The role of reactive oxygen species and lipid peroxidation in the neurodegenerative process after spinal cord injury

The discovery of free radicals in biological materials first took place 50 years ago. Free radicals are classified as reactive nitrogen species (RNS) or reactive oxygen species (ROS). The latter are known to be responsible for the oxidation of lipids, proteins and DNA. Ordinarily, antioxidants ensure the maintenance of the appropriate redox homeostasis. The problem occurs when these protective mechanisms are overtaken by the excessive presence of ROS. Therefore, the presence of the latter results in significant functional consequences in a variety of diseases. The central nervous system (CNS) is an easy target for ROS due to its low antioxidant level and high concentration of Fe2+, oxygen, and polyunsaturated fatty acids (PUFAs). Consequently, the activation of auto-destructive mechanisms after spinal cord injury (SCI), such as the inflammatory response, induce an elevated presence of ROS and lipid peroxidation (LP) of PUFAs, which lead to axonal demyelination and cell death. LP is perhaps one of the most important tissue damaging phenomenon after SCI. LP is a process that spreads over the surface of the cell membrane altering the PUFAs, which in turn causes an impairment of phospholipid-dependent enzymes, disruption of ionic gradients, and even membrane lysis. These alterations reduce the generation and transmission of electrical potentials, and causes membrane and motor dysfunction. A significant increase in LP products is observed after SCI as early as 15 min after injury. Two well-characterized and highly toxic products of LP in SCI are 4-hyroxynonenal (4- HNE) and acrolein. LP after SCI is caused by elevated free radical concentrations that are released primarily by inflammatory cells. In fact, evidence shows that the presence of infiltrating inflammatory cells is significantly correlated with the amount of tissue damage after injury. When the inflammatory response is activated, high concentrations of free radicals, principally superoxide anion (O^2-•) and nitric oxide (NO•), are produced. Together, these molecules have the capacity to generate neurotoxic compounds such as peroxynitrite that initiates the LP process. The discovery of therapeutic strategies that promote neuroprotection has been the aim of several research projects. At the moment, the use of pharmacological compounds is perhaps the most experimentally recurred strategy to counteract LP. These pharmacological interventions include: compounds that either inhibit the formation of ROS and RNS prior to the initiation of LP, compounds that inhibit the propagation of LP reactions or the use of scavengers for lipid radicals (LOO•) and the alkoxyl radical (LO•) posterior to the initiation of LP. Protective autoimmunity is an innovative strategy based on the modulation of autoreactive mechanisms in order to promote neuroprotection. Evidence has demonstrated that immunization with neural-derived antigens modulates this autoreactive response and inhibits LP after SCI. Several neuroprotective strategies have been proposed, in order to decrease the amount of ROS, NO• and LP after SCI. The first objective of this chapter is to describe the relationship between ROS, lipid peroxidation, and the inflammatory response after SCI. The second objective of this chapter is to describe the effects of diverse therapeutic strategies in the before-mentioned mechanisms.