Activation of adenosine A3 receptors reduces ischemic brain injury in rodents
Activation of adenosine A3 receptors reduces ischemic brain injury in rodents
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DOI：
10.1002/jnr.21071
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发表时间：
2006-12-01
影响因子：
4.2
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Chen, Guann-Juh;Harvey, Brandon K.;Wang, Yun
腺苷A3受体（A3R）激动剂已被证明可以减轻心肺损伤，但A3R激动剂在中枢神经系统中的保护作用尚未得到很好的表征。选择性A3R激动剂氯- n -6-（3-碘苄基）-腺苷-5'- n -甲基脲胺（CI-IB-MECA）的保护作用首次在原代皮质培养中进行了研究。在皮质培养中，CI-IB-MECA预处理可拮抗缺氧介导的细胞活力下降。在体内，给麻醉大鼠脑室内或静脉注射Cl-IB-MECA或载药。用短暂性大脑中动脉结扎法诱导动物局灶性脑缺血。脑室内或反复静脉给药（即在MCA结扎前165分钟和15分钟）CI-IB-MECA不会改变缺血期间的血压，但会增加运动活动，并在2天后减少脑梗死。在这些动物中，CI-IB-MECA还降低了受损皮质中TUNEL标记的密度。在A3R基因敲除小鼠中进一步研究了内源性神经保护的可能性。MCA结扎后，与A3R野生型对照相比，A3R敲除组脑梗死发生率增加，提示A3R在缺血时被强直激活。此外，用Cl-IB-MECA脑室内预处理可以减少野生型对照组的梗死大小，但在A3R敲除动物中没有，这表明Cl-IB-MECA诱导的保护是通过A3受体介导的。综上所述，这些数据表明CI-IB-MECA通过激活A3Rs和抑制细胞凋亡来减少脑梗死。(c) 2006 Wiley-Liss, Inc。
Adenosine A3 receptor (A3R) agonists have been shown to reduce cardiac and lung injury, but the protective roles of A3R agonists in the CNS are not well characterized. The protective effect of selective A3R agonist chloro-N-6-(3-iodo-benzyl)-adenosine-5'-N-methyluronamide (CI-IB-MECA) was first examined in primary cortical cultures. In cortical culture, CI-IB-MECA pretreatment antagonized the hypoxia-mediated decrease in cell viability. In vivo, Cl-IB-MECA or vehicle was given intracerebroventricularly or intravenously to anesthetized rats. Animals were subjected to focal cerebral ischemia induced by transient middle cerebral artery (MCA) ligation. Intracerebroventricular or repeated intravenous administration (i.e., at 165 min and 15 min before MCA ligation) of CI-IB-MECA did not alter blood pressure during ischemia but increased locomotor activity and decreased cerebral infarction 2 days after. In these animals, CI-IB-MECA also reduced the density of TUNEL labeling in the lesioned cortex. The possibility of endogeneous neuroprotection was further examined in A3R knockout mice. After MCA ligation, an increase in cerebral infarction was found in the A3R knockouts compared with the A3R wild-type controls, suggesting that A3Rs are tonically activated during ischemia. Additionally, intracerebroventricular pretreatment with Cl-IB-MECA decreased the size of infarction in the wild-type controls, but not in the A3R knockout animals, suggesting that Cl-IB-MECA-induced protection was mediated through the A3 receptors. Collectively, these data suggest that CI-IB-MECA reduced cerebral infarction through the activation of A3Rs and suppression of apoptosis. (c) 2006 Wiley-Liss, Inc.