A nonglucocorticoid steroid analog of methylprednisolone duplicates its high-dose pharmacology in models of central nervous system trauma and neuronal membrane damage.

Prior studies have demonstrated that intensive treatment with high doses of methylprednisolone (MP) can beneficially affect the acutely injured central nervous system by a variety of mechanisms and promote neurological recovery in experimentally injured animals. In view of the fact that these actions are associated only with MP doses greatly in excess of those required for classical glucocorticoid receptor-mediated actions of the steroid, the possibility was examined that this high-dose pharmacology of MP could be duplicated by a nonglucocorticoid analog. Accordingly, U-72099E (17,21-dihydroxy-11 alpha-t-butylacetoxy-1,4-pregnadiene-3,20-dione- 21-hemisuccinate, sodium salt) was synthesized and tested for its ability to duplicate the high-dose effects of MP in a concussive head injury model in mice and in an in vitro model of lipid peroxidation-induced membrane damage using rat brain synaptosomes. The absence of glucocorticoid-related activity of U-72099E was confirmed by its inability to either suppress body weight gain or cause thymic involution in mice treated with doses up to 100 mg/kg/day for 4 days. On the other hand, MP at 30 mg/kg/day for 4 days caused a complete inhibition of body weight gain and a 43.5% reduction in thymus weight. Moreover, U-72099E, at concentrations of 10(-5) M or lower, failed to suppress adrenocorticotropin secretion by mouse AtT-20 pituitary cells in culture, whereas dexamethasone or MP at concentrations of 10(-6) M and lower caused a marked suppression in adrenocorticotropin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)