MD2 contributes to the pathogenesis of perioperative neurocognitive disorder via the regulation of α5GABA(A) receptors in aged mice.
MD2 contributes to the pathogenesis of perioperative neurocognitive disorder via the regulation of α5GABA(A) receptors in aged mice.
复制标题
MD2通过调节老年小鼠的α5GABA(A)受体导致围手术期神经认知障碍的发病机制
DOI：
10.1186/s12974-021-02246-4
复制
发表时间：
2021-09-16
影响因子：
9.3
通讯作者：
Xiong L
中科院分区：
文献类型：
--
作者：
Zuo W;Zhao J;Zhang J;Fang Z;Deng J;Fan Z;Guo Y;Han J;Hou W;Dong H;Xu F;Xiong L
背景
围手术期神经认知障碍（PND）是老年外科患者术后的长期并发症。PND的潜在机制尚不清楚，目前没有有效的治疗方法。目前认为神经炎症在PND的触发中起重要作用。分泌的糖蛋白髓样分化因子2（MD 2）作为Toll样受体4（TLR 4）炎症通路的激活剂发挥作用，并且已知α 5 GABAAR（α 5 GABAAR）在调节炎症诱导的认知缺陷中起关键作用。因此，在本研究中，我们旨在研究MD 2在PND中的作用，并确定α 5 GABAARs是否参与MD 2的功能。
方法
在异氟烷麻醉下对18个月大的C57 BL/6 J小鼠进行剖腹手术以诱导PND。采用巴恩斯迷宫检测大鼠空间参考学习记忆能力，Western blotting检测海马MD 2的表达。通过双侧海马内注射AAV-shMD 2或尾静脉注射合成的MD 2降解肽Tat-CIRP-CMA（TCM）下调MD 2表达以评估MD 2的作用。用Tat-CIRP-CMA处理来自含有皮质和海马的脑组织块的原代培养神经元，以研究下调MD 2表达是否影响α5GABAARs的表达。采用电生理学测量强直电流。在α5GABAARs干预实验中，分别使用L-655，708和L-838，417抑制或激活α5GABAARs。
结果
吸入异氟烷麻醉下的手术诱导了认知障碍，并提高了海马中MD 2的表达。通过AAV-shMD 2或Tat-CIRP-CMA下调MD 2表达改善了经受麻醉和手术的动物的空间参考学习和记忆。此外，Tat-CIRP-CMA处理降低了海马CA 1锥体神经元膜α5GABAARs的表达和紧张性电流。L-655，708抑制α5GABAARs可减轻麻醉和手术后的认知障碍。更重要的是，L-838，417激活α 5GABAAR消除了Tat-CIRP-CMA对麻醉和手术诱导的空间参考学习和记忆障碍的保护作用。
结论
MD 2通过调节α5GABAARs参与了PND的发生，Tat-CIRP-CMA是一种很有前途的抗PND神经保护剂。
Background
Perioperative neurocognitive disorder (PND) is a long-term postoperative complication in elderly surgical patients. The underlying mechanism of PND is unclear, and no effective therapies are currently available. It is believed that neuroinflammation plays an important role in triggering PND. The secreted glycoprotein myeloid differentiation factor 2 (MD2) functions as an activator of the Toll-like receptor 4 (TLR4) inflammatory pathway, and α5GABAA receptors (α5GABAARs) are known to play a key role in regulating inflammation-induced cognitive deficits. Thus, in this study, we aimed to investigate the role of MD2 in PND and determine whether α5GABAARs are involved in the function of MD2.
Methods
Eighteen-month-old C57BL/6J mice were subjected to laparotomy under isoflurane anesthesia to induce PND. The Barnes maze was used to assess spatial reference learning and memory, and the expression of hippocampal MD2 was assayed by western blotting. MD2 expression was downregulated by bilateral injection of AAV-shMD2 into the hippocampus or tail vein injection of the synthetic MD2 degrading peptide Tat-CIRP-CMA (TCM) to evaluate the effect of MD2. Primary cultured neurons from brain tissue block containing cortices and hippocampus were treated with Tat-CIRP-CMA to investigate whether downregulating MD2 expression affected the expression of α5GABAARs. Electrophysiology was employed to measure tonic currents. For α5GABAARs intervention experiments, L-655,708 and L-838,417 were used to inhibit or activate α5GABAARs, respectively.
Results
Surgery under inhaled isoflurane anesthesia induced cognitive impairments and elevated the expression of MD2 in the hippocampus. Downregulation of MD2 expression by AAV-shMD2 or Tat-CIRP-CMA improved the spatial reference learning and memory in animals subjected to anesthesia and surgery. Furthermore, Tat-CIRP-CMA treatment decreased the expression of membrane α5GABAARs and tonic currents in CA1 pyramidal neurons in the hippocampus. Inhibition of α5GABAARs by L-655,708 alleviated cognitive impairments after anesthesia and surgery. More importantly, activation of α5GABAARs by L-838,417 abrogated the protective effects of Tat-CIRP-CMA against anesthesia and surgery-induced spatial reference learning and memory deficits.
Conclusions
MD2 contributes to the occurrence of PND by regulating α5GABAARs in aged mice, and Tat-CIRP-CMA is a promising neuroprotectant against PND.
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影响因子：
25
作者：
Fan, Xuelai;Jin, Wu Yang;Lu, Jie;Wang, Jin;Wang, Yu Tian
通讯作者：
Wang, Yu Tian
DOI：
10.3233/jad-161118
发表时间：
2017
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Kandimalla R;Reddy PH
通讯作者：
Reddy PH
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
25
作者：
McKernan, RM;Rosahl, TW;Whiting, PJ
通讯作者：
Whiting, PJ
影响因子：
82.9
作者：
通讯作者：
--