Zhang Jinghui, Qiao Nana, Ding Xiufang, Wang Jiwen
Department of Pediatrics, Qilu Hospital of Shandong University.
Department of Pediatrics, Jinan Children's Hospital, Jinan, Shandong.
Neuroreport. 2018 Mar 21;29(5):432-439. doi: 10.1097/WNR.0000000000000996.
Excitotoxicity and neuronal death following epilepsy involve α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). It forms a protein complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and co-internalizes upon activation of AMPA receptors after epilepsy. Disruption of the GluA2/GAPDH complex with an interfering peptide, TAT-GluA2NT1-3-2, protects cells against AMPAR-mediated excitotoxicity, which have been identified in in-vitro and in-vivo models of brain ischemia. We postulated that disruption of the GluA2/GAPDH interaction with the TAT-GluA2NT1-3-2 peptide would also protect against AMPAR-induced neuronal injury in an in-vivo model of status epilepticus (SE). In the present study, we divided pilocarpine-induced SE Wistar rats into three main groups: the TAT-GluA2NT1-3-2 peptide group, the TAT-GluA2NT-scram peptide group, and the normal saline group, and injected different doses of peptides stereotaxically into the hippocampus of SE rats to investigate whether the GluA2/GAPDH interaction could be disrupted by our TAT-GluA2NT1-3-2 peptide and determine its most appropriate dose. Then, the dose was administered stereotaxically at different time points after SE to determine the best administration time of neuronal protection. We found that the TAT-GluA2NT1-3-2 peptide can disrupt the GluA2/GAPDH interaction and protects against epilepsy-induced neuronal damage. The GluA2/GAPDH interaction may be a novel therapeutic target for epilepsy.
癫痫发作后的兴奋性毒性和神经元死亡涉及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）。它与甘油醛-3-磷酸脱氢酶（GAPDH）形成蛋白质复合物，并在癫痫发作后AMPA受体激活时共同内化。用干扰肽TAT-GluA2NT1-3-2破坏GluA2/GAPDH复合物可保护细胞免受AMPAR介导的兴奋性毒性，这在脑缺血的体外和体内模型中已得到证实。我们推测，用TAT-GluA2NT1-3-2肽破坏GluA2/GAPDH相互作用也能在癫痫持续状态（SE）的体内模型中预防AMPAR诱导的神经元损伤。在本研究中，我们将匹鲁卡品诱导的SE Wistar大鼠分为三个主要组：TAT-GluA2NT1-3-2肽组、TAT-GluA2NT-乱序肽组和生理盐水组，并将不同剂量的肽立体定向注射到SE大鼠的海马中，以研究我们的TAT-GluA2NT1-3-2肽是否能破坏GluA2/GAPDH相互作用并确定其最合适的剂量。然后，在SE后的不同时间点立体定向给予该剂量，以确定神经元保护的最佳给药时间。我们发现，TAT-GluA2NT1-3-2肽可以破坏GluA2/GAPDH相互作用，并预防癫痫诱导的神经元损伤。GluA2/GAPDH相互作用可能是癫痫的一个新的治疗靶点。
