title: Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse.
abstract: A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30 mg/kg), twice a week, for 9 weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation.
authors.affiliation: CSIR-Indian Institute of Toxicology Research, M. G. Marg, Post Box 80, Lucknow 226 001, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Srivastava
authors.forename: Anubhuti
authors.initials: A
authors.lastname: Dixit
authors.forename: Sharawan
authors.initials: S
authors.lastname: Yadav
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.forename: Mahendra Pratap
authors.initials: MP
authors.lastname: Singh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004298:Dopamine / Q000378:metabolism; D005659:Fungicides, Industrial / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010269:Paraquat / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D005659:Fungicides, Industrial; D006540:Herbicides; D018696:Neuroprotective Agents; D013267:Stilbenes; D008344:Maneb; D003577:Cytochrome P-450 Enzyme System; C414739:Cyp2d22 protein, mouse; D000072467:Cytochrome P450 Family 2; D010269:Paraquat; D000077185:Resveratrol; D004298:Dopamine