Han Wei, Jiang Li, Song Xiaojie, Li Tianyi, Chen Hengsheng, Cheng Li
Department of Neurology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
Front Neurol. 2021 Dec 24;12:808568. doi: 10.3389/fneur.2021.808568. eCollection 2021.
Neurogenesis and angiogenesis are widely recognized to occur during epileptogenesis and important in brain development. Because vascular endothelial growth factor (VEGF) is a critical neurovascular target in neurological diseases, its effect on neurogenesis, microvascular remodeling and epileptogenesis in the immature brain after lithium-pilocarpine-induced status epilepticus (SE) was investigated. The dynamic changes in and the correlation between hippocampal neurogenesis and microvascular remodeling after SE and the influence of VEGF or SU5416 injection into the lateral ventricles at different stages after SE on neurogenesis and microvascular remodeling through regulation of VEGF expression were assessed by immunofluorescence and immunohistochemistry. Western blot analysis revealed that the VEGFR2 signaling pathway promotes phosphorylated ERK and phosphorylated AKT expression. The effects of VEGF expression regulation at different stages after SE on pathological changes in hippocampal structure and spontaneous recurrent seizures (SRS) were evaluated by Nissl staining and electroencephalography (EEG). The results showed that hippocampal neurogenesis after SE is related to microvascular regeneration. VEGF promotion in the acute period and inhibition in the latent period after SE alleviates loss of hippocampal neuron, abnormal vascular regeneration and inhibits neural stem cells (NSCs) ectopic migration, which may effectively alleviate SRS severity. Interfering with VEGF via the AKT and ERK pathways in different phases after SE may be a promising strategy for treating and preventing epilepsy in children.
神经发生和血管生成在癫痫发生过程中广泛存在且在脑发育中具有重要作用，这一点已得到广泛认可。由于血管内皮生长因子（VEGF）是神经疾病中的关键神经血管靶点，因此研究了其对锂-匹罗卡品诱导的癫痫持续状态（SE）后未成熟脑的神经发生、微血管重塑及癫痫发生的影响。通过免疫荧光和免疫组织化学评估SE后海马神经发生与微血管重塑的动态变化及其相关性，以及SE后不同阶段向侧脑室注射VEGF或SU5416通过调节VEGF表达对神经发生和微血管重塑的影响。蛋白质免疫印迹分析显示，VEGFR2信号通路促进磷酸化ERK和磷酸化AKT表达。通过尼氏染色和脑电图（EEG）评估SE后不同阶段VEGF表达调节对海马结构病理变化和自发性反复癫痫发作（SRS）的影响。结果表明，SE后海马神经发生与微血管再生有关。SE急性期促进VEGF表达和潜伏期抑制VEGF表达可减轻海马神经元丢失、异常血管再生并抑制神经干细胞（NSC）异位迁移，这可能有效减轻SRS严重程度。在SE后不同阶段通过AKT和ERK途径干扰VEGF可能是治疗和预防儿童癫痫的一种有前景的策略。
