Inflammatory cell-mediated myelin injury may be an important cause of tissue damage in both acute and chronic central nervous system (CNS) disorders. The 21-aminosteroids are novel derivatives of methylprednisolone without obvious glucocorticoid or mineralocorticoid side effects. We evaluated the ability of 21-aminosteroid, U74500A, to inhibit oxidation of rat brain myelin by human polymorphonuclear leukocytes (PMN) and monocytes. Myelin samples, as confirmed by SDS-PAGE, were incubated with PMN or monocytes and 100 microM U74500A or vehicle. Myelin oxidation by both PMN and monocytes was significantly reduced by U74500A. These observations demonstrate that U74500A can inhibit myelin oxidation by inflammatory cells. Additionally, 100 microM U74500A significantly reduced production of interleukin 1-beta by monocytes exposed to myelin. The aminosteroids may be beneficial in CNS disorders where myelin injury by inflammatory cells appears to contribute, such as acute focal ischemia or multiple sclerosis.