Inflammation and B-cell Lymphoma-2 Associated X Protein Regulate Zinc-Induced Apoptotic Degeneration of Rat Nigrostriatal Dopaminergic Neurons.
Clinical evidences showing zinc (Zn) accumulation in the post-mortem brain of Parkinson's disease (PD) patients and experimental studies on rodents chronically exposed to Zn suggested its role in PD. While oxidative stress is implicated in Zn-induced neurodegeneration, roles of inflammation and apoptosis in degeneration of the nigrostriatal dopaminergic neurons have yet been elusive. The present study investigated the contribution of the nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and B-cell lymphoma 2 (Bcl-2) family proteins in Zn-induced Parkinsonism. Male Wistar rats were treated with/without zinc sulfate (Zn; 20 mg/kg, intraperitoneally), twice a week, for 2-12 weeks. In a few sets, animals were treated intraperitoneally with a NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100 mg/kg), a TNF-α inhibitor, pentoxyfylline (PTX; 50 mg/kg), and an anti-inflammatory agent, dexamethasone (DEX; 5 mg/kg), prior to Zn exposure along with respective controls. Zn caused neurobehavioral impairments and reduction in dopamine and its metabolites, tyrosine hydroxylase (TH)-positive neurons, catalase activity, and expression of TH, Bcl-2, and NOXA. On the contrary, Zn augmented lipid peroxidation, activity of superoxide dismutase, expression of TNF-α, IL-1β, Bcl-xl, and p53-upregulated modulator of apoptosis (PUMA), and translocation of NF-κB and Bax from the cytosol to the nucleus and mitochondria, respectively, with concomitant increase in the mitochondrial cytochrome c release and activation of procaspase-3 and -9. Pre-treatment with PTX, DEX, or PDTC invariably ameliorated Zn-induced changes in behavioral and neurodegenerative indexes, inflammatory mediators, and apoptosis. Results demonstrate that inflammation regulates Bax expression that subsequently contributes to the nigrostriatal dopaminergic neurodegeneration.
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
Amit Kumar
AK
Chauhan
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
Namrata
N
Mittra
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
Vinod
V
Kumar
Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
Devendra Kumar
DK
Patel
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India. chetna@iitr.res.in.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India. chetna@iitr.res.in.
Chetna
C
Singh
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D055442:Metabolome; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017072:Neostriatum / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D034961:Antigens, Nuclear; D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; D053583:Interleukin-1beta; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C539472:Pmaip1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C546339:Rbfox3 protein, rat; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D012701:Serotonin; D045304:Cytochromes c; D014446:Tyrosine 3-Monooxygenase; D015032:Zinc; D004298:Dopamine
Apoptosis; Inflammation; Neurodegeneration; Oxidative stress; Zinc