PDF(Pubmed)
Abstract：
Hippocampal seizures mimicking mesial temporal lobe epilepsy cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive neural stem cells, React-NSCs) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division, and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here, using a mouse model of mesial temporal lobe epilepsy, we show that the epidermal growth factor receptor (EGFR) signaling pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signaling pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis.
摘要：
模仿内侧颞叶癫痫的海马癫痫导致小鼠成年神经源性小生境的严重破坏。癫痫发作引起神经干细胞转换为反应性表型（反应性神经干细胞，React-NSC）以多分支肥大形态为特征，大量激活进入有丝分裂，对称除法,并最终分化为反应性星形胶质细胞。因此,神经发生是慢性受损。这里,使用内侧颞叶癫痫的小鼠模型，我们发现表皮生长因子受体（EGFR）信号通路是诱导React-NSCs的关键，其抑制对神经源性生态位具有有益作用。我们表明，在通过单次海马内注射海人酸诱导癫痫发作后的最初几天，锌和肝素结合表皮生长因子的强烈释放，神经干细胞中EGFR信号通路的两种激活剂，是生产的。给予EGFR抑制剂吉非替尼，临床IV期的化疗药物，防止React-NSC的诱导并保留神经发生。
