Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology

被引:75
作者
Stavrovskaya, IG
Narayanan, MV
Zhang, WH
Krasnikov, BF
Heemskerk, J
Young, SS
Blass, JP
Brown, AM
Beal, MF
Friedlander, RM
Kristal, BS
机构
[1] Burke Med Res Inst, Dementia Res Serv, White Plains, NY 10605 USA
[2] Brigham & Womens Hosp, Dept Neurosurg, Neuroapoptosis Lab, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA 02115 USA
[4] NINDS, Raleigh, NC 27607 USA
[5] CGStat LLC, Raleigh, NC 27607 USA
[6] Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA
[7] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA
关键词
caspases; cell death; apoptosis; antidepressants; antipsychotics;
D O I
10.1084/jem.20032053
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:211 / 222
页数:12
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