Fukuyama Kouji, Okada Motohiro
Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan.
Biomed Pharmacother. 2022 May;149:112846. doi: 10.1016/j.biopha.2022.112846. Epub 2022 Mar 21.
To explore developmental processes of epileptogenesis/ictogenesis and pathophysiology of carbamazepine-resistant epilepsy, we determined effects of high-frequency-oscillation (HFO) on glutamatergic tripartite-synaptic transmission, astroglial expression of connexin43, and intracellular Erk- and Akt-signalling, using genetic rat model (S286L-TG) of autosomal-dominant sleep-related hypermotor epilepsy(ADSHE), which bears rat S286L-mutant Chrna4(corresponding to human S284L-mutant CHRNA4). Artificial physiological ripple- and pathological fast-ripple-burst stimulations use-dependently increased L-glutamate release through connexin43-containing hemichannels by enhancing Erk-signalling alone or both ERK- and Akt-signalling together, respectively. Stimulatory effects of HFO-bursts on astroglial L-glutamate release were enhanced by increasing extracellular K+ levels, Akt- and Erk-signalling-dependently. HFO-bursts also activated connexin43 expression and Akt- and Erk-signallings use-dependently. Extracellular pH elevation enhanced HFO-burst-evoked astroglial L-glutamate release, which was suppressed by therapeutically-relevant concentration of zonisamide via possible carbonic-anhydrase inhibition, but not by that of carbamazepine. Unexpectedly, these responses of S286L-TG to HFO-bursts were almost equal to those of wild-type astrocytes. These results indicated that candidate pathomechanism/pathophysiology of carbamazepine-resistant ADSHE, which enhanced HFO-bursts in S286L-TG neurons may contribute to epileptogenesis/ictogenesis development via activation of connexin43-associated astroglial transmission, which was directly unaffected by mutation, and induced through activated Erk-signalling, followed by Akt-signalling. Therefore, suppression of overexpressed Erk-signalling probably prevents ADSHE onset via indirect inhibition of mutant CHRNA4-associated pathomechanistic developments.
为了探究癫痫发生/发作形成的发育过程以及卡马西平耐药性癫痫的病理生理学，我们使用常染色体显性遗传性睡眠相关运动过多性癫痫（ADSHE）的基因大鼠模型（S286L-TG），该模型携带大鼠S286L突变的Chrna4（对应于人类S284L突变的CHRNA4），确定了高频振荡（HFO）对谷氨酸能三联突触传递、连接蛋白43的星形胶质细胞表达以及细胞内Erk和Akt信号传导的影响。人工生理性涟漪和病理性快速涟漪爆发刺激分别通过单独增强Erk信号传导或同时增强ERK和Akt信号传导，以使用依赖性方式增加通过含连接蛋白43的半通道释放的L-谷氨酸。HFO爆发对星形胶质细胞L-谷氨酸释放的刺激作用通过增加细胞外K⁺水平以Akt和Erk信号传导依赖性方式增强。HFO爆发还以使用依赖性方式激活连接蛋白43表达以及Akt和Erk信号传导。细胞外pH升高增强了HFO爆发诱发的星形胶质细胞L-谷氨酸释放，这可通过治疗相关浓度的唑尼沙胺通过可能的碳酸酐酶抑制作用而受到抑制，但卡马西平则无此作用。出乎意料的是，S286L-TG对HFO爆发的这些反应几乎与野生型星形胶质细胞的反应相同。这些结果表明，卡马西平耐药性ADSHE的候选发病机制/病理生理学，即S286L-TG神经元中增强的HFO爆发可能通过激活与连接蛋白43相关的星形胶质细胞传递促进癫痫发生/发作形成的发展，这种传递不受突变直接影响，而是通过激活Erk信号传导，随后激活Akt信号传导诱导产生。因此，抑制过度表达的Erk信号传导可能通过间接抑制与突变CHRNA4相关的发病机制发展来预防ADSHE的发作。
