title: Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.
abstract: Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.
authors.affiliation: Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Stavrovskaya
authors.forename: Malini V
authors.initials: MV
authors.lastname: Narayanan
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhang
authors.forename: Boris F
authors.initials: BF
authors.lastname: Krasnikov
authors.forename: Jill
authors.initials: J
authors.lastname: Heemskerk
authors.forename: S Stanley
authors.initials: SS
authors.lastname: Young
authors.forename: John P
authors.initials: JP
authors.lastname: Blass
authors.forename: Abraham M
authors.initials: AM
authors.lastname: Brown
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002463:Cell Membrane Permeability / Q000187:drug effects; D015723:Gene Library; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008930:Mitochondria, Liver / Q000378:metabolism; D008956:Models, Chemical; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011398:Promethazine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D020521:Stroke; D013367:Submitochondrial Particles / Q000187:drug effects; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D002147:Calmodulin; D006634:Histamine H1 Antagonists; D010741:Phospholipases A; D020169:Caspases; D011398:Promethazine; D010100:Oxygen; D002118:Calcium