Nortriptyline Protects Mitochondria and Reduces Cerebral Ischemia/Hypoxia Injury

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.

[1]  S. Korsmeyer,et al.  Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Bernardi,et al.  Properties of the Permeability Transition Pore in Mitochondria Devoid of Cyclophilin D* , 2005, Journal of Biological Chemistry.

[3]  A. Halestrap,et al.  A pore way to die , 2005 .

[4]  Jeffrey Robbins,et al.  Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death , 2005, Nature.

[5]  Tetsuya Watanabe,et al.  Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death , 2005, Nature.

[6]  M. Crompton,et al.  Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. , 2004, The Biochemical journal.

[7]  M. Beal,et al.  Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology , 2004, The Journal of experimental medicine.

[8]  Robert H. Brown,et al.  Prophylactic Creatine Administration Mediates Neuroprotection in Cerebral Ischemia in Mice , 2004, The Journal of Neuroscience.

[9]  Nicholls Dg.  Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. , 2004, Current molecular medicine.

[10]  D. Nicholls.  Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. , 2004, Current molecular medicine.

[11]  B. Kristal,et al.  Promethazine: a novel application as a neuroprotectant that reduces ischemia-mediated injury by inhibiting mitochondrial dysfunction. , 2004, Clinical neurosurgery.

[12]  John Calvin Reed,et al.  Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Changlian Zhu,et al.  Mitochondria and ischemic reperfusion damage in the adult and in the developing brain. , 2003, Biochemical and biophysical research communications.

[14]  Eugene M. Johnson,et al.  Cyclosporin A inhibits caspase-independent death of NGF-deprived sympathetic neurons , 2002, The Journal of cell biology.

[15]  Betty Y. S. Kim,et al.  Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice , 2002, Nature.

[16]  T. Wieloch,et al.  Mitochondrial permeability transition in acute neurodegeneration. , 2002, Biochimie.

[17]  N. Plesnila,et al.  BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  G. Rosoklija,et al.  Recruitment of the Mitochondrial-Dependent Apoptotic Pathway in Amyotrophic Lateral Sclerosis , 2001, The Journal of Neuroscience.

[19]  B. Kristal,et al.  Apoptogenic Ganglioside GD3 Directly Induces the Mitochondrial Permeability Transition* , 1999, The Journal of Biological Chemistry.

[20]  T. Wieloch,et al.  Blockade of the Mitochondrial Permeability Transition Pore Diminishes Infarct Size in the Rat after Transient Middle Cerebral Artery Occlusion , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  L. Scorrano,et al.  The mitochondrial permeability transition , 2022, BioFactors.

[22]  G. Kroemer,et al.  Disruption of the outer mitochondrial membrane as a result of large amplitude swelling: the impact of irreversible permeability transition , 1998, FEBS letters.

[23]  D. Zorov,et al.  The Ca2+‐induced pore opening in mitochondria energized by succinate‐ferricyanide electron transport , 1997, FEBS letters.

[24]  B. Kristal,et al.  Mitochondrial Permeability Transition in the Central Nervous System: Induction by Calcium Cycling‐Dependent and ‐Independent Pathways , 1997, Journal of neurochemistry.

[25]  C. Piantadosi,et al.  Release of cytochrome c from liver mitochondria during permeability transition. , 1997, Biochemical and biophysical research communications.

[26]  M. Moskowitz,et al.  Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Moskowitz,et al.  Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury , 1997, The Journal of experimental medicine.

[28]  J. Lemasters,et al.  Cyclosporin A delays mitochondrial depolarization induced by N-methyl-D-aspartate in cortical neurons: evidence of the mitochondrial permeability transition. , 1996, Neuroscience.

[29]  A. F. Schinder,et al.  Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity , 1996, The Journal of Neuroscience.

[30]  G. Kroemer,et al.  Bcl-2 inhibits the mitochondrial release of an apoptogenic protease , 1996, The Journal of experimental medicine.

[31]  K. Gunter,et al.  Mitochondrial calcium transport: physiological and pathological relevance. , 1994, The American journal of physiology.

[32]  L. Scorrano,et al.  The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. , 1994, The Journal of biological chemistry.