Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ₂₅₋₃₅ peptide-induced toxicity in vitro and in vivo in mice.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.
INSERM U788 and Université PARIS SUD, Faculté de Médecine, UMR- S788, 94276 Le Kremlin-Bicêtre, France.|Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
Fadia
F
El Bitar
INSERM U710 and Université de Montpellier 2, 34095 Montpellier, France.
Johann
J
Meunier
INSERM U710 and Université de Montpellier 2, 34095 Montpellier, France.
Vanessa
V
Villard
INSERM U710 and Université de Montpellier 2, 34095 Montpellier, France.
Marion
M
Alméras
Washington University in St. Louis, School of Medicine, Department of Developmental Biology, St. Louis, MO 63110, USA.
Kathiresan
K
Krishnan
Washington University in St. Louis, School of Medicine, Department of Developmental Biology, St. Louis, MO 63110, USA.
Douglas F
DF
Covey
INSERM U710 and Université de Montpellier 2, 34095 Montpellier, France.
Tangui
T
Maurice
INSERM U788 and Université PARIS SUD, Faculté de Médecine, UMR- S788, 94276 Le Kremlin-Bicêtre, France.
Yvette
Y
Akwa
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D016501:Neurites / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011284:Pregnenolone / Q000494:pharmacology*; D051381:Rats
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C018370:pregnenolone sulfate; D019314:Dehydroepiandrosterone Sulfate; D011284:Pregnenolone