Genetic inactivation of adenosine A2A receptors attenuates acute traumatic brain injury in the mouse cortical impact model
Genetic inactivation of adenosine A2A receptors attenuates acute traumatic brain injury in the mouse cortical impact model
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DOI：
10.1016/j.expneurol.2008.09.012
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发表时间：
2009-01-01
影响因子：
5.3
通讯作者：
Zhou, Yuanguo
中科院分区：
文献类型：
--
作者：
Li, Wei;Dai, Shuangshuang;Zhou, Yuanguo
在包括中风和帕金森病在内的几种神经系统疾病的动物模型中，A(2A)受体(A(2A)R)的失活已被证明对脑损伤具有神经保护作用。然而，尽管腺苷水平显著升高，A(2A)在创伤性脑损伤(TBI)中的作用仍不清楚。在本研究中，我们研究了A(2A)Rs基因失活在急性期的影响。A(2A)R基因敲除(KO)小鼠及其野生型(WT)仔鼠用落体重物造成皮质撞击损伤。对照组仅行开颅术加颅脑损伤。伤后24 h，KO组小鼠的神经功能缺失评分明显低于WT组。与行为学改变相一致的是，KO组小鼠的脑含水量、组织学改变以及损伤皮质的TUNEL阳性细胞数均显著低于WT仔鼠。此外，KO小鼠脑脊液中的谷氨酸水平也显著低于WT仔鼠。此外，我们还发现，在脑损伤后12h，KO小鼠的肿瘤坏死因子-α和IL-1β的mRNA和蛋白水平均高于WT仔鼠。而在伤后24小时，WT组小鼠血清中肿瘤坏死因子-α和IL-1β水平持续升高，而KO组小鼠血清中的肿瘤坏死因子-α和IL-1β水平显著下降。这些结果表明，A(2A)R的基因失活对脑损伤具有保护作用，这主要与抑制谷氨酸水平有关。(C)2008 Elsevier Inc.保留所有权利。
The inactivation of the A(2A) receptor (A(2A)R) has been shown to neuroprotect against brain injury in several animal models of neurological disorders including stroke and Parkinson's disease. However, despite marked elevation of adenosine level, the role of the A(2A) in traumatic brain injury (TBI) remains unclear. In the present study, we investigated the effects of genetic inactivation of A(2A)Rs in the acute stage. The A(2A)R knock-out (KO) mice and their wild-type (WT) littermates Were subjected to cortical impact injury by a dropping weight. The control group Was only craniotomized withoyt TBI. At 24 h post-TBI, the neurological deficit scores of the KO mice were significantly lower than that of WT littermates. Consistent with the behavioral changes, the brain water contents as well as histological changes and the TUNEL-positive cells of the injured cortex of the KO mice were significantly lower than that of WT littermates. Furthermore, the glutamate level in the cerebral spinal fluid (CSF) of the KO mice was also significantly lower than that of WT littermates. In addition, we found that at 12 h post-TBI the mRNA and protein levels of TNF-alpha and IL-1 beta were higher in the KO mice than that in the WT littermates. However, at 24 h post-TBI, the level of TNF-alpha and IL-1 beta continually increased in the WT mice but largely declined in the KO mice. These results suggest that the genetic inactivation of A(2A)R protects against TBI, which is mainly associated with the Suppression of glutamate level. (C) 2008 Elsevier Inc. All rights reserved.