Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke.
OBJECTIVE
Presenilin1 (PS1) regulates Notch1 signaling activity, which liberates Notch intracellular domain (NICD). Notch activation promotes neural progenitor cell (NPC) self-renewal in the developing brain. In this study, we tested whether atorvastatin-induced NPC proliferation after stroke is mediated by PS1 and Notch1 activation.


METHODS
PS1 and NICD expressions were measured in retired breeder rats subjected to middle cerebral artery occlusion that were left untreated or treated with atorvastatin. To investigate the mechanisms of atorvastatin-induced NPC self-renewal, subventricular zone (SVZ) neurosphere culture and knockdown of Notch1 gene expression by short interfering RNA were used. SVZ neurosphere formation, cell proliferation, real-time polymerase chain reaction, and Western blotting were performed.


RESULTS
Atorvastatin significantly increased the numbers of newly generated neuroblasts and promoted PS1 and NICD expression in the ipsilateral and homologous contralateral SVZ compared with saline-treated control rats. Increased SVZ neurosphere formation and cell proliferation were found in cultured neurospheres derived from normal rat and poststroke rat SVZs treated in vitro with atorvastatin compared with untreated neurospheres (P<0.05). Atorvastatin significantly increased PS1 and hairy and enhancer of split1 (Hes1) gene expression in cultured SVZ neurospheres. Inhibition of PS1 significantly decreased NICD expression. Short interfering RNA knockdown of Notch1 expression, decreased NPC proliferation, and NICD and hairy and enhancer of split1 expression in cultured neurosphere cells.


CONCLUSIONS
These data indicate that atorvastatin increases the NPC pool in older rats and that it also upregulates PS1 expression and Notch1 signaling activity, which in turn, facilitate an increase in SVZ NPC proliferation.
Chen
Jieli
J
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA. Jieli@neuro.hfh.edu
Zacharek
Alex
A
Li
Ang
A
Cui
Xu
X
Roberts
Cynthia
C
Lu
Mei
M
Chopp
Michael
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D020768:Middle Cerebral Artery / Q000601:surgery; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D053764:Presenilin-1 / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D020521:Stroke / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000072056:Transcription Factor HES-1
D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D051792:Basic Helix-Loop-Helix Proteins; D006538:Heptanoic Acids; D018398:Homeodomain Proteins; D053764:Presenilin-1; D011758:Pyrroles; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat; C497763:Notch1 protein, rat