过刊浏览

小鼠中度颅脑创伤急性期激活腺苷A2A受体强化草酰乙酸的神经保护作用

杨楠, 黄治中, 谭思维, 陈惺, 彭艳, 周元国, 宁亚蕾^*

陆军军医大学大坪医院陆军特殊职业疾病防控研究室；创伤、烧伤与复合伤国家重点实验室分子生物学中心，重庆 400042

摘要

本文旨在探讨联合应用谷氨酸清除剂草酰乙酸(oxaloacetate, OA)和腺苷A2A受体(adenosine A2A receptor, A2AR)激动剂CGS21680在中度颅脑创伤(traumatic brain injury, TBI)急性期中的神经保护作用和机制。使用C57BL/6J小鼠建立中度TBI模型，伤后急性期分别单纯使用OA、CGS21680或联合使用OA和CGS21680，伤后24 h检测神经功能评分、脑含水量、脑脊液谷氨酸浓度、脑组织IL-1β和TNF-α水平、谷氨酸草酰乙酸转氨酶(glutamate oxaloacetate aminotransferase, GOT)水平和活性及ATP浓度。结果表明，与TBI组相比，单纯使用CGS21680加重脑损伤，包括加重神经功能缺损、提高脑含水量、脑脊液谷氨酸水平和促进神经炎症；单纯使用OA可以抑制脑脊液谷氨酸水平和脑含水量的升高，并提高脑组织ATP浓度；联合使用OA和CGS21680改善了神经功能评分，降低了脑含水量、脑脊液谷氨酸浓度以及脑组织IL-1β和TNF-α的mRNA含量和蛋白水平，增加了ATP水平，且效果优于单纯使用OA组。此外，单纯使用CGS21680提高了脑组织GOT活性，早期联合使用OA和CGS21680提高了脑组织GOT的mRNA水平和活性，提示激活A2AR可提高GOT效能，促进OA代谢谷氨酸的能力，这可能是联合用药组A2AR激活不仅没有加重损伤，反而强化OA神经保护作用的机制。本研究为A2AR激动剂和OA运用于TBI临床治疗提供了新的思路。

关键词： 创伤性脑损伤; 腺苷A2A受体; 草酰乙酸; 谷氨酸草酰乙酸转氨酶; 能量代谢

Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate 

YANG Nan, HUANG Zhi-Zhong, TAN Si-Wei, CHEN Xing, PENG Yan, ZHOU Yuan-Guo, NING Ya-Lei^*

Department of Army Occupational Disease, Daping Hospital, Army Medical University; The Molecular Biology Center, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing 400042, China

Abstract

The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1β and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected. The results showed that neurological deficit, brain water content, glutamate concentration in CSF, and the inflammatory cytokine IL-1β and TNF-α production were exacerbated in CGS21680 treated mice. Administrating OA suppressed the rise of both glutamate concentration in CSF and brain water content, and elevated the ATP level of cerebral tissue. More interestingly, neurological deficit, brain edema, glutamate concentration, IL-1β and TNF-α levels were ameliorated significantly in mice treated with OA combined with CGS21680. The combined treatment exhibited better therapeutic effects than single OA treatment. We also observed that GOT activity was enhanced in single CGS21680 treatment group, and both the GOT mRNA level and GOT activity were up-regulated in early-stage combined treatment group. These results suggest that A2AR can improve the efficiency of GOT and potentiate the ability of OA to metabolize glutamate. This may be the mechanism that A2AR activation in combination group augmented the neuroprotective effect of OA rather than aggravated the brain damages. Taken together, the present study provides a new insight for the clinical treatment of TBI with A2AR agonists and OA.

Key words: traumatic brain injury; adenosine A2A receptor; oxaloacetate; glutamate oxaloacetate aminotransferase; energy metabolism

收稿日期：　　录用日期：

通讯作者：宁亚蕾　　E-mail: ylning@outlook.com

DOI: 10.13294/j.aps.2022.0051

引用本文：

杨楠, 黄治中, 谭思维, 陈惺, 彭艳, 周元国, 宁亚蕾. 小鼠中度颅脑创伤急性期激活腺苷A2A受体强化草酰乙酸的神经保护作用[J]. 生理学报 2022; 74 (4): 505-512.

YANG Nan, HUANG Zhi-Zhong, TAN Si-Wei, CHEN Xing, PENG Yan, ZHOU Yuan-Guo, NING Ya-Lei. Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate . Acta Physiol Sin 2022; 74 (4): 505-512 (in Chinese with English abstract).