The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha.
No neuroprotective compounds are clinically available for the treatment of ischemic stroke. The potential salutary effect of pifithrin alpha, a novel-specific inhibitor of the transcription factor p53, administered 1-6 h following focal reversible cerebral ischemia, was investigated. Studies measuring histological, motor, and behavioral outcomes showed significant improvements in pifithrin alpha-treated animals. Pifithrin alpha reduced the number of apoptotic cells in the ischemic brain by inhibiting the binding of p53 to its DNA sites as it reduced the expression of the p53-related gene p21(WAF) without changing the amount of p53 protein itself.
Leker
Ronen R
RR
Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hebrew University-Hadassah Medical School, Hadassah University Hospital, Ein Kerem, Jerusalem 91120, Israel. lekerr@nih.ninds.gov
Aharonowiz
Michal
M
Greig
Nigel H
NH
Ovadia
Haim
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D004185:Disability Evaluation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052160:Benzothiazoles; D018696:Neuroprotective Agents; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin