Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against A[β.sub.25-35] peptide-induced toxicity in vitro and in vivo in mice

Rationale Pregnenolone sulfate (PREGS) and dehydroepian drosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. Objective The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against A[β.sub.25-35] peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. Methods B104 cells pretreated with the steroids before A[β.sub.25-35] were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with A[β.sub.25-35] and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. Results ent-PREGS and PREGS significantly attenuated the A[β.sub.25-35]-induced decrease in cell viability. Both steroids prevented the A[β.sub.25-35]-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the A[β.sub.25-35]-in duced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite out growth per se and prevented the A[β.sub.25-35]-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the A[β.sub.25-35]-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before A[β.sub.25-35] in con trast to the natural steroids. Conclusion The unnatural steroids ent-PREGS and entDHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD. Keywords Alzheimer'sdisease * Neurosteroid Enantiomer * β-amyloid toxicity * Learning and memory * Oxidative stress * Pregnenolone sulphate * Dehydroepiandrosterone sulphate * Neuroprotection * Memory