3.1. Pharmacological therapies

connections adjacent to the lesion. Furthermore, the reactive astrocytes contribute to the release of pro-inflammatory cytokines, such as TNF-α, INF-γ, IL-1β, and IL-6, which inhibit differentiation processes of neural stem cells (NSC) [65], and contribute to the chronic inflam-

In addition, the formation of a glial scar favors cavitation, a process detrimental to regeneration at the injury site. This phenomenon can lead to the extension of the injury size days or even weeks after the lesion, resulting in the formation of an encapsulated scar, which prevents

At the chronic stage, the central canal is frequently involved in fluid-filled cyst development, which gives rise to malformations in the SC parenchyma; this condition is known as syringomyelia [68]. This term, first introduced by Ollivier D'Angers in 1827, derives from the Greek word for tube (syrinx) and is used to describe dilation of the central canal extending over many segments. Before trauma, CSF normally flows into the inner parts of the brain and SC. However, SCI evokes morphological changes, which disrupt correct circulation enhancing the volumetric growth of cavities. Syringomyelia appears to be related to irregular pressure con-

Hydromyelia, a closely related term that is often used interchangeably, also refers to a dilatation of the central canal by CSF. Some have defined hydromyelia as a congenital dilatation [70] of the central canal, which is partially lined with ependymal cells, strongly associated with hydrocephalus, an obstruction of the foramina of Luschka and Magendie [71]. The term syringomyelia has been affixed to every kind of intramedullary cyst, with some authors defining it as a cavity distinct from the central canal and lined by ependymal cells or primarily glial cells [71, 72]. However, others restrict its use to certain subtypes of cystic lesions and distinguish syringomyelia, hydromyelia, or myelomalacia as separate entities. In spite of this, some authors combine these terms into syringohydromyelia or hydrosyringomyelia [71]. Lee et al. stated that a clear communication between intramedullary cavities and the ventricular system is rarely demonstrated, making it difficult to differentiate syringomyelia from hydromyelia, although a truly eccentric location within the spinal cord may be more characteristic of syringomyelia than of hydromyelia [73]. Batzdorf states that the distinction between syringomyelia and hydromyelia is

In recent years, neuroprotective or neuroregenerative strategies regarding the injury site have been chosen to mitigate autodestructive events following a SCI. These strategies include: preservation or regeneration of damaged neural tissue, neutralization of toxic mediators, and

Although there is a substantial evidence showing new preclinical strategies that aim to promote neuroprotection, achieved with certain efficiency in murine SCI models [75], there are few clinically approved treatments available to patients with SCI. Currently, clinical treatments

ditions and hydrodynamic mechanisms related to the CSF [68, 69].

no longer considered absolute or critical [72].

increasing tissue resistance to toxicity [74].

3. Therapy after acute SCI

matory response [62].

30 Essentials of Spinal Cord Injury Medicine

neuronal connection [66, 67].

During the last 25 years, different preclinical and clinical studies evaluating neuroprotection in SCI have been conducted. As previously mentioned, careful consideration of the time frame for treatment after SCI is essential when selecting a therapeutic option. At the clinical level, conventional norms have recommended initiating treatment within the first 3 hours following injury. However, some preclinical studies have begun treatment administration within the first hour after lesion, which complicates the clinical application of these therapies [75]. Diverse drugs have been used in preclinical and clinical studies, with each having different effects depending of the therapeutic objective. However, the majority of drugs studied as possible neuroprotective agents focus solely on one type of damage, with some being tailored to specific mechanisms of the primary injury. The vast majority of these have consisted of pharmacological treatments, although many preclinical studies have included additional therapeutic strategies for acute and chronic SCI. Current pharmacological agents used in the treatment of acute SCI can be grouped into: ionic channel blockers, inhibitors of N-Methyl-D-asparate acid (NMDA), and AMPA-kainate receptors, inhibitors of FR and LP, antiapoptotics, and immunosupressors or immunomodulators [77]. All the therapies and their therapeutic objectives are mentioned in Table 1.



Therapy Mechanism of

2. Immunophilin ligands a) Cyclosporine A

3. Immunomodulatory peptides

b) Tacrolimus

a) Monocyte locomotion inhibitory factor (MLIF)

b) Nogo-A

c) A91

Clinical therapies

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

↓ VCAM-1, pro-inflammatory cytokines (IL-1β, IL-6, IL-12,

(+) T-cell-mediated protective

(+)T-cell-mediated protective

Methylprednisolone () Immune response Contradicting data, with some showing

GM-1 Ganglioside ↓ Excitatory neurotoxicity Improved motor recovery evaluated by American

and IFN-γ)

autoimmunity

autoimmunity

Minocycline Multiple anti-inflammatory pathways

Table 1. Pharmacological treatments used in acute SCI.

