Neuroprotection by caffeine in the MPTP model of parkinson’s disease and its dependence on adenosine A2A receptors.

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. [ABSTRACT FROM AUTHOR]