechopen.72781

and uninjured serotonergic projections, facilitates growth of new fibers, and stimulates rubrospinal projection neuron growth.

NgR immunization markedly reduced the total lesion volume, improved locomotor recovery and grid walking performance.

points) for cervical patients. Currently under study in a phase III trial in patients with acute cervical SCI which commenced in

Promotes axonal sprouting and functional recovery. [117, 179]

()Rho protein Significant improvement in long-term motor scores (18.5 ASIA

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute…

Promotes growth and incorporation of primary myelinated and unmyelinated afferent axons, and intervenes in the support and directionality of axons with

Fibrin-stabilizing factor (Factor XII), also contained in Tissucol, favors migration of MSCs on the highly reticulated structure of the glue and increases their

Facilitates axonal guidance and cell adherence by delivering ECM

progenitor neuronal cells.

components, such as fibronectin, laminin, collagen, and polyornithine, alongside

Minimizes the formation of glial scar and promotes astrocyte and microglia

[180]

[174, 175]

37

[176]

[177, 178]

[181, 182]

[183]

[184]

injury.

Schwann cells.

proliferation.

migration.

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute… http://dx.doi.org/10.5772/intechopen.72781 37


Table 3. Pharmacological therapies in chronic SCI.

4. Therapies for chronic SCI

36 Essentials of Spinal Cord Injury Medicine

Therapy Mechanism of

Antagonists of Rho signaling pathway

Preclinical therapies

a) C3 transferase

b) Y27632

c) Fasudil

d) P21

a) 2,2<sup>0</sup>

(BPY).

b) Decorine

c) Olomoucine

d) α,α'-dipyridyl

e) Ibuprofen

Glial scar inhibitors


neuroprotection ↑ Increase ↓ Decrease (�) Blocked (+) Activated

(�)Rho protein (�)Rho protein, nonselective inhibitor

(�)Rho protein

(�)Rho protein

(�) prolyl 4 hydroxylase

(�) TGF-β

(�) prolyl-4 hydroxylase

(�) CDK1/Cycline B and related kinases

Many patients with chronic SCI experience little partial recovery with the use of acute phase treatments. When compared to acute SCI treatments, the efficacy of therapies that promote axonal regeneration in chronic models is reduced due to the generalized stability, induced by protective means or restoration promoters not present during the acute phase [165]. Studies indicate that this period of stability is reached in up to 3 months [166], followed by a progres-

Treatments for chronic SCI focus on avoiding or improving characteristic pathophysiological mechanisms, such as glial scar formation, demyelination, and astrogliosis. Moreover, it must be emphasized that while strategies for acute SCI are limited to preventing further damage, therapeutic strategies for chronic SCI instead focus on promoting neuronal regeneration and treating accompanying symptoms of chronic complications. Pharmacological and nonpharmacological therapies utilized in the treatment of chronic SCI are summarized in Tables 3 and 4.

Treatment outcome References

[165] [166]

[167]

[168]

[169]

[170]

[171] [172]

[173]

Stimulates axonal growth and improves motor function.

Promotes axonal regeneration and motor function recovery.

Conjoint administration with MP promotes recovery of motor activity and reflex movements, as well as tissue preservation. Capable of stimulating axonal regeneration and improving

Enhances recovery by limiting tissue loss and stimulating axonal

Growth of corticospinal tract neurons through the injury site and

Limits astroglial proliferation and increases GAP-43 expression,

Suppresses glial scar formation, favors axonal growth.

motor function of extremities.

improved motor function recovery.

improving motor function. Decreases collagen synthesis.

growth.

sive decline of neurologic functions in rodents that underwent SCI [167, 168].



Preclinical therapies

fibrin glue

Clinical therapies

Muscle electrical stimulation

Glial scar removal with NeuroRegen scaffold.

Cell therapies a) NSC transplant

b) Oligodendrocyte precursor cells

c) MSCs transplant

d) Schwann cells transplant

e) Degenerated peripheral nerves with MSCs and

↑ Growth factor (+) neural regeneration

Physical therapy ↓ Spasticity Upregulation of BDNF, IGF-1, other

Spinal cord stimulation ↑ Spinal cord electric stimulus Treated patients were able to initiating

Induces axonal regeneration and myelination with molecules associated to GAP-43 and neuritin, which are present in axonal growth cones and axonal

http://dx.doi.org/10.5772/intechopen.72781

Improves axonal plasticity and regeneration, motor function.

function, as well as an increase in muscle

limb movement and improve posture control, bladder emptying (urinary retention), and sexual function. This therapy also provoked escalated extension-flexion movements. Additional trials (NCT02592668, NCT02313194) are now ongoing to assess safety/feasibility and validate this exciting finding, with results expected by 2018.

functions, as well as the recovery of somatosensory-evoked potentials of lower

and thoracic transplant (n = 12; NCT01321333). Preliminary results from these trials do not show increased complication rates, although results on motor and sensitive recovery remain

Cervical transplant (n = 31; NCT02163876)

Asterias Biotherapeutics Inc. phase I/II dose-escalation trial (n = 35;

This study is expected to be completed in

Phase II/III clinical trial in South Korea (NCT01676441) by Pharmicell Co. with intraparenchymal and intrathecal administration of MSC. Results are still pending, with an estimated completion

An open-label phase I trial (n = 10) by the Miami Project to Cure Paralysis is now

[209]

39

[210– 215]

[216]

[217]

[218]

[219, 220]

[220]

[220– 222]

[220]

remyelinization.

growth factors.

size and strength

↑ Muscle electric stimulus Improvement in their motor and sensory

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute…

↑ Spinal cord regeneration Better recovery of autonomous nervous

limbs.

pending.

