**4.3 Mesenchymal cells**

Mesenchymal stem cells, or mesenchymal stromal cells (MSCs), are adult multipotent cells that have the capacity for self-renewal, proliferation, and differentiation. MSCs are an alternative for the experimental treatment of a spinal cord injury (contusions, transection, or ischemia). They have shown that they favor axonal regeneration and improve locomotor function [42–45]. They also have the ability to form bridging cell bundles at the TSCI epicenter [45–48] and can be differentiated both in vitro and in vivo in neurons, astrocytes, oligodendrocytes, Schwann cells, and microglia [49, 50].

Vaquero and colleagues have observed that after a TSCI, the use of MSCs and Schwann cells as therapy was beneficial not only because they observed axonal regeneration, but also because at different times (up to 9 months with transplantation), animals with severe contusions eventually recovered locomotive function (with a score of 16 on the BBB scale) [51–55]. Other studies have shown that MSCs give positive results when used in diseases or damage the nervous system by secreting growth factors such as neural growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). They can also secrete cytokines such as interleukin-6 (IL-6), colony stimulating factor 1 (CSF-1), monocyte chemoattractant protein (MCP), colony stimulating factor (CSF), and stromal cell derived factor (SDF-1) [42, 56]. In addition, they promote angiogenesis, proliferate after transplantation, aid neuronal survival, and decrease apoptosis [56]. Moreover, another important factor of MSCs is the immunomodulatory effect, since they are capable of secreting soluble inflammatorymediating factors such as indolamine 2–3 dioxygenase (IDO), inducible nitric oxide synthase (iNOS), and homo-oxygenase 1. They can also secrete the human leukocyte G antigen, transforming factor β (TGF-β), interleukin 6 (IL-6), and prostaglandin E2. These soluble factors promote the inhibition of CD4+CD8+ T cells [57]. It has been shown in contusions and compressions that using MSCs helps decrease proinflammatory cytokines such as TNF-α and IL-6, and promotes the secretion of anti-inflammatory cytokines such as IL-4, IL-10, and IL-13, which promotes the activation of M2 macrophages by fostering a neuroprotective environment [58, 59].

## **5. Exogenous factors**

Neurotrophins are structural proteins consisting of four families, which are involved in events in the development of the CNS such as survival, differentiation, and axonal growth. Among these, we find neuronal growth factor NGF, neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5), and brain-derived growth factor (BDNF). These neurotrophins bind directly to Trk receptors (tropomycin kinase receptors): NGF binds to its TrkA receptor, BDNF and NT4/5 bind to the same TrkB receptor, and NT-3 binds to its TrkC receptor. They also have a high affinity for the p75 receptor, NTR [60].

Studies on contusions, transections, and hemisections have shown that the most studied neurotrophins are BDNF and NT-3. The use of BDNF has been seen to promote neuroprotection, form collateral branches, and promote plasticity [61]. It also favors axonal growth, thus improving locomotor function [62, 63]. Moreover, in different models of contusion, transection, and hemisections, it was demonstrated that the exogenous use of NT-3 favors axonal regrowth and improvement of locomotor function [64, 65].

As for NGF and NT4/5, they are the least studied within TSCI models. NGF has been shown to promote the growth of sensory axons [66, 67], and in a contusion study, it reduced neuronal death, thus promoting an improvement in locomotive function [68]. NT4/5, like BDNF, can promote neuroprotection and axonal growth in a full-section model [69].

Another factor used chondroitinase ABC (ChABC), an enzyme from the bacteria *Proteus Vulgaris*. ChABC can bind to the chains of the GAG glycosaminoglycans, within the disaccharides, which favors the digestion of chondroitin sulfates (CSPGs) [70]. It has been seen that both in hemisection and transection models, this enzyme favors axonal growth [71, 72]. Moreover, in the presence of growth factors such as NT-3 and BDNF, it promotes the proliferation of oligodendrocytes, increasing remyelination and favoring improvement in locomotor function [71, 73, 74].

#### **6. Pharmacological use**

Successful drug trials on animals have been carried out and have advanced to human clinical trials; however, none of them has shown a clear improvement on patients. Some of the drugs used in TSCIs will be mentioned.

Methylprednisolone (MPP) is a synthetic steroid from the glucocorticoid group, which is used for its immunosuppressive and anti-inflammatory properties. Its mechanism of action is to inhibit the formation of arachidonic acid and decrease inflammation. In studies of animals with a TSCI, it has been observed that the administration of MPP favors the reduction of apoptosis. It also induces the interaction with the glucocorticoid receptor HIF-1α, which decreases the damage of oligodendrocytes [75]. In clinical studies with acute injuries, the use of MPP has been shown to improve functionality and sensitivity when compared to patients who only took the placebo [76–78].

Another drug used is riluzole, a benzothiasilic anticonvulsant, which acts as a blocker of sodium channels. Fehlings and colleagues compared the effect of riluzole with phenytoin in an acute contusion injury model, where they observed promoted functional recovery [79]. In studies with patients with acute injury, riluzole has been observed to prompt sensory and locomotor improvement [80].

Minocycline, a second-generation synthetic tetracycline, has also been used as an antibacterial agent. This medication can stay in the CNS longer than the usual tetracycline since it can cross the blood-brain barrier. It can act as a neuroprotector *Strategies to Repair Spinal Cord Injuries: Single Vs. Combined Treatments DOI: http://dx.doi.org/10.5772/intechopen.93392*

by reducing inflammation and preventing cell death [81]. In studies with patients with acute cervical and thoracic injuries, it was observed that the administration of minocycline did not cause side effects in patients. Additionally, in patients with cervical injuries, it improved locomotor function when compared to patients who took only the placebo. However, in patients with thoracic lesions, no changes were observed. In this study, it was concluded that the effect of minocycline with more patients should be evaluated to verify its efficacy [82].
