Inhibition of nNOS reduces ischemic cell death through down-regulating calpain and caspase-3 after experimental stroke |
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| Authors: | Ming Sun Yumei Zhao Yi Gu Chao Xu |
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| Institution: | 1. Department of Food and Nutrition,College of Human Ecology, Yonsei University, Seoul 120-749, Republic of Korea;2. Department of Food and Nutrition, Korea University, Seoul 136-703, Republic of Korea;3. Cardiology Division, Yonsei Cardiovascular Hospital and Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea;4. Department of Food and Nutrition, Changwon National University, Changwon 641-773, Republic of Korea;1. Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, CS, Italy;2. Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan;1. Department of Neurology, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico;2. Clinical Translational Research Center, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico;1. Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA;2. Gerontology Institute, Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China;3. Department of Physics, Oakland University, Rochester, MI, 48309, USA |
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| Abstract: | In vitro nitric oxide (NO) regulates calpain and caspase-3 activation, and in vivo neuronal nitric oxide synthase (nNOS), calpain and caspase-3 participate in the ischemic brain injury. Our objective was to investigate whether nNOS was involved in the ischemic brain injury through activating calpain and caspase-3 during experimental stroke. Rats received 1-h ischemia by intraluminant filament, and then reperfused for 23 h (R 23 h). nNOS inhibitor 7-nitroindozale (7-NI, 50 mg/kg) was administrated intraperitoneally 5 min before ischemia. Our data showed that treatment with 7-NI markedly reduced neurological deficits, the brain swelling, and the infarct volume at R 23 h. Enzyme studies revealed significant suppression of the activities of m-calpain and caspase-3 in penumbra and core, and the activities of μ-calpain in penumbra, but not in core, in 7-NI-treated rats versus vehicle-treated rats. Western blot analysis demonstrated that 7-NI markedly increased the levels of MAP-2 and spectrin in penumbra and core compared with vehicle-treated rats. Histopathological studies displayed that 7-NI significantly reduced the necrotic cell death in penumbra and core, and apoptotic cell death in penumbra, but not in core. These data demonstrate the involvement of NO produced by nNOS in the ischemic neuronal injury through affecting the activation of calpain and caspase-3 in penumbra and core after experimental stroke, which provides a new perspective on possible mechanisms of action of nNOS inhibition in cerebral ischemia. |
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