**2. Pathophysiology**

The Spinal Cord Injury could be divided by its etiology in traumatic and nontraumatic. The traumatic type is caused by physical damage (traffic accident, sportive, and fall), whereas nontraumatic is occasioned by an illness/sickness, such as tumors, infections or degenerative diseases which directly affect the SC [8]. In addition, SCI can be divided into primary and secondary injury [1, 9].

Primary injury is caused at the moment of physical damage and leads to irreversible affection on gray matter during the first hour post-lesion. There are three main mechanisms of injury: contusion, when there is not a visible alteration in its morphology, producing a necrotic region at the injury area; laceration or transection, when there is an extreme trauma or penetration, affecting SC conduction of nervous impulses depending on whether the tissue is partial or totally transected; compression from vertebral fractures leading ischemic damage in the area where blood flow was disrupted [10, 11].

After injury, superficial blood vessels undergo to vasospasm which provokes damage in the microvasculature of gray matter [12]. Reduction in the perfusion has two important implications: hypoxia and ischemia; which may involve to neurogenic shock characterized by arterial hypotension, bradycardia, arrhythmia, and intraparenchymal hemorrhage that causes neuronal death by necrosis. Afterwards, primary injury provokes the rupture of blood brain barrier and a cascade of destructive secondary phenomena leading to a further damage in SC and neurological dysfunction [1, 13]. Therefore, the primary lesion results in the development of a succession of cellular and molecular changes that alter gene expression patterns, which are processes that are already part of the secondary injury [11, 12]. During the acute phase, injury to the blood vessels and severe hemorrhages cause massive influx of inflammatory cells, cytokines, and vasoactive peptides. This phase is almost characterized by ionic deregulation that leads to edema, thus interrupting the conduction of nerve impulses. Following, subacute phase involves a sequence of events like ischemia, vasospasm, thrombosis, inflammatory response, free radicals (FR) production, lipid peroxidation (LPO), and activation of autoimmune responses causing apoptosis. The huge inflammatory responses after the acute and subacute phase, together with the disruption of the blood-brain barrier (BBB), contribute to the progressively swelling of the SC. This generalized edema may increase the mechanical pressure of the SC, aggravating the injury [1, 11, 14].

To counteract all these acute effects after SCI, neuroprotective strategies have been investigated to rapidly intervene decreasing the neuronal death occurring after damage mechanisms. Many pharmacological and nonpharmacological therapies have been developed, and others are still under investigation, this in order to improve the quality of life of patients.

#### **3. Neuroprotective therapy after acute SCI**

As we review previously, SCI leads to motor and sensory dysfunction, first with the primary mechanical injury and then with the complex cascade of secondary damaging events [15]. For several years, basic science, preclinical, and clinical studies are focused in overcoming elements involved in accurate recovery from SCI [1]. An ideal neuroprotective therapy must reduce neurological symptoms including degenerative changes; starting from there, we can discriminate between potential clinical therapies, which could have a better effect [16]. While these therapies are being searched, there are many preclinical and clinical investigations exploring pharmacological and nonpharmacological treatments.

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

This range of therapeutic approaches includes: ionic channel blockers, inhibitors of NMDA and AMPA-kainate receptors, inhibitors of FR and LPO, anti-apoptotic drugs, calpain inhibitors, immunosuppressive or immunomodulatory drugs, immunophilin ligands, immunomodulatory peptides, hypoglycemic agents, and gonadal

Tetrodotoxin (TTX) is a low-molecular-weight guanidine neurotoxin that acts as a specific blocker of voltage-gated sodium (NaV) channel [17]. TTX has neuroprotective properties by blocking NaV channels, preventing neuronal death by diminishing

The beneficial effects of TTX in preclinical studies include a reduction of white matter loss after SCI [17–19], promoting a motor function restoration. The effect of TTX is time-dependent [20]. The administration of TTX 15 minutes after a SCI helps to restore the function of hindlimbs [21]. Despite these promissory effects, there are some limitations for the use of TTX in patients, one of them is its toxicity. This may appear as a consequence of its systemic distribution and it can involve the blocking of diaphragmatic nerves ending in respiratory tract paralysis [17]. Even with previous findings, current studies are needed to improve its use in SCI.

Riluzole is a benzothiazole anticonvulsant drug with neuroprotective effects in the SCI [22]. One of the mechanisms by which riluzole operates is the inhibition in the presynaptic terminals of glutamate, and this helps to limit the glutamateinduced toxicity [23]. In addition, riluzole blocks the NaV-gated channels, avoiding swelling and neuronal acidosis. Riluzole blocks the entry of H+ to the neurons

Nimodipine is a dihydropyridinic Ca+2 channel antagonist that boosts the brain's blood flow, without compromising metabolism [26, 27]. It reduces malondialdehyde (MDA) levels, ED-1 markers for activated macrophages and myeloperoxidase (MPo). Studies have shown that nimodipine helps reducing FR, oxidative damage, resulting in the reduction of the damaged area and the infiltration of the inflammatory cells to the region, allowing SCI restoration [26]. Furthermore, the effect of inhibiting Ca+2 flux by nimodipine reduces apoptosis and tissue damage after SCI,

of glutamate and excitotoxicity [22]. Investigations have shown that the interruption of events associated with glutamate release on the presynaptic space by reducing Ca+2 influxes provokes a glutamate-mediated LPO reduction [23, 24]. Administration of riluzole within 12 hours of SCI was well tolerated and suggests

that it may have a beneficial effect on motor outcome [25].

exchanger; this prevents the Ca+2 from inducing the release

/Ca+2 exchange, and neuronal glutamate release [18].

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

hormones.

*3.1.1.1 Sodium*

*3.1.1.1.1 Tetrodotoxin*

*3.1.1.1.2 Riluzole*

through the Na+

*3.1.1.2 Calcium*

*3.1.1.2.1 Nimodipine*

increasing cell viability [27].

/H+

*3.1.1 Ionic channel blockers*

depolarization, cellular Na+

**3.1 Preclinical pharmacological therapies**
