Liang Wenpeng, Wang Jie, Sui Jiahui, Yun Feng, Shen Yuntian, Zhou Jing, Wu Youjia, Shen Dingding, Zhang Qi
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China.
Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China.
Int Immunopharmacol. 2023 Mar;116:109802. doi: 10.1016/j.intimp.2023.109802. Epub 2023 Feb 2.
Inflammation is considered to be involved in epileptogenesis. However, the relationship between fever and inflammation as well as the mechanisms of fever in the occurrence and development of childhood epilepsy need further investigation. Here, we described an in vivo model of hyperthermia-induced seizures in zebrafish larvae with pentylenetetrazole (PTZ) exposure. Hyperthermia increased the susceptibility to seizure and the production of pro-inflammatory factors in PTZ-induced zebrafish larvae. As mutations in GABRG2 have been associated with fever-associated epilepsy, we used a Tg(hGABRG2) zebrafish model expressing mutant human GABRG2(F343L) to further investigate the involvement of inflammation in fever-induced seizures. Our data indicated that hyperthermia also increased the locomotor activity in Tg(hGABRG2) zebrafish larvae. Although the production of pro-inflammatory factors was upregulated by GABRG2 mutation, hyperthermia did not change the production of pro-inflammatory factors significantly. Lipopolysaccharide (LPS) stimulation was sufficient to increase the locomotor activity in zebrafish larvae, suggesting that inflammation contributed to fever-associated epilepsy. The expression of GABRG2 was increased with PTZ induction, especially at a higher temperature. Moreover, inhibition of inflammation by dexamethasone (DEX) reduced the excitability of zebrafish larvae, especially at a higher temperature. Finally, in vitro experiments proved that LPS stimulation increased the production of IL-1β and IL-6 in GABRG2(F343L) transfected cells. Collectively, our study demonstrated that neuroinflammation was induced in febrile seizures, and the increased expression of IL-1β and IL-6 might be responsible for epileptogenesis. The vicious cycle between fever and inflammation might induce seizure onset, and anti-inflammatory strategies might be a potential treatment for fever-associated epilepsy.
炎症被认为与癫痫发生有关。然而，发热与炎症之间的关系以及发热在儿童癫痫发生和发展中的机制仍需进一步研究。在此，我们描述了一种通过戊四氮（PTZ）暴露诱导斑马鱼幼体高热惊厥的体内模型。高热增加了PTZ诱导的斑马鱼幼体对惊厥的易感性以及促炎因子的产生。由于GABRG2基因突变与发热相关癫痫有关，我们使用表达突变型人GABRG2（F343L）的Tg（hGABRG2）斑马鱼模型进一步研究炎症在发热诱导惊厥中的作用。我们的数据表明，高热也增加了Tg（hGABRG2）斑马鱼幼体的运动活性。尽管GABRG2突变上调了促炎因子的产生，但高热并未显著改变促炎因子的产生。脂多糖（LPS）刺激足以增加斑马鱼幼体的运动活性，表明炎症促成了发热相关癫痫。PTZ诱导后GABRG2的表达增加，尤其是在较高温度下。此外，地塞米松（DEX）抑制炎症可降低斑马鱼幼体的兴奋性，尤其是在较高温度下。最后，体外实验证明LPS刺激增加了GABRG2（F343L）转染细胞中IL-1β和IL-6的产生。总体而言，我们的研究表明热性惊厥中诱导了神经炎症，IL-1β和IL-6表达增加可能是癫痫发生的原因。发热与炎症之间的恶性循环可能诱导癫痫发作，抗炎策略可能是发热相关癫痫的一种潜在治疗方法。
