Chen Mingyue, He Weiwei, Ding Xiaomi, Wang Shenglin, Zhang Min, Cao Xing, Tan Juan, Jiang Guohui
Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Institute of Neurological Diseases, North Sichuan Medical College Nanchong, Sichuan, China.
Am J Transl Res. 2022 Sep 15;14(9):6222-6233. eCollection 2022.
Epilepsy is a common central nervous system disorder with pathological mechanisms including inflammation, ion channel impairment, and neurotransmitter imbalance. Despite the rapid development of current anti-epileptic drugs, epilepsy is not well controlled, so there is still a need for research on the mechanisms and new drug targets for epilepsy. CXCL14 is a member of the CXC family of chemokines, and its receptor is currently unknown. Chemokines are the third major communication mediators in the central nervous system and play a role in many diseases. Therefore, we explore the expression of CXCL14 in epilepsy and its possible mechanisms.
We chose the kainic acid (KA) mouse model as the epilepsy model, and studied the expression of CXCL14 in this model by western blot. Subsequently, after knocking down CXCL14, we explored the effect of CXCL14 on seizures by electrophysiology and FJB (Fluoro-Jade B) staining. Western blot and ELISA were used to explore the possible mechanism of CXCL14 affecting seizures.
CXCL14 expression gradually increased after a seizure until it peaked at 72 hours and then gradually decreased again. The knockdown of CXCL14 resulted in prolonged seizure latency, decreased seizure grade, and reduced degenerative necrosis of neurons in mice. Levels of GABA (γ-aminobutyric acid), GAD67 (glutamate decarboxylase 67) and GABA receptor (γ-aminobutyric acid A receptor) were increased.
Our results suggest that CXCL14 expression is increased after seizures and may exacerbate seizures by regulating GABA metabolism. Based on this, CXCL14 could be a new target for epilepsy treatment and antiepileptic drug development.
癫痫是一种常见的中枢神经系统疾病，其病理机制包括炎症、离子通道损伤和神经递质失衡。尽管目前抗癫痫药物迅速发展，但癫痫仍未得到很好的控制，因此仍需要对癫痫的发病机制和新的药物靶点进行研究。CXCL14是CXC趋化因子家族的成员，其受体目前尚不清楚。趋化因子是中枢神经系统中的第三类主要通讯介质，在许多疾病中发挥作用。因此，我们探讨CXCL14在癫痫中的表达及其可能的机制。
我们选择海藻酸（KA）小鼠模型作为癫痫模型，并通过蛋白质免疫印迹法研究该模型中CXCL14的表达。随后，在敲低CXCL14后，我们通过电生理学和FJB（氟玉红B）染色探讨CXCL14对癫痫发作的影响。采用蛋白质免疫印迹法和酶联免疫吸附测定法探讨CXCL14影响癫痫发作的可能机制。
癫痫发作后CXCL14表达逐渐增加，直至72小时达到峰值，然后再次逐渐下降。敲低CXCL14可导致小鼠癫痫发作潜伏期延长、发作等级降低以及神经元变性坏死减少。γ-氨基丁酸（GABA）、谷氨酸脱羧酶67（GAD67）和GABA受体（γ-氨基丁酸A型受体）水平升高。
我们的结果表明，癫痫发作后CXCL14表达增加，可能通过调节GABA代谢加重癫痫发作。基于此，CXCL14可能成为癫痫治疗和抗癫痫药物研发的新靶点。
