Li Hsin-Hua, Lin Pin-Jiun, Wang Wei-Han, Tseng Li-Ho, Tung Hsin, Liu Wen-Yuan, Lin Chih-Li, Liu Chiung-Hui, Liao Wen-Chieh, Hung Ching-Sui, Ho Ying-Jui
Department of Medical Research, Institute of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan, Republic of China.
Department of Psychology, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan, Republic of China.
Exp Physiol. 2021 Aug;106(8):1814-1828. doi: 10.1113/EP089624. Epub 2021 Jun 26.
What is the central question of this study? Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control. What is the central question of this study? Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression.
The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first-line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter-1, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35 mg/kg, every other day for 13 days) to induce the epilepsy model. Ceftriaxone (10 or 50 mg/kg), Val (50 or 100 mg/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose-dependent manner. The combination of CEF (10 mg/kg) and Val (50 mg/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.
本研究的核心问题是什么？癫痫与γ-氨基丁酸（GABA）能系统和谷氨酸能系统之间的活动失衡有关。目前尚不清楚分别使用丙戊酸和头孢曲松同时增加GABA能活性和降低谷氨酸能活性是否能更好地控制癫痫发作。本研究的核心问题是什么？在癫痫大鼠模型中，头孢曲松可抑制癫痫发作和认知缺陷，并恢复海马神经元密度和新生细胞数量。头孢曲松与丙戊酸联合治疗在抑制癫痫发作方面显示出相加作用。
癫痫的病理生理学通常被认为是抑制性GABA和兴奋性谷氨酸神经传递之间的失衡。丙戊酸（Val）作为一种GABA激动剂，是治疗癫痫的一线抗癫痫药物之一，但它有不良反应。在动物研究中，头孢曲松（CEF）可提高谷氨酸转运体-1的表达，增强突触谷氨酸的再摄取，增加新生细胞数量，并具有神经保护作用。在本研究中，我们评估了CEF和Val联合应用对大鼠癫痫模型行为和神经元指标的影响。雄性Wistar大鼠腹腔注射戊四氮（35mg/kg，隔日一次，共13天）诱导癫痫模型。在第四次注射戊四氮后，连续7天每日注射头孢曲松（10或50mg/kg）、丙戊酸（50或100mg/kg）或CEF与Val的组合。癫痫大鼠表现出癫痫发作以及运动和认知功能障碍。CEF和Val治疗以剂量依赖的方式减少癫痫发作，并增强运动和认知功能。CEF（10mg/kg）和Val（50mg/kg）的组合显著改善了行为。组织学上，与对照动物相比，癫痫大鼠神经元密度较低，海马新生细胞减少，但基底外侧杏仁核凋亡增加，而CEF、Val或CEF与Val联合治疗均可使其恢复。研究结果表明，低剂量的CEF和Val联合应用对癫痫的发作抑制、神经保护以及运动和认知功能的改善具有有益作用。
