title: Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity.
abstract: Exercise induces oxidative stress, which may activate adaptive antioxidant responses. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the defense of oxidative stress by regulating the expression of antioxidant enzymes, gamma-glutamylcysteine ligase (γGCL) and heme oxygenase-1 (HO-1). We investigated whether treadmill exercise protects dopaminergic neurons by regulating the Nrf2 antioxidant system in a 1-methyl-4-phenylpyridine (MPP(+))-induced parkinsonian rat model. We found that MPP(+) induced early decreases in total glutathione level and Nrf2/γGCLC (catalytic subunit of γGCL) expression, but late upregulation of HO-1 expression in association with loss of nigral dopaminergic neurons and downregulation of tyrosine hydroxylase and dopamine transporter expression in the striatum. Treadmill exercise for 4weeks induced upregulation of Nrf2 and γGCLC expression, and also prevented the MPP(+)-induced downregulation of Nrf2/γGCLC/glutathione, HO-1 upregulation, and nigrostriatal dopaminergic neurodegeneration. Moreover, the protective effect of exercise was blocked by the knockdown of Nrf2 using a lentivirus-carried shNrf2 delivery system. These results demonstrate an essential role of Nrf2 in the exercise-mediated protective effect that exercise enhances the nigrostriatal Nrf2 antioxidant defense capacity to protect dopaminergic neurons against the MPP(+)-induced toxicity.
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Tsou
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Shih
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Ching
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Jui-Yen
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Chauying J
authors.initials: CJ
authors.lastname: Jen
authors.affiliation: Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Lung
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Fong-Sen
authors.initials: FS
authors.lastname: Wu
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: jichuang@mail.ncku.edu.tw.
authors.forename: Jih-Ing
authors.initials: JI
authors.lastname: Chuang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000534:rehabilitation; D018384:Oxidative Stress / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat
keywords: Dopaminergic neurons; HO-1; MPP(+); Nrf2; Parkinson's disease; Treadmill exercise; γGCLC