Lazaroids: Mechanisms of Action and Implications for Disorders of the CNS

Abstract

Oxygen radical-induced lipid peroxidation to cerebrovascular or brain parenchymal cell membranes has been implicated as a pathophysiological mechanism in both acute and chronic neurodegenerative disorders, including brain and spinal cord trauma, ischemic and hemorrhagic stroke, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis. As a result, pharmacological strategies have been aimed at antagonizing lipid peroxidative damage in a safe and effective manner. Perhaps the first successful antioxidant neuroprotective approach is high dose treatment with the glucocorticoid steroid methylprednisolone, which has been reported to be effective in improving neurological recovery after blunt spinal cord injury in animals and humans. After a determination that these effects were based upon inhibition of posttraumatic lipid peroxidative reactions rather than steroid receptor interactions, a new class of 21-aminosteroids (“lazaroids”) was discovered. The lazaroids are more effective inhibitors of lipid peroxidation and, at the same time, devoid of glucocorticoid side effect potential. One of them, tirilazad (U-74006F), was found protective in a variety of preclinical neuroprotection models and is currently the subject of Phase III clinical trials. Thus far, the compound has been demonstrated to significantly improve 3-month survival and neurological recovery after subarachnoid hemorrhage in humans. Although tirilazad does penetrate the injured CNS, much of its protective activity is mediated by an action on vascular endothelium. Recently, the 21-aminosteroids have been followed up with a newer series of non-steroidal compounds, the pyrrolopyrimidines, which possess even greater antioxidant efficacy and brain penetration that may be useful for the treatment of chronic neurodegenerative disorders.