It has been suggested that
reactive oxygen species (ROS) play a role in the pathophysiology of brain damage. A number of therapeutic approaches, based on scavenging these radicals, have been attempted both in experimental models and in the clinical setting. In an experimental rat and mouse model of
closed-head injury (CHI), we have studied the total tissue nonenzymatic
antioxidant capacity to combat ROS. A major mechanism for neutralizing ROS uses endogenous low-molecular weight
antioxidants (LMWA). This review deals with the source and nature of ROS in the brain, along with the endogenous defense mechanisms that fight ROS. Special emphasis is placed on LMWA such as ascorbate,
urate,
tocopherol,
lipoic acid, and
histidine-related compounds. A novel electrochemical method, using cyclic voltammetry for the determination of total tissue LMWA, is described. The temporal changes in brain LMWA after CHI, as part of the response of the tissue to high ROS levels, and the correlation between the ability of the brain to elevate LMWA and clinical outcome are addressed. We relate to the beneficial effects observed in heat-acclimated rats and the detrimental effects of injury found in
apolipoprotein E-deficient mice. Finally, we summarize the effects of cerebroprotective pharmacological agents including the
iron chelator desferal,
superoxide dismutase, a stable radical from the
nitroxide family, and
HU-211, a nonpsychotoropic
cannabinoid with
antioxidant properties. We conclude that ROS play a key role in the pathophysiology of
brain injury, and that their neutralization by endogenous or exogenous
antioxidants has a protective effect. It is suggested, therefore, that the brain responds to ROS by increasing LMWA, and that the degree of this response is correlated with clinical recovery. The greater the response, the more favorable the outcome.