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 MPTP neurotoxicity was compared in wild-type (WT) and A2AR gene global knockout (A2A KO) mice, as well as in 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 (25 mg/kg ip) 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.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…We demonstrate that glial α-synuclein forms inclusions, increases aggre- & Gestal-Otero, 2002;Noyce et al, 2012). Adenosine A2A receptor knockout mice are protected in animal models of PD (Kachroo & Schwarzschild, 2012;Xu et al, 2016), and adenosine antagonists are in clinical used for Parkinson's disease in Japan (Kondo, Mizuno,, & Japanese Istradefylline Study Group, 2015). Nt5e expression is altered in PD post-mortem brains (Garcia-Esparcia, Hernández-Ortega, Ansoleaga, Carmona, & Ferrer, 2015).…”

How does adenosine control neuronal dysfunction and neurodegeneration?

“…; Xu et al . ), pointing toward a possible role of glial A 2A R in the exacerbation of brain damage (Yu et al . ; Rebola et al .…”

“…Some studies reported that the selective elimination of A 2A R from forebrain neurons was ineffective to afford neuroprotection (Huang et al 2006;Xu et al 2016), pointing toward a possible role of glial A 2A R in the exacerbation of brain damage (Yu et al 2008;Rebola et al 2011;Orr et al 2015). Indeed, A 2A R are located in astrocytes (Nishizaki et al 2002;Lee et al 2003a;Yu et al 2008;Matos et al 2012aMatos et al ,b, 2015Orr et al 2015) and microglia (Saura et al 2005;Rebola et al 2011;Madeira et al 2015), where they exert numerous effects ranging from the control of glutamate uptake (Nishizaki et al 2002;Matos et al 2012a,b), metabolism , iNOS induction and NO formation (Brodie et al 1998;Saura et al 2005;Merighi et al 2015), and release of cytokines Rebola et al 2011;Madeira et al 2015;Newell et al 2015), of neurotrophins and of growth factors (Heese et al 1997;Brambilla et al 2003;Gomes et al 2013;George et al 2015) to name a few.…”

New Pharmacological Approaches to Treating Non-Motor Symptoms of Parkinson’s Disease

“…Based on its binding profile and clinical effects of other adenosine antagonists, JNJ-40255293 may help alleviate fatigue in PD patients in a similar manner to istradefylline and caffeine. Whether selective adenosine antagonists potentially share the disease modifying or neuroprotective benefits in PD that have been attributed to caffeine is yet to be determined [67]. …”