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Nitric oxide-producing microglia mediate thrombin-induced degeneration of dopaminergic neurons in rat midbrain slice culture 香月, 博志 大川原, 賦 柴田, 治樹 久米, 利明 赤池, 昭紀 香月, 博志 カツキ, ヒロシ Katsuki, Hiroshi 香月 カツキ Katsuki 博志 ヒロシ Hiroshi Okawara, Mitsugu Shibata, Haruki 久米, 利明 クメ, トシアキ Kume, Toshiaki 久米 クメ Kume 利明 トシアキ Toshiaki 赤池, 昭紀 アカイケ, アキノリ Akaike, Akinori 赤池 アカイケ Akaike 昭紀 アキノリ Akinori 491.17 Dopamine neuron Inflammation Mitogen-activated protein kinase Neurodegeneration Parkinson's disease application/pdf 論文(Article) Activated microglia are considered to play important roles in degenerative processes of midbrain dopaminergic neurons. Here we examined mechanisms of neurotoxicity of thrombin, a protease known to trigger microglial activation, in organotypic midbrain slice cultures. Thrombin induced a progressive decline in the number of dopaminergic neurons, an increase in nitric oxide (NO) production, and whole tissue injury indicated by lactate dehydrogenase release and propidium iodide uptake. Microglia expressed inducible NO synthase (iNOS) in response to thrombin, and inhibition of iNOS rescued dopaminergic neurons without affecting whole tissue injury. Inhibitors of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) attenuated thrombin-induced iNOS induction and dopaminergic cell death. Whole tissue injury was also attenuated by inhibition of ERK and p38 MAPK. Moreover, depletion of resident microglia from midbrain slices abrogated thrombin-induced NO production and dopaminergic cell death, but did not inhibit tissue injury. Finally, antioxidative drugs prevented thrombin-induced dopaminergic cell death without affecting whole tissue injury. Hence, NO production resulting from MAPK-dependent microglial iNOS induction is a crucial event in thrombin-induced dopaminergic neurodegeneration, whereas damage of other midbrain cells is MAPK-dependent but is NO-independent. http://www.blackwellpublishing.com/jnc_enhanced/ Blackwell Science 2006-06 eng journal article AM http://hdl.handle.net/2298/10009 https://kumadai.repo.nii.ac.jp/records/21866 10.1111/j.1471-4159.2006.03752.x http://hdl.handle.net/2298/9868 00223042 AA00703243 Journal of Neurochemistry 97 5 1232 1242 https://kumadai.repo.nii.ac.jp/record/21866/files/J Neu0097-1232.pdf application/pdf 1.2 MB 2020-03-02