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

E. D. Hall, J. M. McCall, R. L. Chase, P. A. Yonkers, J. M. Braughler

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

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-11α-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, wereas dexamethasone or MP at concentrations of 10-6 M and lower caused a marked suppression in adrenocorticotropin secretion. Despite its nearly complete lack of glucocorticoid activity, U-72099E was equally effective yet more potent than MP in protecting rat brain synaptosomes from a lipid peroxidation-induced reduction in γ-aminobutyric acid uptake. Using xanthine and xanthine oxidase to peroxidatively impair synaptosomal γ-aminobutyric acid uptake, MP or U-72099E caused a dose-dependent preservation of γ-aminobutyric acid uptake with optimal concentrations being 100 and 30 μM, respectively. In an investigator-blinded protocol, mice were treated i.v. with either MP, U-72099E or vehicle within 3 to 5 min after a reproducible and quantifiable concussive head injury. Using a grip test at 1 hr after trauma to assess neurological status of injured mice, MP produced a dose-related improvement in neurological recovery (P < .05 at 60 mg/kg) compared with vehicle-treated animals. A similar improvement in neurological status was observed in mice treated with U-72099E; however, the optimal dose was 30 mg/kg. These results demonstrate that a nonglucocorticoid steroid, which would be devoid of many 'steroid'-related side effects, can duplicate the efficacy and surpass the potency of MP in models of central nervous sytem trauma.

Original languageEnglish
Pages (from-to)137-142
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume242
Issue number1
StatePublished - 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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