title: Cyclooxygenase-2 Directs Microglial Activation-Mediated Inflammation and Oxidative Stress Leading to Intrinsic Apoptosis in Zn-Induced Parkinsonism.
abstract: Inflammation is decisive in zinc (Zn)-induced nigrostriatal dopaminergic neurodegeneration; however, the contribution of cyclooxygenase-2 (COX-2) is not yet known. The present study aimed to explore the role of COX-2 in Zn-induced Parkinsonism and its association with the microglial activation. Male Wistar rats were treated intraperitoneally (i.p.) with Zn as zinc sulphate (20 mg/kg) along with respective controls for 2-12 weeks. In a few sets, animals were also treated with/without celecoxcib (CXB, 20 mg/kg, i.p.), a selective COX-2 inhibitor. Indexes of the nigrostriatal neurodegeneration, oxidative stress, inflammation and apoptosis were measured in the animals/nigrostriatal tissue. Zn induced time-dependent increase in the expression of COX-2 while COX-1 expression was unaltered. Zn reduced the neurobehavioral activities, striatal dopamine content, tyrosine hydroxylase (TH) expression and number of dopaminergic neurons. While oxidative stress; microglial activation; expression of microglial cell surface marker-CD11b; cytochrome c release; caspase-9/3 activation; level of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6 and Bcl-2-associated protein x (Bax) translocation from the cytosol to mitochondria were induced in the Zn-treated group, expression of B-cell lymphoma-2 (Bcl-2) was found to be reduced. CXB significantly attenuated Zn-induced increase in COX-2 expression and restored TH-expression, dopamine content, level of inflammatory cytokines and neurobehavioral indexes towards normalcy. Moreover, CXB also attenuated Zn-induced increase in microglial activation, oxidative stress and apoptotic markers towards normal levels. Results of the study thus demonstrate that COX-2 induces microglial activation that provokes the release of inflammatory mediators, which in turn augments oxidative stress and intrinsic apoptosis leading to dopaminergic neurodegeneration in Zn-induced Parkinsonism.
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, Uttar Pradesh, 226 001, India.|CSIR-IITR Campus, Academy of Scientific and Innovative Research, Lucknow, Uttar Pradesh, 226 001, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Chauhan
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, Uttar Pradesh, 226 001, India.|CSIR-IITR Campus, Academy of Scientific and Innovative Research, Lucknow, Uttar Pradesh, 226 001, India.
authors.forename: Namrata
authors.initials: N
authors.lastname: Mittra
authors.affiliation: Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226 001, India.
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
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, Uttar Pradesh, 226 001, India. chetna@iitr.res.in.|CSIR-IITR Campus, Academy of Scientific and Innovative Research, Lucknow, Uttar Pradesh, 226 001, India. chetna@iitr.res.in.
authors.forename: Chetna
authors.initials: C
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015032:Zinc / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; D051546:Cyclooxygenase 2; D015032:Zinc
keywords: Cyclooxygenase-2; Neuroinflammation; Nigrostriatal dopaminergic neurodegeneration; Oxidative stress; Zinc