2018.

NCT02302157).

date of 2020.

#### Preclinical therapies

Preclinical therapies

38 Essentials of Spinal Cord Injury Medicine

d) Polyethylene glycol

Seals injured membranes and allows

Repairs cell membranes in the CNS, although it does not provide three-

Compounds facilitate cellular adherence, differentiation, Schwann cell growth, and

Improves phrenic motor output after high cervical SCI, improving spontaneous respiratory motor recovery.

Promotes repair by anti-inflammatory molecule secretion and stimulation of macrophage polarization, secretion of trophic and neurotrophic factors. Promotes angiogenesis, prevents apoptosis, and stabilizes the BSB through astrocyte regulation, forming axonal guidance filaments through the injury site. Increased preservation of white matter and host Schwann cells and astrocyte ingress, as well as axon ingrowth and

Improves neurite outgrowth and endogenous remyelination, as well as white matter preservation, sensory, and

Induces significant motor recovery.

Spontaneous recovery of forelimb functions reflected the extent of the lesion on the ipsilateral side and improved motor recovery when compared to the groups receiving individual treatments. Histological results showed increased

neuronal regeneration.

Allows the transplanted cells to differentiate into neuroglial cells and permits proper axonal regeneration and growth across the injury site, leading to

Facilitates the axonal regeneration in the region caudal to the injury site.

significant motor recovery. Increases motor function.

[185]

[186]

[187, 188]

[189– 195]

[196, 197, 201]

[198– 200, 202– 204]

[205]

[206, 207]

[208]

[122]

dimensional support.

axonal regeneration.

myelination.

motor recovery.

Matrix conformed by multiple growth factors and extracellular proteins

Integrates with host circuits to enhance

Modulate inflammatory response,

Stimulation of remyelination

Phagocytosis of debris and microbes,

↑ NT-3, BDNF, EGF, βfgf, GDNF, PDGF, αfgf, HGF, IGF-1, and calpain inhibitor in a fibrin gel conjointly with NSC

Integrate with host circuits to enhance

growth factor signaling

transplantation

() ECM molecules

behavioral recovery

↑ Growth factor () glial scar

Myelin-associated inhibitors () ECM molecules ↓ spasticity

them to reassemble

behavioral recovery

promote angiogenesis

e) Matrigel

Cell therapies a)Neural stem cells

cells

b) Mesenchymal stem

c) Schwann cells

d) OECs

Combination therapy a) Cocktail with 10 growth factors.

b) Anti-Nogo-A antibody followed by ChABC and physical rehabilitation.

c) ChABC and NSCs

d) A91 and surgical glial

scar removal.



[5] Dumont RJ et al. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clinical

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute…

http://dx.doi.org/10.5772/intechopen.72781

41

[6] Lee J, Thumbikat P. Pathophysiology, presentation and management of spinal cord

[7] Mautes AE et al. Vascular events after spinal cord injury: Contribution to secondary

[8] Fleming JC et al. The cellular inflammatory response in human spinal cords after injury.

[9] Sinescu C et al. Molecular basis of vascular events following spinal cord injury. Journal

[10] Profyris C et al. Degenerative and regenerative mechanisms governing spinal cord

[11] Esposito E, Cuzzocrea S. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Current Medicinal Chemistry. 2009;16(24):

[12] Nesic O et al. DNA microarray analysis of the contused spinal cord: Effect of NMDA

[13] Agrawal SK, Nashmi R, Fehlings MG. Role of L- and N-type calcium channels in the pathophysiology of traumatic spinal cord white matter injury. Neuroscience. 2000;99(1):

[14] Wagner I et al. Radiopacity of intracerebral hemorrhage correlates with perihemorrhagic

[15] Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity.

[16] D'Autréaux B, Toledano MB. ROS as signaling molecules: Mechanisms that generate specificity in ROS homeostasis. Nature Reviews. Molecular Cell Biology. 2007;8(10):813-824 [17] Sapolsky RM. Cellular defenses against excitotoxic insults. Journal of Neurochemistry.

[18] Liu D, Xu GY, Pan E, McAdoo DJ. Neurotoxicity of glutamate at the concentration

[19] Faden AI, Simon RP. A potential role for excitotoxins in the pathophysiology of spinal

[20] Xu G-Y et al. Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord. Experimental Neurology. 2004 Jun;187(2):329-336 [21] Matute C et al. The link between excitotoxic oligodendroglial death and demyelinating

released upon spinal cord injury. Neuroscience. 1999;93(4):1383-1389

cord injury. Annals of Neurology. 1988 Jun;23(6):623-626

diseases. Trends in Neurosciences. 2001;24:224-230

receptor inhibition. Journal of Neuroscience Research. 2002;68(4):406-423

edema. European Journal of Neurology. 2011;19(3):525-528

Journal of Molecular Medicine. 2000;78(1):3-13

Neuropharmacology. 2001;24(5):254-264

pathogenesis. Physical Therapy. 2000;80(7):673-687

injury. Neurobiology of Disease. 2004;15:415-436

injury. Surgery. 2015;33(6):238-247

Brain. 2006;129(12):3249-3269

3152-3167

179-188

2001;76(6):1601-1611

of Medicine and Life. 2010;3(3):254-261

Table 4. Nonpharmacological therapies in chronic SCI.
