title: Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease.
abstract: Robust epidemiological data link higher levels of the antioxidant urate to a reduced risk of developing Parkinson׳s disease (PD) and to a slower rate of its progression. Allopurinol, an inhibitor of xanthine oxidoreductase (XOR), blocks the oxidation of xanthine to urate. The present study sought to determine whether lowering levels of urate using allopurinol results in exacerbated neurotoxicity in a dual pesticide mouse model of PD. Although oral allopurinol reduced serum and striatal urate levels 4-fold and 1.3-fold, respectively, it did not alter the multiple motor deficits induced by chronic (7 week) intermittent (biweekly) exposure to intraperitoneal Paraquat (PQ) plus Maneb (MB). However, striatal dopamine content, which was unaffected after either allopurinol or chronic pesticide exposure alone, was significantly reduced by 22% in mice exposed to the combination. Stereological assessment showed that the numbers of dopaminergic nigral neurons were significantly reduced by 29% and the tyrosine hydroxylase (TH) negative neurons unaffected after PQ+MB treatments. This reduction in TH-positive neurons was not affected by allopurinol treatment. Of note, despite the expectation of exacerbated oxidative damage due to the reduction in urate, protein carbonyl levels, a marker of oxidative damage, were actually reduced in the presence of allopurinol. Overall, allopurinol lowered urate levels but did not exacerbate dopaminergic neuron degeneration, findings suggesting that basal levels of urate in mice do not appreciably protect against oxidative damage and neurotoxicity in the PQ+MB model of PD, and/or that allopurinol produces an antioxidant benefit offsetting its detrimental urate-lowering effect.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: akach2@gmail.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Kachroo
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008344:Maneb / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology*; D010575:Pesticides / Q000633:toxicity*; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D010575:Pesticides; D008344:Maneb; D014527:Uric Acid; D000493:Allopurinol; D010269:Paraquat; D004298:Dopamine
keywords: Allopurinol; Maneb; Paraquat; Parkinson׳s disease; Urate