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Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease.
Brain Res. 2014 May 14; 1563:103-9.BR

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+Show Affiliations

MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: akach2@gmail.com.MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

24680743

Citation

Kachroo, Anil, and Michael A. Schwarzschild. "Allopurinol Reduces Levels of Urate and Dopamine but Not Dopaminergic Neurons in a Dual Pesticide Model of Parkinson's Disease." Brain Research, vol. 1563, 2014, pp. 103-9.
Kachroo A, Schwarzschild MA. Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease. Brain Res. 2014;1563:103-9.
Kachroo, A., & Schwarzschild, M. A. (2014). Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease. Brain Research, 1563, 103-9. https://doi.org/10.1016/j.brainres.2014.03.031
Kachroo A, Schwarzschild MA. Allopurinol Reduces Levels of Urate and Dopamine but Not Dopaminergic Neurons in a Dual Pesticide Model of Parkinson's Disease. Brain Res. 2014 May 14;1563:103-9. PubMed PMID: 24680743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease. AU - Kachroo,Anil, AU - Schwarzschild,Michael A, Y1 - 2014/03/26/ PY - 2013/10/04/received PY - 2014/03/03/revised PY - 2014/03/19/accepted PY - 2014/4/1/entrez PY - 2014/4/1/pubmed PY - 2014/12/15/medline KW - Allopurinol KW - Maneb KW - Paraquat KW - Parkinson׳s disease KW - Urate SP - 103 EP - 9 JF - Brain research JO - Brain Res VL - 1563 N2 - 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. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/24680743/Allopurinol_reduces_levels_of_urate_and_dopamine_but_not_dopaminergic_neurons_in_a_dual_pesticide_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(14)00393-X DB - PRIME DP - Unbound Medicine ER -