title: Minocycline Rescues from Zinc-Induced Nigrostriatal Dopaminergic Neurodegeneration: Biochemical and Molecular Interventions.
abstract: Accumulation of zinc (Zn) in dopaminergic neurons is implicated in Parkinson's disease (PD), and microglial activation plays a critical role in toxin-induced Parkinsonism. Oxidative stress is accused in Zn-induced dopaminergic neurodegeneration; however, its connection with microglial activation is still not known. This study was undertaken to elucidate the role and underlying mechanism of microglial activation in Zn-induced nigrostriatal dopaminergic neurodegeneration. Male Wistar rats were treated intraperitoneally with/without zinc sulphate (20 mg/kg) in the presence/absence of minocycline (30 mg/kg), a microglial activation inhibitor, for 2-12 weeks. While neurobehavioral and biochemical indexes of PD and number of dopaminergic neurons were reduced, the number of microglial cells was increased in the substantia nigra of the Zn-exposed animals. Similarly, Zn elevated lipid peroxidation (LPO) and activities of superoxide dismutase (SOD) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; however, catalase activity was reduced. Besides, Zn increased an association of NADPH oxidase subunit p67(phox) with membrane, cytochrome c release from the mitochondria and cleavage of pro-caspase 3. Zn attenuated the expression of tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT-2) while augmented the expression of dopamine transporter (DAT) and heme oxygenase-1 (HO-1). Minocycline alleviated Zn-induced behavioural impairments, loss of TH-positive neurons, activated microglial cells and biochemical indexes and modulated the expression of studied genes/proteins towards normalcy. The results demonstrate that minocycline reduces the number of activated microglial cells and oxidative stress, which rescue from Zn-induced changes in the expression of monoamine transporter and nigrostriatal dopaminergic neurodegeneration.
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, New Delhi, 110 025, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Brajesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, New Delhi, 110 025, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Chauhan
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research, New Delhi, 110 025, India.
authors.forename: Deepali
authors.initials: D
authors.lastname: Singh
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India. singhchetnaitrc@rediffmail.com.|Academy of Scientific and Innovative Research, New Delhi, 110 025, India. singhchetnaitrc@rediffmail.com.
authors.forename: Chetna
authors.initials: C
authors.lastname: Singh
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001522:Behavior, Animal; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D055442:Metabolome; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity; D019255:NADPH Oxidases / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015032:Zinc
chemical_list: D034961:Antigens, Nuclear; D039481:CD11b Antigen; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C546339:Rbfox3 protein, rat; D045304:Cytochromes c; D051547:Heme Oxygenase-1; D014446:Tyrosine 3-Monooxygenase; D019255:NADPH Oxidases; D053148:Caspase 3; D008911:Minocycline; D015032:Zinc; D004298:Dopamine
keywords: Dopaminergic neurodegeneration; Microglia; Minocycline; Oxidative stress; Parkinson’s disease; Zinc