Treatment of secondary brain injury by perturbing postsynaptic density protein-95-NMDA receptor interaction after intracerebral hemorrhage in rats.
Treatment of secondary brain injury by perturbing postsynaptic density protein-95-NMDA receptor interaction after intracerebral hemorrhage in rats.
复制标题
DOI：
10.1177/0271678x18762637
复制
发表时间：
2019-08
期刊：
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Wang Z;Chen Z;Yang J;Yang Z;Yin J;Duan X;Shen H;Li H;Wang Z;Chen G
突触后密度蛋白-95 （Postsynaptic density protein-95, PSD95）在神经元突触的形成、分化、重塑和成熟过程中发挥重要作用。本研究旨在评估PSD95在脑出血（ICH）后认知功能障碍和突触损伤中的潜在作用。PSD95与NMDA受体亚基nr2b -神经递质一氧化氮合酶（nNOS）相互作用可形成介导兴奋性信号的信号蛋白复合物。除NR2B-nNOS外，PSD95还可与neurexin-1-neuroligin-1结合形成复合物，参与维持突触功能。在本研究中，我们发现脑出血后PSD95-NR2B-nNOS复合物的形成增加，神经素-1-神经素-1- psd95复合物的形成减少，并伴有神经元死亡变性和行为功能障碍的增加。PSD95抑制剂dat - nr2b9c有效抑制PSD95与NR2B-nNOS的相互作用，促进神经素-1-神经脂素-1-PSD95复合物的形成。此外，Tat-NR2B9c治疗可显著降低脑出血大鼠神经元的死亡变性和基质金属蛋白酶9活性，减轻炎症反应和神经行为障碍，提高认知和学习能力。抑制PSD95-NR2B-nNOS复合物的形成可以挽救脑出血后继发性脑损伤和行为认知障碍。PSD95有望成为改善脑出血患者预后的靶点。
Postsynaptic density protein-95 (PSD95) plays important roles in the formation, differentiation, remodeling, and maturation of neuronal synapses. This study is to estimate the potential role of PSD95 in cognitive dysfunction and synaptic injury following intracerebral hemorrhage (ICH). The interaction between PSD95 and NMDA receptor subunit NR2B-neurotransmitter nitric oxide synthase (nNOS) could form a signal protein complex mediating excitatory signaling. Besides NR2B-nNOS, PSD95 also can bind to neurexin-1–neuroligin-1 to form a complex and participates in maintaining synaptic function. In this study, we found that there were an increase in the formation of PSD95-NR2B-nNOS complex and a decrease in the formation of neurexin-1–neuroligin-1-PSD95 complex after ICH, and this was accompanied by increased neuronal death and degeneration, and behavior dysfunction. PSD95 inhibitor Tat-NR2B9c effectively inhibited the interaction between PSD95 and NR2B-nNOS, and promoted the formation of neurexin-1–nueuroligin-1-PSD95 complex. In addition, Tat-NR2B9c treatment significantly reduced neuronal death and degeneration and matrix metalloproteinase 9 activity, alleviated inflammatory response and neurobehavioral disorders, and improved the cognitive and learning ability of ICH rats. Inhibition of the formation of PSD95-NR2B-nNOS complex can rescue secondary brain injury and behavioral cognitive impairment after ICH. PSD95 is expected to be a target for improving the prognosis of patients with ICH.