title: Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A2A receptors.
abstract: 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 A2A subtype of adenosine receptor (A2AR) have been found to confer protection in animal models of PD, the dependence of caffeine's neuroprotective effects on the A2AR is not known. To definitively determine its A2AR 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 A2AR gene global knockout (A2A KO) mice, as well as in central nervous system (CNS) cell type-specific (conditional) A2AR knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A2AR KO mice caffeine pretreatment (25mg/kgip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A2AR global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A2AR cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A2AR 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 A2AR, although the specific cellular localization of these receptors remains to be determined.
authors.affiliation: Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: kuixu@hotmail.com.
authors.forename: K
authors.initials: K
authors.lastname: Xu
authors.affiliation: Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: dilucadaniel@gmail.com.
authors.forename: D G
authors.initials: DG
authors.lastname: Di Luca
authors.affiliation: Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: orrumarco@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Orrú
authors.affiliation: Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: xuy@helix.mgh.harvard.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurology, 715 Albany Street, C314, Boston University School of Medicine, Boston, MA 02118, United States. Electronic address: chenjf@bu.edu.
authors.forename: J-F
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: michaels@helix.mgh.harvard.edu.
authors.forename: M A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D004298:Dopamine
keywords: MPTP; adenosine A(2A) receptors; caffeine; neuroprotection; parkinson’s disease