Antioxidant therapies in traumatic brain and spinal cord injury

Abstract

Free radical formation and oxidative damage have been extensively investigated and validated as important contributors to the pathophysiology of acute central nervous system injury. The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact. A key component in this event is peroxynitrite-induced lipid peroxidation. As discussed in this review, peroxynitrite formation and lipid peroxidation irreversibly damages neuronal membrane lipids and protein function, which results in subsequent disruptions in ion homeostasis, glutamate-mediated excitotoxicity, mitochondrial respiratory failure and microvascular damage. Antioxidant approaches include the inhibition and/or scavenging of superoxide, peroxynitrite, or carbonyl compounds, the inhibition of lipid peroxidation and the targeting of the endogenous antioxidant defense system. This review covers the preclinical and clinical literature supporting the role of ROS and RNS and their derived oxygen free radicals in the secondary injury response following acute traumatic brain injury (TBI) and spinal cord injury (SCI) and reviews the past and current trends in the development of antioxidant therapeutic strategies. Combinatorial treatment with the suggested mechanistically complementary antioxidants will also be discussed as a promising neuroprotective approach in TBI and SCI therapeutic research. This article is part of a Special Issue entitled: Antioxidants and antioxidant treatment in disease.

Antioxidant therapies in traumatic brain injury: a review

“…U-83836E treatment can attenuate post-traumatic LP in cerebral cortical tissue or mithochondria together with a preservation of aerobic respiratory function and Ca++-buffering capacity (45). More recently U-83836E has also been shown to inhibit calpain-mediated cytoskeletal degradation signifying the intricate relationship between post-traumatic LP, disruptions in neuronal Ca2+ homeostasis and calpain-mediated cytoskeletal damage (12). If U-83836E given prophylactically, enhances Na+/K+ and Mg2+/Ca2+-ATPase activities and attenuates edema in cerebral trauma in rats (46).…”

“…Factors contributing to the failure of the tirilazad study were the apparent inability of the agent to cross the blood-brain barrier in high enough concentrations in severely injured patients as well as gender differences in treatment outcomes and drug metabolism. On the other hand, PEG-SOD was limited in its therapeutic value based on its large size and rather narrow therapeutic window to scavenge the short-lived primordial O2•− radical (12). Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a derivative of antipyrin and was approved as free radical scavenger.…”

“…The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact (12). Various mechanisms are postulated to promote free radical production, including glutamate release, intracelular calcium overload, increase in arachidonic acid and its metabolites, hemoglobin denaturation, and iron ion release (1).…”

Effects of lithium chloride and methylprednisolone on experimental spinal cord injury

“…Treatment results of patients with spinal cord injury are still poor despite various treatment approach and efforts. The aim of the entire treatment effort is to prevent secondary tissue damage [3][4][5]. There are reports suggesting that LiCl protects the cultured neurons against glutamateinduced excitotoxicity and apoptosis mediated by N-methyl-D-aspartate (NMDA) receptors [6].…”

The role of free radicals and reactive species following traumatic brain injury

“…Activation of NMDA receptors has been shown to contribute to post-traumatic LP 7 probably via causing an early increase of cytosolic Ca ++ which ignites the production of free radicals by several mechanisms 8 including the Ca ++ induced activation of phospholipases and arachidonic acid cascade, conversion of xanthine dehydrogenase to xanthin oxidase, induction of nitric oxide synthase (NOS) and mitochondrial leak. The ignited reactive species will attack cellular and mitochondrial membranes causing LP 9 . The inflicted oxidative damage causes further deterioration of Ca ++ homeostasis 10 probably by targeting mitochondria and stimulating the formation of the membrane permeability transition pore 11 which contributes to delayed Ca ++ dysregulation 12 .…”