title: Involvement of NADPH oxidase and glutathione in zinc-induced dopaminergic neurodegeneration in rats: similarity with paraquat neurotoxicity.
abstract: An association between excessive zinc (Zn) accumulation in brain and incidences of Parkinson's disease (PD) has been shown in several epidemiological and experimental investigations. The involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and glutathione (GSH) in the pathogenesis of PD has also been proposed in a few studies. Despite the implicated role of oxidative stress in PD, the entire mechanism of Zn-induced dopaminergic neurodegeneration has not yet been clearly understood. The present study aimed to investigate the involvement of NADPH oxidase and GSH in Zn-induced dopaminergic neurodegeneration and also to assess its similarity with paraquat (PQ)-induced rat model of PD. Male Wistar rats were treated either with Zn (20 mg/kg; i.p.) or PQ (5 mg/kg; i.p.) in the presence and absence of NADPH oxidase inhibitor, apocynin (10 mg/kg; i.p.) and a GSH precursor, N-acetyl cysteine (NAC; 200 mg/kg; i.p.) either alone or in combination along with the respective controls. Apocynin and/or NAC pre-treatment significantly alleviated Zn- and PQ-induced changes in neurobehavioral deficits, number of dopaminergic neurons and contents of the striatal dopamine and its metabolites. Apocynin and/or NAC also mitigated Zn- and PQ-induced alterations in oxidative stress, NADPH oxidase activation and cytochrome c release, caspases-9 and -3 activation and CD11b expression. The results obtained thus suggest that Zn induces oxidative stress via the activation of NADPH oxidase and depletion of GSH, which in turn activate the apoptotic machinery leading to dopaminergic neurodegeneration similar to PQ.
authors.affiliation: Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow-226001, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Brajesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.forename: Israr
authors.initials: I
authors.lastname: Ahmad
authors.forename: Smriti
authors.initials: S
authors.lastname: Shukla
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
authors.forename: Garima
authors.initials: G
authors.lastname: Srivastava
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Haushila Prasad
authors.initials: HP
authors.lastname: Pandey
authors.forename: Chetna
authors.initials: C
authors.lastname: Singh
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D039481:CD11b Antigen / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000098:Acetophenones; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; C079789:neutrophil cytosol factor 67K; D012701:Serotonin; D045304:Cytochromes c; C056165:acetovanillone; D014446:Tyrosine 3-Monooxygenase; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020169:Caspases; D005978:Glutathione; D010269:Paraquat; D004298:Dopamine; D000111:Acetylcysteine