*3.1.6 Immunosuppressive or immunomodulatory drugs.*

### *3.1.6.1 Inhibitors of cyclooxygenase*

## *3.1.6.1.1 Indomethacin*

Indomethacin, a nonsteroidal anti-inflammatory (NSAID) drug, acts as a nonselective cyclooxygenase inhibitor. It has shown that it inhibits the synthesis of prostaglandins and ameliorates the effects of secondary injuries like tissue necrosis in SCI [55–57]. RhoA is a convergent intracellular pathway that limits axonal growth; its inhibition with indomethacin prevents oligodendrocyte loss and induces myelination across damaged white matter [58]. Nevertheless, the administration of nonselective cyclooxygenase inhibitors is a controversial issue since these compounds could inhibit platelet aggregation and may produce gastrointestinal ulceration [55]. Moreover, there is evidence that a single injection of indomethacin in SCI had a minimal effect on functional recovery and anatomical repair [57].

#### *3.1.6.1.2 Meloxicam*

Meloxicam is a drug derived from enolic acid, which inhibits prostaglandin biosynthesis under inflammatory conditions via the inhibition of COX-2. It has minimal gastric toxicity. Meloxicam has shown to reduce SCI-induced oxidative stress and exert neuroprotection by inhibiting LPO, GSH depletion, and DNA fragmentation [59, 60]. Despite these interesting results, meloxicam has not been further studied. Therefore, more studies are needed to know about its clinical management in SCI.

#### *3.1.7 Immunophilin ligands*

## *3.1.7.1 Cyclosporine A*

Cyclosporine A (CsA) is an immunosuppressant agent compound formed by 11 amino cyclic peptides, and it is obtained from *Tolypocladium inflatum*. CsA inhibits T-helper lymphocytes, cytotoxic and inflammatory responses in macrophages, inducible nitric oxide synthase (iNOs) expression avoiding the formation of nitric oxide (NO)-derived cytotoxic species, Cox-2 mRNA accumulation, tumor necrosis factor (TNFα) production and reduces cytokines and interleukins production (IL-1, IL-2, and IL-6). Also, CsA reduced the apoptosis of SC cells and increased the protein expression levels of cyclophilin-D (Cyp-D) and apoptosis-inducing factor (AIF) [61, 62]. This compound is capable of inducing motor recovery after SCI [63].

**165**

*Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art*

Tacrolimus or FK506 is an immunosuppressant macrolide drug, isolated from *Streptomyces tsukubaensis*, and it is approved by The Food and Drug Administration (FDA) [64, 65]. An indirect neuroprotective effect results from its immunosuppressant action on T-cells that infiltrate SCI, and this action modulates inflammation. On the other hand, FK506 inhibits caspase-3 and NF-kB, improving functional recovery with the increase of rostral axonal sparing and oligodendroglial survival [66, 67]. Additionally, this compound is capable of reducing FR and thereby LPO. These neuroprotective effects improve if the administration of FK506 is during the first 30 min after injury [65]. The studies suggest that FK506 might be a

Immunization with neural derived peptides (INDP) such as A91, a peptide derived from the 87–99 immunogenic sequence of myelin basic protein has shown to induce neuroprotection and motor recovery after SCI [68]. Its mechanism of action is related to the activation of T-lymphocytes inducing an anti-inflammatory Th2 response that allows microglia to differentiate into a M2 phenotype. Th2 response is capable of producing brain-derived neurotrophic factor (BDNF), a molecule strongly related to tissue protection [69]. INDP has shown that anti-A91 T-lymphocytes promote tissue protection by inhibiting the expression of iNOS, reducing ON production [68] and decrease LPO after SCI [70]. On the other hand, it has been shown that all these beneficial effects contribute to the preservation of neural tissue by preventing apoptosis [71], the survival of neurons in rubrospinal tract [72] and promoting a better neurological recovery in models of SCI [46]. Studies suggest that A91 might be an immune modulating treatment for SCI.

Metformin is a hypoglycemic agent used for therapy of type 2 diabetes mellitus; it is an AMP-activated protein kinase (AMPK) agonist. Metformin also acts through signaling pathway of mTOR and p70S6K causing an inhibition of apoptosis and inflammation. This drug is also capable of stimulating autophagy and reducing expression of NF-kB-mediated inflammation [73, 74]. Studies indicate that long-term use of metformin has been proved effective as a pharmacological treatment for some CNS disorders like Parkinson's disease, Huntington's disease, and ischemic brain injury. Using a rat model of traumatic SCI, the administration of metformin helps restoring the dysfunctional autophagy-lysosome pathways providing neuroprotection, decreasing neuronal death and mitigating apoptosis [75, 76]. The immediate administration of metformin after the injury showed diminishing complications, reflecting a decrease on histopathological signs of neuroinflammation, including TNFα and IL-1β inflammatory cytokines in the SC [73]. Although these outcomes are promising, subsequent studies are required to determine the risk

Androgens and estrogens are multi-active steroidal hormones that have neuroprotective effects in neural injuries; both testosterone and estradiol improve safeguard against apoptosis and promote motor and sensitive recovery. Also, reduce inflammation and FR generation and have been involved in regulating the

ad optimal doses for the use of metformin on clinical studies.

*DOI: http://dx.doi.org/10.5772/intechopen.89539*

good drug for treating SCI in humans.

*3.1.8 With neural derived peptides*

*3.1.7.2 Tacrolimus*

*3.1.9 Metformin*

*3.1.10 Gonadal hormones*

*Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art DOI: http://dx.doi.org/10.5772/intechopen.89539*
