Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A_2A 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_2AR) have been found to confer protection in animal models of PD, the dependence of caffeine's neuroprotective effects on the A_2AR is not known. To definitively determine its A_2AR 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_2AR gene global knockout (A_2A KO) mice, as well as in central nervous system (CNS) cell type-specific (conditional) A_2AR knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A_2AR KO mice caffeine pretreatment (25 mg/kg ip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A_2AR global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A_2AR cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A_2AR 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_2AR, although the specific cellular localization of these receptors remains to be determined.