title: Neuronal Nitric Oxide Synthase Negatively Regulates Zinc-Induced Nigrostriatal Dopaminergic Neurodegeneration.
abstract: The study aimed to investigate the role of NO and neuronal NO synthase (nNOS) in Zn-induced neurodegeneration. Animals were treated with zinc sulfate (20 mg/kg), twice a week, for 2-12 weeks along with control. In a few sets, animals were also treated with/without a NO donor, sodium nitroprusside (SNP), or S-nitroso-N-acetyl penicillamine (SNAP) for 12 weeks. Moreover, human neuroblastoma (SH-SY-5Y) cells were also employed to investigate the role of nNOS in Zn-induced toxicity in in vitro in the presence/absence of nNOS inhibitor, 7-nitroindazole (7-NI). Zn caused time-dependent reduction in nitrite content and total/nNOS activity/expression. SNP/SNAP discernibly alleviated Zn-induced neurobehavioral impairments, dopaminergic neurodegeneration, tyrosine hydroxylase (TH) expression, and striatal dopamine depletion. NO donors also salvage from Zn-induced increase in lipid peroxidation (LPO), mitochondrial cytochrome c release, and caspase-3 activation. While Zn elevated LPO content, it attenuated nitrite content, nNOS activity, and glutathione level along with the expression of TH and nNOS in SH-SY-5Y cells. 7-NI further augmented Zn-induced changes in the cell viability, oxidative stress, and expression of TH and nNOS. The results obtained thus demonstrate that Zn inhibits nNOS that partially contributes to an increase in oxidative stress, which subsequently leads to the nigrostriatal dopaminergic neurodegeneration.
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Brajesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Chauhan
authors.affiliation: Phototoxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-IITR, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Dwivedi
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Deepali
authors.initials: D
authors.lastname: Singh
authors.affiliation: Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-IITR, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
authors.affiliation: Phototoxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-IITR, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Ratan Singh
authors.initials: RS
authors.lastname: Ray
authors.affiliation: Department of Biotechnology, Jamia Hamdard Deemed University, New Delhi, 110 062, Delhi, India.
authors.forename: Swatantra Kumar
authors.initials: SK
authors.lastname: Jain
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, 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.
authors.forename: Chetna
authors.initials: C
authors.lastname: Singh
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000473:pathology*; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015032:Zinc / Q000009:adverse effects*
chemical_list: D007191:Indazoles; D020030:Nitric Oxide Donors; D009573:Nitrites; D009599:Nitroprusside; D026423:S-Nitroso-N-Acetylpenicillamine; D045304:Cytochromes c; D052248:Nitric Oxide Synthase Type I; D014446:Tyrosine 3-Monooxygenase; D053148:Caspase 3; D005978:Glutathione; D015032:Zinc; C080122:7-nitroindazole
keywords: Dopaminergic neurodegeneration; Neuronal nitric oxide synthase; Nitric oxide; Oxidative stress; Zinc