Phenolic A ring requirement for the neuroprotective effects of steroids

Estrogens are reported to reduce the incidence of Alzheimer's disease and 17beta-estradiol (betaE2), the potent, naturally occurring estrogen, exerts neuroprotective effects in a variety of in vivo and in vitro model systems. The present study elucidates the structural requirements of steroids and related compounds for neuroprotectivity at low nM doses. All estrogens tested with an intact phenolic A ring protected SK-N-SH neuroblastoma cells from the toxic effects of serum-deprivation. All 3-O-methyl ether cogeners tested were inactive indicating the importance of a phenolic A ring. The diphenolic estrogen mimic diethylstilbesterol (DES) was neuroprotective and retention of a single phenolic function was sufficient to retain neuroprotective activity. The di-O-methyl ether of DES was inactive. The following steroids which lack a phenolic A ring were also inactive: testosterone; dihydrotestosterone; progesterone; corticosterone; prednisolone; 6 alpha-methylprednisolone; aldosterone; and cholesterol. Finally, phenol, lipophilic phenols, and tetrahydronapthol were inactive. These results suggest that a phenolic A ring and at least three rings of the steroid nucleus are necessary for the neuroprotective activity of estrogens.