title: Memantine attenuates cell apoptosis by suppressing the calpain-caspase-3 pathway in an experimental model of ischemic stroke.
abstract: Ischemic stroke, the second leading cause of death worldwide, leads to excessive glutamate release, over-activation of N-methyl-D-aspartate receptor (NMDAR), and massive influx of calcium (Ca2+), which may activate calpain and caspase-3, resulting in cellular damage and death. Memantine is an uncompetitive NMDAR antagonist with low-affinity/fast off-rate. We investigated the potential mechanisms through which memantine protects against ischemic stroke in vitro and in vivo. Middle cerebral artery occlusion-reperfusion (MCAO) was performed to establish an experimental model of ischemic stroke. The neuroprotective effects of memantine on ischemic rats were evaluated by neurological deficit scores and infarct volumes. The activities of calpain and caspase-3, and expression levels of microtubule-associated protein-2 (MAP2) and postsynaptic density-95 (PSD95) were determined by Western blotting. Additionally, Nissl staining and immunostaining were performed to examine brain damage, cell apoptosis, and neuronal loss induced by ischemia. Our results show that memantine could significantly prevent ischemic stroke-induced neurological deficits and brain infarct, and reduce ATP depletion-induced neuronal death. Moreover, memantine markedly suppressed the activation of the calpain-caspase-3 pathway and cell apoptosis, and consequently, attenuated brain damage and neuronal loss in MCAO rats. These results provide a molecular basis for the role of memantine in reducing neuronal apoptosis and preventing neuronal damage, suggesting that memantine may be a promising therapy for stroke patients.
authors.affiliation: Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Shanghai Changzheng Hospital, Shanghai 200003, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
authors.forename: Ruhui
authors.initials: R
authors.lastname: Lin
authors.affiliation: Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.affiliation: Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: fjtcm1958@sina.com.
authors.forename: Lidian
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China. Electronic address: yunwang@fudan.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D002536:Cerebral Arteries / Q000601:surgery; D002561:Cerebrovascular Disorders / Q000601:surgery; D003470:Culture Media / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D003470:Culture Media; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C489787:MAP2 protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D005947:Glucose; D008559:Memantine
keywords: Apoptosis; Calpain; Caspase-3; Ischemic stroke; Memantine