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(Stroke. 2008;39:455.)
© 2008 American Heart Association, Inc.

Original Contributions

Nortriptyline Protects Mitochondria and Reduces Cerebral Ischemia/Hypoxia Injury

Wen-hua Zhang, MD; Hongyan Wang, PhD; Xin Wang, PhD; Malini V. Narayanan, MD; Irina G. Stavrovskaya, PhD; Bruce S. Kristal, PhD Robert M. Friedlander, MD, MS

From the Neuroapoptosis Laboratory (W.Z., H.W., X.W., M.V.N., R.M.F.), Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Department of Neurosurgery (W.Z.), Qilu Hospital, Shandong University, Jinan, China; Burke Medical Research Institute (I.G.S., B.S.K.), White Plains, NY; and the Department of Neuroscience (B.S.K.), Weill Medical College of Cornell University, New York, NY.

Correspondence to Robert M. Friedlander, MD, MS, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, LMRC 113, Boston, MA 02115. E-mail rfriedlander{at}rics.bwh.harvard.edu

Background and Purpose— Nortriptyline, an antidepressant, was identified as a strong inhibitor of mitochondrial permeability transition by our screening of a library of 1040 drugs. Because mitochondrial permeability transition and consequent mitochondrial dysfunction have been implicated in acute neuronal death, we proposed to investigate the possible neuroprotective effects of nortriptyline in cerebral ischemia.

Methods— The effects of nortriptyline were first studied in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons, a cellular model of cerebral ischemia. Mitochondrial membrane potential, mitochondrial factor release, and caspase 3 activation were evaluated after its treatment. Nortriptyline was also studied in a mouse model, which was established by occlusion of the middle cerebral artery. The infarct volume, neurological function, and biochemical events were examined in the absence or the presence of nortriptyline.

Results— Nortriptyline inhibits oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, downstream release of mitochondrial factors, and activation of caspase 3 in primary cerebrocortical neurons. Furthermore, it decreases infarct size and improves neurological scores after middle cerebral artery occlusion in mice.

Conclusions— The ability of nortriptyline to inhibit mitochondrial factor release and caspase activation and further protect the animals correlates to its inhibitory effect on mitochondrial permeability transition in isolated mitochondria. This study indicated that nortriptyline is neuroprotective against cerebral ischemia. It also suggested mitochondrial permeability transition might be a valuable therapeutic target for acute neurodegeneration.

Key Words: cell death • cerebral ischemia • mitochondrial permeability transition • neuroprotection • nortriptyline

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