Department of Neurology, Xiangya Hospital, Central South University, Hunan, 410008, China.
Department of Radiology, Xiangya Hospital, Central South University, Hunan, 410008, China.
Mol Neurobiol. 2016 Jan;53(1):561-576. doi: 10.1007/s12035-014-9020-2. Epub 2014 Dec 11.
Studies have shown that neurogenesis and angiogenesis do exist in temporal lobe epilepsy (TLE). The ephrin ligands and Eph receptors are the largest members of receptor tyrosine kinases, and their interaction via cell-cell contact participates in cell proliferation, differentiation, migration, and tissue remodeling. However, there is little information about the function of the ephrin-A5/EphA4 complex in TLE. In the current study, we found that ephrin-A5 was expressed in astrocytes, while EphA4 existed in endothelial cells in the hippocampus in a mouse model of TLE. Furthermore, the messenger RNA (mRNA) and protein levels of both ephrin-A5 and EphA4 and the binding capacity of ephrin-A5/EphA4 showed gradual increase in spatiotemporal course. When ephrin-A5-Fc was injected into the hippocampus at 3 days post-status epilepticus (SE) for 7 days, the spontaneous recurrent seizure (SRS) frequency and intensity of the mice attenuated in the following 2 weeks. Furthermore, doublecortin-positive neuronal progenitor cells were reduced in the subgranular zone, and the density of microvessels decreased in the hilus. The molecular mechanism was attributed to ephrin-A5-Fc-induced inhibition of phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt), and also EphA4 and VEGF reduction. In summary, interaction between ephrin-A5 and EphA4 could mediate the ERK and Akt signaling pathways in pilocarpine-induced epilepsy, and intervention of the ephrin/Eph interaction may play an essential role in the suppression of newborn neuron generation, microvessel remodeling, and SRS in a mouse model of TLE. The ephrin-A5/EphA4 communication may provide a potential therapy for the treatment of TLE.
研究表明，神经发生和血管生成确实存在于颞叶癫痫（TLE）中。ephrin 配体和 Eph 受体是受体酪氨酸激酶家族中最大的成员，它们通过细胞-细胞接触相互作用参与细胞增殖、分化、迁移和组织重塑。然而，关于 Ephrin-A5/EphA4 复合物在 TLE 中的作用的信息很少。在本研究中，我们发现 Ephrin-A5 在星形胶质细胞中表达，而 EphA4 存在于 TLE 小鼠模型海马中的内皮细胞中。此外，ephrin-A5 和 EphA4 的信使 RNA（mRNA）和蛋白水平及其结合能力在时空过程中逐渐增加。当 Ephrin-A5-Fc 在癫痫持续状态（SE）后 3 天注射到海马中 7 天时，小鼠的自发性反复性发作（SRS）频率和强度在接下来的 2 周内减弱。此外，在颗粒下区减少了双皮质素阳性神经前体细胞，而门区的微血管密度降低。分子机制归因于 Ephrin-A5-Fc 诱导的磷酸化 ERK（p-ERK）和磷酸化 Akt（p-Akt）以及 EphA4 和 VEGF 的减少。总之，ephrin-A5 和 EphA4 之间的相互作用可以介导匹鲁卡品诱导的癫痫中的 ERK 和 Akt 信号通路，并且 Ephrin/Eph 相互作用的干预可能在抑制新生神经元生成、微血管重塑和 TLE 小鼠模型中的 SRS 中发挥重要作用。ephrin-A5/EphA4 通讯可能为 TLE 的治疗提供一种潜在的治疗方法。
