The Journal of Experimental Medicine
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Published 19 July 2004. doi:10.1084/jem.20032053
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 211-222
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Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology

Irina G. Stavrovskaya1, Malini V. Narayanan2, Wenhua Zhang2, Boris F. Krasnikov1, Jill Heemskerk3, S. Stanley Young4, John P. Blass1,5, Abraham M. Brown1,6, M. Flint Beal5, Robert M. Friedlander2, and Bruce S. Kristal1,5,6

1 Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605
2 Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
3 Technology Development, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892
4 CGStat LLC, Raleigh, NC 27607
5 Department of Neurology and Neuroscience and 6 Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

Address correspondence to Bruce Kristal, Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605. Phone: (914) 597-2333; Fax: (914) 597-2757; email: bkristal{at}burke.org

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.

Key Words: caspases • cell death • apoptosis • antidepressants • antipsychotics

Abbreviations used in this paper: CNS, central nervous system; CsA, cyclosporine A; HTPD, heterocyclic, tricyclic, and phenothiazine-derived; LDH, lactate dehydrogenase; MCA, middle cerebral artery; MCAO, MCA occlusion; mPT, mitochondrial permeability transition; OGD, oxygen-glucose deprivation; PLA2, phospholipase A2; SAR, structure–activity relationship.


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