https://scholars.lib.ntu.edu.tw/handle/123456789/564619
標題: | Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl-4-phenylpyridinium-induced neurotoxicity | 作者: | Hung S.-Y. Liou H.-C. Kang K.-H. RUEY-MEEI WU Wen C.-C. WEN-MEI FU |
公開日期: | 2008 | 卷: | 74 | 期: | 6 | 起(迄)頁: | 1564-1575 | 來源出版物: | Molecular Pharmacology | 摘要: | Heme oxygenase-1 (HO-1) is up-regulated in response to oxidative stress and catalyzes the degradation of pro-oxidant heme to carbon monoxide (CO), iron, and bilirubin. Intense HO-1 immunostaining in the Parkinsonian brain is demonstrated, indicating that HO-1 may be involved in the pathogenesis of Parkinsonism. We here locally injected adenovirus containing human HO-1 gene (Ad-HO-1) into rat substantia nigra concomitantly with 1-methyl-4- phenylpyridinium (MPP+). Seven days after injection of MPP + and Ad-HO-1, the brain was isolated for immunostaining and for measurement of dopamine content and inflammatory cytokines. It was found that overexpression of HO-1 significantly increased the survival rate of dopaminergic neurons; reduced the production of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in substantia nigra; antagonized the reduction of striatal dopamine content induced by MPP+; and also up-regulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) expression in substantia nigra. Apomorphine-induced rotation after MPP+ treatment was also inhibited by Ad-HO-1. On the other hand, inhibition of HO enzymatic activity by zinc protoporphyrin-IX facilitated the MPP+-induced rotatory behavior and enhanced the reduction of dopamine content. HO-1 overexpression also protected dopaminergic neurons against MPP+-induced neurotoxicity in midbrain neuron-glia cocultures. Overexpression of HO-1 increased the expression of BDNF and GDNF in astrocytes and BDNF in neurons. Our results indicate that HO-1 induction exerts neuroprotection both in vitro and in vivo. Pharmacological or genetic approaches targeting HO-1 may represent a promising and novel therapeutic strategy in treating Parkinsonism. Copyright ? 2008 The American Society for Pharmacology and Experimental Therapeutics. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/564619 | ISSN: | 0026895X | DOI: | 10.1124/mol.108.048611 | SDG/關鍵字: | 1 methyl 4 phenylpyridinium; adenovirus vector; apomorphine; brain derived neurotrophic factor; dopamine; glial cell line derived neurotrophic factor; heme oxygenase 1; interleukin 1beta; protoporphyrin zinc; tumor necrosis factor alpha; animal cell; animal experiment; animal model; animal tissue; article; cell survival; circling behavior; controlled study; dopaminergic nerve cell; enzyme inhibition; gene; gene overexpression; ho 1 gene; immunohistochemistry; neuroprotection; neurotoxicity; nonhuman; parkinsonism; pathogenesis; priority journal; protein expression; rat; substantia nigra; 1-Methyl-4-phenylpyridinium; Adenoviridae; Animals; Brain-Derived Neurotrophic Factor; Cell Death; Cells, Cultured; Coculture Techniques; Dopamine; Enzyme Induction; Glial Cell Line-Derived Neurotrophic Factor; Heme Oxygenase-1; Humans; Interleukin-1beta; Neuroglia; Neurons; Parkinson Disease, Secondary; Rats; Rats, Wistar; RNA, Messenger; Tumor Necrosis Factor-alpha |
顯示於: | 藥理學科所 |
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