2.1.4. Glutamate excitotoxicity

SCI affects the regular equilibrium of glutamate and aspartate in the CNS, leading to significant alterations. Fifteen minutes after SCI, glutamate concentration increases to concentrations six times higher than physiological levels [18]. This increase is due to the overstimulation of ionotropic glutamate receptors (GluRs), provoked by the massive entry of Ca2+ and Na+ . This ion flow can induce a secondary increase of intracellular Ca2+, leading to an overstimulation of viable neurons and neuronal death. This toxic effect, known as excitotoxicity [19], leads to neuronal and oligodendrocytic death [18, 20].

This phenomenon is mainly evidenced in glial cells, with axonal-myelinating oligodendrocytes showing greater susceptibility. Excitotoxicity signals are regulated by 2-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) and kainate type GluRs; their overactivation facilitates oligodendrocyte death and consequent demyelination after SCI [21].

#### 2.1.5. FR production

Microvascular disruption, ionic deregulation, glutamate increase, mitochondrial dysfunction, and the activation of inflammatory mechanisms stimulate the formation of FR [4, 6, 22]. The cascade of FR production begins with intracellular Ca2+ elevation and the production of uncoupled electrons, which bind to O2 molecules, transforming them into superoxide radicals (O2 ) capable of increasing oxidative damage by promoting further FR formation [23].

Damage induced by FR, denominated oxidative stress or nitrosative stress, occurs when excessive amounts of ROS and reactive nitrogen species (RNS) are produced, along with low levels of antioxidant defenses. FR production following SCI can damage cellular lipids, proteins, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA), causing mutations or irreversible damage, which leads to cellular death [24]. Moreover, peroxidase (Prx) 1/6 and manganese superoxide dismutase (MnSOD) are modified by phosphorylation, oxidation, or nitration during oxidative stress after injury, inhibiting their antioxidant functions [25].
