Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy

Q1 Health Professions

Animal models and experimental medicine Pub Date : 2024-10-22 DOI:10.1002/ame2.12478

Awais Sattar, Zohabia Rehman, Hammad Murtaza, Waseem Ashraf, Tanveer Ahmad, Faleh Alqahtani, Imran Imran

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Abstract

Background

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress.

Methods

Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed.

Results

Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.

Conclusion

Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

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Brivaracetam 和 rufinamide 组合提高了角膜点燃癫痫模型的发作阈值并改善了神经行为缺陷。

背景：除癫痫发作外，癫痫患者还会出现多种神经精神和认知并发症，这进一步降低了他们的生活质量。本研究深入探讨了分别以 10 毫克/千克和 20 毫克/千克的剂量单独或联合使用溴乙酰乙胺和鲁非那胺对角膜点燃诱导的全身性癫痫发作和行为改变的影响。此外，观察到的抽搐频率和行为变化与点燃后诱导的氧化应激标志物活性变化相关：方法：对成年 C57BL/6 小鼠进行点燃，每天两次，每次经角膜 50Hz 电刺激（3 mA），每次 3 秒，持续 12 天，直到动物达到完全点燃状态。点燃过程结束后，对动物进行一系列行为测试，并评估神经化学变化：结果：角膜点燃后的动物表现出强烈的全身抽搐，行为表型改变，表现为阳性症状（运动过度）、阴性症状（焦虑和失神）以及语义记忆和工作记忆缺陷。BRV 10 + RFM 20 双联疗法提高了抽搐阈值和4-5期癫痫发作的开始倾向，改善了表型缺陷，即焦虑、抑郁和记忆障碍。此外，这种联合疗法还能减轻电击诱导的氧化还原损伤，这体现在受到重复性脑损伤的动物大脑中丙二醛和乙酰胆碱酯酶水平降低，谷胱甘肽抗氧化活性提高：根据我们的研究结果，这种双重疗法在缓解癫痫引起的神经行为合并症和氧化还原平衡变化方面提供了支持性证据。

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