Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury.
OBJECTIVE
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.
Zhang
Wen-hua
WH
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, LMRC 113, Boston, MA 02115, USA.
Wang
Hongyan
H
Wang
Xin
X
Narayanan
Malini V
MV
Stavrovskaya
Irina G
IG
Kristal
Bruce S
BS
Friedlander
Robert M
RM
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009661:Nortriptyline / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D018759:Adrenergic Uptake Inhibitors; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D045304:Cytochromes c; D009661:Nortriptyline; D005947:Glucose; D010100:Oxygen; D002118:Calcium