Lipid antioxidants in acute central nervous system injury

Oxygen radical-mediated lipid peroxidation increasingly has been suggested to be an important factor in post-traumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacologic agents with lipid antioxidant activity in models of spinal cord and brain injury. The glucocorticoid steroid methylprednisolone has been shown to possess significant antioxidant efficacy, and when administered to animals or human beings in antioxidant doses, it improves chronic neurologic recovery after spinal cord injury. This activity of methylprednisolone is independent of the steroid's glucocorticoid receptor-mediated actions and has been surpassed by the novel antioxidant 21-aminosteroids that have been developed that are devoid of glucocorticoid activity but have greater antioxidant efficacy than methylprednisolone. One of these, tirilazad mesylate (U-74006F), has been shown to be quite effective in animal models of brain and spinal cord injury and is the subject of phase III clinical trials. The consistent benefit afforded by antioxidant compounds further supports the concept that lipid peroxidation is an important therapeutic target for acute pharmacologic neuroprotection.