Oxygen radical-mediated lipid peroxidation (LP) has been suggested increasingly to be an important factor in posttraumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacological agents with
lipid antioxidant activity in models of spinal cord and
brain injury. Intensive pretreatment of animals with the endogenous
lipid peroxyl radical scavenger
vitamin E (i.e.,
alpha-tocopherol) has been shown to decrease posttraumatic
spinal cord ischemia and to enhance chronic neurological recovery. However, the slow CNS tissue uptake of
vitamin E requires chronic dosing, making it an impractical agent for treatment of acute neural injury. The
glucocorticoid steroid, methyl-
prednisolone (MP), has been shown to possess significant
antioxidant efficacy and, when administered to animals or humans in
antioxidant doses, improves chronic neurological recovery after
spinal cord injury. This activity of MP is independent of the
steroid's
glucocorticoid receptor-mediated actions, as evidenced by the efficacy of the novel
antioxidant 21-aminosteroids, which are devoid of
glucocorticoid activity but have greater
antioxidant efficacy than MP. One of these,
tirilazad mesylate (U-74006F), has been shown to be effective in animal models of brain and
spinal cord injury and is currently the subject of phase II clinical trials. Recently, compounds that combine the amino functionality of the 21-amino-steroids with the
peroxyl radical scavenging
chromanol portion of
vitamin E (i.e., 2-methylaminochromans) also have shown promise as
neuroprotective agents. The consistent benefit afforded by
antioxidant compounds further supports the concept that LP is an important therapeutic target for acute pharmacological neuroprotection.