Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor
Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor
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DOI：
10.1038/jcbfm.2014.45
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发表时间：
2014-06-01
影响因子：
6.3
通讯作者：
Sironi, Luigi
中科院分区：
文献类型：
--
作者：
Gelosa, Paolo;Lecca, Davide;Sironi, Luigi
ADP反应性P2 Y（12）受体在血小板和小胶质细胞上表达。临床数据显示，替格瑞洛（一种直接作用的可逆结合P2 Y（12）受体拮抗剂）可减少包括卒中在内的总心血管事件。在本研究中，我们研究了永久性大脑中动脉闭塞（MCAo）的Sprague-Dawley大鼠脑损伤中P2 Y（12）受体的表达和替格瑞洛的作用。在MCAo后10分钟、22小时和36小时用替格瑞洛3 mg/kg或媒介物经口处理大鼠，并在48小时后处死。免疫荧光分析显示P2 Y（12）受体的缺血相关调节，其在lba 1（+）静息小胶质细胞中组成性表达。MCAo后，活化的小胶质细胞主要集中在病变周围，缺血核心内存在较少的细胞。替格瑞洛显著减弱了MCAo后2、24和48小时通过磁共振成像（MRI）评估的缺血性损伤的进展，表达小胶质细胞/单核细胞标志物艾德-1的浸润细胞的数量，促炎介质的脑表达，（白细胞介素1（IL-1）、单核细胞趋化蛋白1（MCP-1）、一氧化氮合酶（iNOS））和相关的神经损伤。在转基因荧光报告基因CX 3CR 1-绿色荧光蛋白（GFP）小鼠中，MCAo后72小时，替格瑞洛显著减少GFP（+）小胶质细胞以及早期和晚期浸润的血源性细胞。在原代培养的小胶质细胞中，替格瑞洛完全抑制ADP诱导的趋化性（P < 0.01）。我们的研究结果表明，替格瑞洛对缺血诱导的脑损伤具有保护作用，这种作用至少部分是通过抑制P2 Y（12）介导的小胶质细胞活化和趋化性介导的。
The ADP-responsive P2Y(12) receptor is expressed on both platelets and microglia. Clinical data show that ticagrelor, a direct-acting, reversibly binding P2Y(12)-receptor antagonist, reduces total cardiovascular events, including stroke. In our present study, we investigated the expression of P2Y(12) receptors and the effects of ticagrelor on brain injury in Sprague-Dawley rats subjected to a permanent middle cerebral artery occlusion (MCAo). Rats were treated per os with ticagrelor 3 mg/kg or vehicle at 10 minutes, 22; and 36 hours after MCAo and killed after 48 hours. lmmunofluorescence analysis showed an ischemia-related modulation of the P2Y(12) receptor, which is constitutively expressed in lba1(+) resting microglia. After MCAo, activated microglia was mainly concentrated around the lesion, with fewer cells present inside the ischemic core. Ticagrelor significantly attenuated the evolution of ischemic damage evaluated by magnetic resonance imaging (MRI) at 2, 24, and 48 hours after MCAo-, the number of infiltrating cells expressing the microglia/monocyte marker ED-1, the cerebral expression of proinflammatory mediators (interleukin 1 (IL-1), monocyte chemoattractant protein 1 (MCP-1), nitric oxide synthase (iNOS)) and the associated neurologic impairment. In transgenic fluorescent reporter CX3CR1-green fluorescent protein (GFP) mice, 72 hours after MCAo, ticagrelor markedly reduced GFP(+) microglia and both early and late infiltrating blood-borne cells. Finally, in primary cultured microglia, ticagrelor fully inhibited ADP-induced chemotaxis (P < 0.01). Our results show that ticagrelor is protective against ischemia-induced cerebral injury and this effect is mediated, at least partly, by inhibition of P2Y(12)-mediated microglia activation and chemotaxis.