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首页> 外文期刊>The European Journal of Neuroscience >ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice
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ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice

机译：ATP P2Y1受体控制小鼠脑缺血所致的认知缺陷和神经毒性，但不能控制神经胶质的改变

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ATP is a pleiotropic cell-to-cell signaling molecule in the brain that functions through activation of the P2 receptors (P2R), encompassing ionotropic P2XR or metabotropic P2YR. Noxious brain insults increase the extracellular levels of ATP and previous studies have implicated different P2R, namely P2Y1R, in the control of ischemic brain damage, but it remains to be defined if P2Y1R antagonists also alleviate the behavioral impairments associated with brain ischemia. Furthermore, as P2Y1R can control neuronal and glial functions, we explored if P2Y1R antagonist-mediated protection would mainly involve neuronal and/or glial processes. Adult male mice subject to permanent middle cerebral artery occlusion (pMCAO) displayed an infarcted cortical area (2,3,5-triphenyltetrazolium chloride staining), decreased neurological score with decreased working and reference memory performance (Y-maze, object recognition and aversive memory), accompanied by neuronal damage (FluoroJade C), astrogliosis (glial fibrillary acidic protein) and microgliosis (CD11b). All of these changes were attenuated by intracerebroventricular pre-treatment (10 min before pMCAO) with the generic P2R antagonist 4-[(E)-{4-formyl-5-hydroxy-6-methyl-3-[(phosphono-oxy)methyl]pyridin-2-yl}diazenyl]benzene-1,3-disulfonic acid (PPADS, 0.5-1.0 nmol/μL). In contrast, the selective P2Y1R antagonist (1R*,2S*)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphono-oxy)bicycle[3.1.0] hexane-1-methanol dihydrogen phosphate ester (MRS2500, 1.0-2.0 nmol/μL) afforded equivalent behavioral benefits but only prevented neuronal damage but not astrogliosis or microgliosis upon pMCAO. These results indicated that P2Y1R-associated neuroprotection mainly occurred through neuronal mechanisms, whereas other P2R were also involved in the control of astrocytic reactivity upon brain injury. The generic ATP P2 receptor (P2R) antagonist PPADS (1.0 nmol) and the selective P2Y1R antagonist MRS2500 (2.0 nmol, icv) attenuated brain infarct and memory deficits upon brain ischemia (MCAO). PPADS prevented MCAO-induced neuronal damage, astrogliosis and microgliosis, whereas the selective P2Y1R blockade only affected neuronal damage. Thus P2Y1R neuroprotection mainly occurs through neuronal mechanisms, whereas other P2R control astrocytic reactivity upon brain injury.
机译：ATP是大脑中的多效性细胞间信号分子，通过激活P2受体（P2R）起作用，包括离子型P2XR或代谢型P2YR。有害的脑损伤会增加ATP的细胞外水平，以前的研究已经暗示了在缺血性脑损伤的控制中存在不同的P2R（即P2Y1R），但是P2Y1R拮抗剂是否还能减轻与脑缺血有关的行为障碍尚待确定。此外，由于P2Y1R可以控制神经元和神经胶质功能，因此我们探索了P2Y1R拮抗剂介导的保护是否主要涉及神经元和/或神经胶质过程。成年雄性小鼠遭受永久性大脑中动脉闭塞（pMCAO），表现出梗死的皮质区域（2,3,5-三苯基四唑氯化锌染色），神经系统评分降低，工作和参考记忆性能（Y迷宫，物体识别和厌恶记忆）降低），并伴有神经元损伤（FluoroJade C），星形胶质增生（神经胶质纤维酸性蛋白）和小胶质增生（CD11b）。所有这些变化通过通用P2R拮抗剂4-[（E）-{4-甲酰基-5-羟基-6-甲基-3-[（膦酰氧基））脑室内预处理（pMCAO之前10分钟）减弱。甲基]吡啶-2--2-基}二氮烯基]苯-1,3-二磺酸（PPADS，0.5-1.0 nmol /μL）。相反，选择性P2Y1R拮抗剂（1R *，2S *）-4- [2-碘-6-（甲基氨基）-9H-嘌呤-9-基] -2-（膦酰氧基）自行车[3.1.0]己烷-1-甲醇磷酸二氢酯（MRS2500，1.0-2.0 nmol /μL）具有同等的行为优势，但只能预防神经元损伤，而不能预防pMCAO引起的星形胶质变或小胶质变。这些结果表明，P2Y1R相关的神经保护主要通过神经元机制发生，而其他P2R也参与脑损伤后星形胶质反应性的控制。通用ATP P2受体（P2R）拮抗剂PPADS（1.0 nmol）和选择性P2Y1R拮抗剂MRS2500（2.0 nmol，icv）减轻了脑缺血（MCAO）后的脑梗塞和记忆缺陷。 PPADS预防了MCAO诱导的神经元损伤，星形胶质细胞增生和微胶质细胞增生，而选择性P2Y1R阻滞仅影响神经元损伤。因此，P2Y1R神经保护主要通过神经元机制发生，而其他P2R在脑损伤后控制星形胶质细胞反应性。

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