title: Mitochondrial dysfunction and oxidative stress promote apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade following chronic rotenone intoxication in rats.
abstract: Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2-4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade.
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Tsu-Kung
authors.initials: TK
authors.lastname: Lin
authors.affiliation: Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Ching-Hsiao
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Shang-Der
authors.identifier: 0000-0001-7879-2579
authors.initials: SD
authors.lastname: Chen
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liou
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Chi-Ren
authors.initials: CR
authors.lastname: Huang
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.|Department of Biological Science, National Sun Yet-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Yao-Chung
authors.initials: YC
authors.lastname: Chuang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism*; D007306:Insecticides / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000009:adverse effects* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494828:Bax protein, rat; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D007306:Insecticides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D012402:Rotenone; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3