Inhibition of lipid peroxidation in central nervous system trauma and ischemia

A novel group of compounds, the 21-aminosteroids ("lazaroids"), have been designed that are potent inhibitors of oxygen free radical-induced, iron-catalyzed lipid peroxidation (LP) in microvascular and nervous tissue. One of these, tirilazad mesylate (U-74006F), has been selected for clinical evaluation as a cerebroprotective agent. In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including: increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP-induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the levels of endogenous vitamin E. The major site of action appears to be the blood-brain barrier based upon its known localization in cerebrovascular endothelium and numerous studies showing an attenuation of subarachnoid hemorrhage (SAH), injury, and ischemia-induced blood-brain barrier permeability. Tirilazad has demonstrated neuroprotective efficacy in multiple preclinical models of spinal cord and head injury, SAH, and focal cerebral ischemia, as measured by a decrease in cerebral vasospasm, blood-brain barrier compromise, post-traumatic ischemia, edema, ischemic neuronal necrosis and infarction, and improved neurological recovery. This efficacy is correlated with a reduction in markers of oxygen radical-induced LP. Phase III clinical trials are currently ongoing in spinal cord and head injury, SAH, and ischemic stroke. Initial results from a European/Australian/New Zealand trial in SAH have shown a significant decrease in mortality and an increase in the incidence of good recovery.