Treatment outcome References

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

[104, 106– 109]

33

[110–114]

[115, 116]

[117, 118]

[100, 119– 125]

[126–128]

[129–131]

[132–134]

and interferes with cytokine production (IL-1, IL-2 e IL-6), cytoskeleton motility of neutrophils, and

activation of iNOS or ROS production. Reduces LP levels, glutamate excitotoxicity, and demyelination processes, increasing neuronal

NF-kB and caspase 3 inhibition, leading to improved recovery and reduced neuronal loss.

transplantation, improves MSCs survival and

Tacrolimus may induce neuroregeneration by

Motor recovery and survival of ventral and corticospinal tract neurons associated with a reduction in iNOS gene expression and up regulation of IL-10 and TGF-β expression. MLIF also reduces the concentration of nitric oxide and the levels of lipid peroxidation in systemic

Nogo-A-derived peptide p472 and the transfer of anti-Nogo-A T-cells showed a significant

Promotes motor recovery and the long-term

Reduces LP levels, iNOS expression, NO levels, caspase 3 activity, and TNF-α concentration. A91 combined with GME induced a better motor recovery, a higher number of myelinated axons, and better rubrospinal neuron survival than A91 alone.

improved motor recovery and others showing no

Improved motor recovery and decreased cell death through inhibition of caspase 3, matrix metalloproteinases, NO levels, and TNF-α.

Spinal Injury Association (ASIA) motor, light

recovery and increased side effects.

touch, and pinprick scores.

In mesenchymal stem cells (MSCs)

neurological recovery after SCI.

binding to heat shock protein 90.

survival and motor recovery.

() Calcineurin activity Inhibits the proliferation of T-helper lymphocytes

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

circulation.

reduction in neuronal loss.

production of BDNF and NT-3.

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute… http://dx.doi.org/10.5772/intechopen.72781 33


Table 1. Pharmacological treatments used in acute SCI.

Therapy Mechanism of

32 Essentials of Spinal Cord Injury Medicine

Calcium

a) Memantine

b) Gacyclidine

c) NBQX

a) PUFAs

Inhibitors of FR and LP

b) Glutathione (GSH)

Antiapoptotics a) zDEVD-fmk

b) LEHD-fmk

a) Indomethacin

b) Celecoxib

c) Meloxicam

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

a) Nimodipine ↓Oxidative damage caused by FR

Inhibitors of NMDA and AMPA-kainate receptors

receptor

antagonist.

ROS and RNS.

() Caspase 3 and 9 respectively

() COX 1 and COX 2

Immunosuppressive or immunomodulatory drugs

() COX 2

() COX 2

1. Inhibitors of cyclooxygenase

↓ Neurological damage by glutamate and NMDA.

()noncompetitive NMDA

AMPA-kainate receptor

↓FR formation, scavenging of

() FR by the free thiol group.

Treatment outcome References

[82, 83]

[84, 85]

[86, 87]

[88]

[89–96]

[97–100]

[101, 102]

[103, 104]

[103]

[105]

Decreases LP end products, such as MDA and 4-Hydroxy Acrolein, resulting in a better motor recovery. However, it should be noted that nimodipine does not allow membrane repair.

Noncompetitive NMDA antagonist that prevents neurotoxicity. In combination with antiapoptotic agents, provides better histological and clinical results, diminished necrosis and apoptosis.

Improved motor recovery, neural tissue preservation in a dose–dependent manner. In rats, gacyclidine exerts dose- and time-dependent

Improves mitochondrial function and reduces levels of ROS and lipid peroxidation products.

Prevents white matter damage, increases synaptic connections, neuronal survival, and improves motor recovery. Possesses antioxidant and anti-

Anti-excitotoxic peptide through the inhibition of the union between specific ligands and inotropic GluRs by the modulation of redox reactions. Improves motor recovery, rubrospinal tract neuronal survival, blood flow stabilization.

The application of z-DEVD-fmk reduces secondary tissue injury and helps preserve motor function. Electron microscopy showed that z-LEHD-fmk treatment protects neurons, glia, myelin, axons,

neuroprotection.

inflammatory effects.

and intracellular organelles.

Mixed results: some report improved neurological function and blood flow to injury site, as well as decreased neuronal damage, while

Reduction of prostanoids and FR synthesis, inhibition of arachidonic acid pathways. Increased motor recovery and diminished

Improved neurological function, amelioration of LP.

others report delayed recovery.

damaged spinal tissue.

#### 3.2. Nonpharmacological therapies

Nonpharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established. This may be due in part because of methodological weaknesses in available studies. However, preclinical studies have demonstrated neuroprotective effect, although results from clinical studies remain controversial and require further studies. These treatments are summarized in Table 2.

