Novel analogs of allopregnanolone show improved efficiency and specificity in neuroprotection and stimulation of proliferation

• DOI: 10.1111/jnc.13693
• Publication Date: 2016-06-03T10:45:22Z
• Authors: Mona Karout; Michel Miesch; Philippe Geoffroy; Stephanie Kraft; Hans‐Dieter Hofmann; Ayikoe Guy Mensah...; Matthias Kirsch
• Keywords: Allopregnanolone

The natural neurosteroid allopregnanolone exerts beneficial effects in animal models of neurodegenerative diseases, nervous system injury and peripheral neuropathies. It not only has anti-apoptotic activity, but also promotes proliferation progenitor cells. With respect to using it as a therapeutic tool, such pleiotropic actions might create unwanted side effects. Therefore, we have synthesized analogs analyzed their neuroprotective proliferative identify compounds with higher efficiency less ambiguous biological actions. Proliferation-promoting 3α 3β isomers 3-O-allyl-allopregnanolone 12 oxo-allopregnanolone were studied adult subventricular zone stem cell cultures primary hippocampal by measuring 5-ethynyl-2'-deoxyuridine incorporation. Neuroprotective activity against amyloid beta 42-induced death was determined quantifying caspase 3/7 activity. significantly stimulated all culture systems, whereas the ineffective. stimulatory effect 3α-O-allyl-allopregnanolone than that allopregnanolone. In neural cultures, specifically enhanced Nestin-positive progenitors. addition, promoted differentiation doublecortin-positive neurons. treated 42, both α β O-allyl- showed increased compared allopregnanolone, completely preventing amyloid-induced activation. These results structural proliferation-promoting neurosteroid. Interestingly, stereoisomers found distinct profiles raising possibility exploiting properties neurosteroids or without simultaneously stimulating neurogenesis. Cover Image for this issue: doi: 10.1111/jnc.13344.