*3.1.7.2 Tacrolimus*

*Neuroprotection - New Approaches and Prospects*

*3.1.6 Immunosuppressive or immunomodulatory drugs.*

*3.1.6.1 Inhibitors of cyclooxygenase*

*3.1.6.1.1 Indomethacin*

*3.1.6.1.2 Meloxicam*

management in SCI.

*3.1.7.1 Cyclosporine A*

*3.1.7 Immunophilin ligands*

neurodegeneration, degradation of cytoskeleton, and apoptosis via caspase-3 due to its proteolytic activities, in SCI. The influx of Ca+2 stimulates Ca+2-dependent enzymes, within them are calpains, which seem to play a role in proteolysis by contributing to apoptosis in CNS cells. The cell death decreases mRNA expression and transcription of myelin basic protein (MBP) and proteolipid protein (PLP), which are axonal neurofilament proteins [49, 51, 52]. The administration of a calpain inhibitor such as E-64-d (1 mg/kg) to injured rats blocks apoptosis and helps to re-establish MBP and PLP genes [51]. The administration of other calpain inhibitors such as SJA 6017 and calpeptin has demonstrated their ability to induce neuroprotection after SCI [53, 54]. Despite the study efforts and the promising therapeutic effects for functional neuroprotection, there are no clinical trials testing these drugs, so further studies are needed for the use of calpain inhibitors in patients.

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].

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

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].

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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 good drug for treating SCI in humans.