Therapy Mechanism of neuroprotection ↑ Increase ↓ Decrease () Blocked (+) Activated

> Pluripotent cells capable of differentiating into every type of cell

lineage cells

↑Neurological outcome

↑Neurological outcome

Table 2. Nonpharmacological therapies used in acute SCI.

Obtained from bone marrow; capable of differentiating into every type of

cell

cell

Physical therapy ↓ Spasticity

Physical therapy ↓ Spasticity

Found in the center and periphery of the olfactory nerve; capable of differentiating into neuronal or glial

Obtained from bone marrow; capable of differentiating into every type of

b) Embryonic stem

cells.

c) Olfactory ensheathing cells (OECs)

d) MSCs

Low-energy extracorporeal shockwave therapy

Clinical therapies Cell therapy Autologous transplant of MSC

(ESWT)

Treatment outcome References

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

[148]

35

[149]

[150, 151]

[152]

[152–156]

[157–161]

[162–164]

remyelinating potential of Schwann cells, permitting the transmission of action potentials through regenerated axons wrapped in Schwann cells.

Induce motor recovery through the ability to transform into astrocytes, oligodendrocytes,

and/or neurons in vitro prior to transplantation, in order to avoid their

Enhanced locomotor recovery, axon myelination, and neuroprotection.

immunogenicity. Modulate the

MSCs may facilitate recovery from SCI by remyelinating spared white matter tracts and/or enhancing axonal growth with low

inflammatory microenvironment to reduce pro-inflammatory cytokine levels.

decreased neural cell death. Stimulates angiogenesis and neurogenesis.

Upregulates the expression of NT3, NT4, BDNF, and GDNF, while reducing levels of apoptosis-related proteins such as caspase 3

Induces axonal regeneration, broadening the

Improved motor, sensory recovery, and

Improved sexual function and bladder and

Increased levels of BDNF, NGF, NT3, and

Further translational studies are required in order to provide favorable results in patients similar to those seen in animal models of SCI. However, patients with incomplete SCI saw an improvement on their ASIA score after

scope of physical therapy from neuroprotection to neuroregeneration.

neurological outcome.

receiving physical therapy.

bowel control

NT4.

tumorigenicity.

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

↑ Electric stimulus Improved motor and sensory recovery,

and 9.


a) Schwann cells (+) Myelination Treatment with these cells improves sensitive and motor functions due to the [146, 147] Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute… http://dx.doi.org/10.5772/intechopen.72781 35


Table 2. Nonpharmacological therapies used in acute SCI.

3.2. Nonpharmacological therapies

34 Essentials of Spinal Cord Injury Medicine

Therapy Mechanism of neuroprotection ↑ Increase ↓ Decrease () Blocked (+) Activated

from M1 to M2

() FR formation

() FR formation

() Chondroitin sulfate proteoglycans (CSPGs)

() Inflammatory response

a) Schwann cells (+) Myelination Treatment with these cells improves sensitive

Resveratrol ↑ Transcription factor Nrf-2 and sirtuin (SIRT) 1

Hypothermia Vasoconstriction,

Preclinical therapies

Vitamins a) Vitamin B3 (niacin)

b) Vitamin C (ascorbic acid)

Gene therapy Chondroitinase gene therapy via lentiviral vector (LV-ChABC)

Cell therapy

c) Vitamin E (alphatocopherol)

Nonpharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established. This may be due in part because of methodological weaknesses in available studies. However, preclinical studies have demonstrated neuroprotective effect, although results from clinical studies remain controversial and

Treatment outcome References

[135]

[136, 137]

[137, 138]

[139–142]

[143]

[144, 145]

[146, 147]

Reduced p65 NF-κB phosphorylation, reducing M1 markers such as iCD86, IL-12, and IL-6 and increasing anti-inflammatory M2 markers, such as CD206, IL-10, and IL-13.

Reduces tissue damage and improves

Improves cell survival and motor function

Reduces neutrophil infiltration, production of inflammatory cytokines (IL-1β, IL-10, TNF-α), and myeloperoxidase (MPO) by inhibition of NF-κB; diminishes iNOS expression, apoptosis, and caspase-3, as well as inducing important locomotor recovery.

Decreases the degree of the hemorrhage at the injured site and neurotoxicity by reducing the levels of glutamate and

Prevents changes in the BBB, thus hindering extravasation of leukocytes into the CNS. Inactivation of production of pro-

inflammatory cytokines, such as IL-1β, IL-18,

, NO, and OH

functional recovery in rats.

significantly following SCI.

Reduced cavitation and enhanced preservation of spinal neurons and axons. Improved sensorimotor function and increased neuronal survival correlated with

reduced apoptosis.

glutamanergic receptors.

and TNF-α. Also reduces O2

and motor functions due to the

FR. Reduces cell death and apoptotic mechanisms through caspase-3 and cytochrome C inhibition.

require further studies. These treatments are summarized in Table 2.

Phenotypic shift in macrophages
