Okanari Kazuo, Teranishi Hitoshi, Umeda Ryohei, Shikano Kenshiro, Inoue Masanori, Hanada Toshikatsu, Ihara Kenji, Hanada Reiko
Department of Pediatrics, Faculty and Medicine, Oita University, Oita, Japan.
Department of Neurophysiology, Faculty and Medicine, Oita University, Oita, Japan.
Behav Brain Res. 2024 Apr 27;464:114920. doi: 10.1016/j.bbr.2024.114920. Epub 2024 Feb 23.
Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.
癫痫是一种复发性神经系统疾病，涉及大脑中异常的神经递质动力学，已成为全球关注的健康问题。癫痫发作的机制被认为涉及兴奋性和抑制性神经递质之间的相对失衡。尽管近年来癫痫发病机制的临床和基础研究取得了进展，但癫痫发作期间使用和不使用抗癫痫药物（AEDs）时神经递质变化与行为之间的复杂关系仍不清楚。为了研究左乙拉西坦（LEV）、卡马西平（CBZ）和芬氟拉明（FFR）等AEDs对成年斑马鱼戊四氮（PTZ）诱导癫痫发作中关键神经递质的影响，我们检测了谷氨酸、γ-氨基丁酸（GABA）、血清素（5-HT）、5-羟吲哚乙酸（5-HIAA）、胆碱、乙酰胆碱、去甲肾上腺素、多巴胺（DA）、3,4-二羟基苯乙酸（DOPAC）和腺苷的变化。在本研究中，我们观察到PTZ诱导癫痫发作后大脑中5-HT和DA水平立即升高。行为测试清楚地表明，所有这些AEDs都能抑制PTZ诱导的癫痫发作。用这些AEDs治疗PTZ诱导的癫痫发作后，CBZ降低了谷氨酸水平，FFR增加了GABA水平；然而，给予LEV后大脑中未观察到神经递质变化。因此，我们证明了在给予LEV、CBZ或FFR时，PTZ诱导癫痫发作期间一系列与行为变化相关的神经递质变化。这些发现将有助于更详细地了解AED治疗下与行为和神经递质变化相关的癫痫发病机制。
