Journal
NEUROSCIENCE
Volume 322, Issue -, Pages 129-137Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2016.02.035
Keywords
adenosine A(2A) receptors; MPTP; caffeine; neuroprotection; parkinson's disease
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Funding
- NIH [5R01ES010804, 5K24NS60991]
- DOD grant [W81XWH-11-1-0150]
- parkinson's disease Foundation
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Considerable epidemiological and laboratory data have suggested that caffeine, a nonselective adenosine receptor antagonist, may protect against the underlying neurodegeneration of parkinson's disease (PD). Although both caffeine and more specific antagonists of the A(2A) subtype of adenosine receptor (A(2A)R) have been found to confer protection in animal models of PD, the dependence of caffeine's neuroprotective effects on the A(2A)R is not known. To definitively determine its A(2A)R dependence, the effect of caffeine on 1-methyl-4-phenyl-1,2,3,6 tetra-hydropyridine (MPTP) neurotoxicity was compared in wild-type (WT) and A(2A)R gene global knockout (A(2A) KO) mice, as well as in central nervous system (CNS) cell type-specific (conditional) A(2A)R knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A(2A)R KO mice caffeine pretreatment (25 mg/kg ip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A(2A)R global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A(2A)R cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A(2A)R cKO mice, both caffeine's locomotor stimulant and protective properties were undiminished. Taken together, these results indicate that neuroprotection by caffeine in the MPTP model of PD relies on the A(2A)R, although the specific cellular localization of these receptors remains to be determined. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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