Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice
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Pregnenolone sulfate (PREGS) and dehydroepiandrosterone 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.
The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25–35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice.
B104 cells pretreated with the steroids before Aβ25–35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25–35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured.
ent-PREGS and PREGS significantly attenuated the Aβ25–35-induced decrease in cell viability. Both steroids prevented the Aβ25–35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25–35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25–35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25–35-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 Aβ25–35 in contrast to the natural steroids.
The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.
KeywordsAlzheimer’s disease Neurosteroid Enantiomer β-amyloid toxicity Learning and memory Oxidative stress Pregnenolone sulphate Dehydroepiandrosterone sulphate Neuroprotection Memory
We thank Dr A. Meiniel for generously providing us with B104 neuroblastoma cells. We thank the Flow Cytometry Core Facility at King Faisal Specialist Hospital & Research Center (Riyadh) for help in cytometry experiments. This work is supported in part by external resources of the Institut National de la Santé et de la Recherche Médicale (INSERM, Paris) and the University of Montpellier 2 (Montpellier), and by the United States National Institutes of Health grant GM 47969 (DFC).
Conflict of interest
JM and VV are now employees of Amylgen (Montpellier). TM is the scientific director of Amylgen and scientific board adviser of Anavex Life Sciences (Hoboken, NJ, USA). DFC holds equity in Sage Therapeutics Inc. The companies were not involved, scientifically or financially, in the present experiments. The authors declare that they have no other conflict of interest.
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