Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A2A receptors.
Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A2A receptors.
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DOI：
10.1016/j.neuroscience.2016.02.035
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发表时间：
2016-05-13
期刊：
影响因子：
3.3
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
--
作者：
Xu K;Di Luca DG;Orrú M;Xu Y;Chen JF;Schwarzschild MA
大量流行病学和实验室数据表明，咖啡因（一种非选择性腺苷受体拮抗剂）可以预防帕金森病 (PD) 的潜在神经退行性变。尽管咖啡因和 A2A 腺苷受体 (A2AR) 亚型更特异的拮抗剂已被发现对 PD 动物模型具有保护作用，但咖啡因的神经保护作用对 A2AR 的依赖性尚不清楚。为了明确确定其 A2AR 依赖性，在野生型 (WT) 和 A2AR 基因整体敲除 (A2A KO) 小鼠以及出生后前脑神经元或星形胶质细胞中缺乏受体的中枢神经系统细胞类型特异性（条件性）A2AR 敲除 (cKO) 小鼠中比较了咖啡因对 MPTP 神经毒性的影响。在 WT 和杂合 A2AR KO 小鼠中，咖啡因预处理（25 mg/kg ip）显着减弱了 MPTP 诱导的纹状体多巴胺消耗。相比之下，在纯合 A2AR 全基因敲除小鼠中，咖啡因对 MPTP 毒性没有影响。在前脑神经元 A2AR cKO 小鼠中，咖啡因失去了其运动兴奋作用，而其神经保护作用大部分保留了下来。在星形细胞 A2AR cKO 小鼠中，咖啡因的运动兴奋剂和保护作用均未减弱。综上所述，这些结果表明咖啡因在 PD MPTP 模型中的神经保护作用依赖于 A2AR，尽管这些受体的具体细胞定位仍有待确定。
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.