Ahmad Shahnawaz, Samim Mohammed, Jain Seema, Vohora Divya
Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India.
Front Pharmacol. 2025 Aug 15;16:1621729. doi: 10.3389/fphar.2025.1621729. eCollection 2025.
Epilepsy is a chronic and complex brain disorder characterized by frequent seizures, cognitive impairments, neuroinflammation, oxidative stress, and imbalances in neurotransmitters. Developing an effective therapeutic intervention to target these pathological interventions remains a challenge. Trimetazidine (TMZ), the most commonly known anti-ischemic agent, has emerged as a promising candidate for its role in epilepsy due to its diverse mechanisms of action. This study investigates the neuroprotective, anticonvulsant, anti-inflammatory, antioxidant, and neuromodulatory effects of TMZ in managing epilepsy.
Kindling was induced by administering Pentylenetetrazole (30 mg/kg, ) to Swiss albino mice on every alternate day; TMZ (5, 10, and 20 mg/k ) or sodium valproate (200 mg/kg ) was given for 5 weeks. Seizure severity was assessed on the Racine scale, and cognitive function and learning were evaluated using the elevated plus maze and the passive avoidance apparatus. Muscle strength was measured using the rotarod test. Neuroinflammatory biomarkers (IL-1β, IL-1R1, IL-6, NF-κB, TNF-α, HMGB-1, TLR-4), oxidative stress markers (MDA, GSH, SOD, catalase), and neurotransmitter (GABA, glutamate, dopamine, serotonin) levels were estimated in the hippocampus and cerebral cortex using commercially available sandwich ELISA kits.
TMZ, primarily at 10 and 20 mg/kg, significantly reduced seizure scores and improved the transfer latency, step-down latency, and motor abilities in the PTZ-kindled animals. It significantly reduced proinflammatory molecules IL-1β, IL-1R1, IL-6, NF-κB, TNF-α, HMGB-1, TLR-4. Additionally, it increased antioxidant enzyme activity (GSH, SOD, catalase) while lowering MDA levels and restoring GABA, dopamine, and serotonin levels, as well as suppressing glutamate levels, comparable to VPA at 200 mg/kg/day .
TMZ, at doses of 10 and 20 mg/kg p.o., demonstrated anticonvulsant and antioxidant activity, suppressed kindling progression, and restored neurotransmitter balance. Furthermore, TMZ has shown anti-inflammatory activity against neuroinflammation during epilepsy.
癫痫是一种慢性复杂的脑部疾病，其特征为频繁发作、认知障碍、神经炎症、氧化应激以及神经递质失衡。开发针对这些病理干预的有效治疗方法仍然是一项挑战。曲美他嗪（TMZ）是最广为人知的抗缺血药物，由于其多样的作用机制，已成为癫痫治疗中有前景的候选药物。本研究调查了曲美他嗪在癫痫治疗中的神经保护、抗惊厥、抗炎、抗氧化和神经调节作用。
每隔一天给瑞士白化小鼠腹腔注射戊四氮（30mg/kg）以诱导点燃；给予曲美他嗪（5、10和20mg/kg）或丙戊酸钠（200mg/kg），持续5周。根据拉辛量表评估癫痫发作严重程度，使用高架十字迷宫和被动回避装置评估认知功能和学习能力。使用转棒试验测量肌肉力量。使用市售夹心ELISA试剂盒在海马体和大脑皮层中评估神经炎症生物标志物（IL-1β、IL-1R1、IL-6、NF-κB、TNF-α、HMGB-1、TLR-4）、氧化应激标志物（MDA、GSH、SOD、过氧化氢酶）和神经递质（GABA、谷氨酸、多巴胺、5-羟色胺）水平。
主要是10和20mg/kg剂量的曲美他嗪显著降低了戊四氮点燃动物的癫痫发作评分，并改善了转移潜伏期、步下潜伏期和运动能力。它显著降低了促炎分子IL-1β、IL-1R1、IL-6、NF-κB、TNF-α、HMGB-1、TLR-4。此外，它增加了抗氧化酶活性（GSH、SOD、过氧化氢酶），同时降低了MDA水平，并恢复了GABA、多巴胺和5-羟色胺水平，以及抑制了谷氨酸水平，与200mg/kg/天的丙戊酸相当。
口服剂量为10和20mg/kg的曲美他嗪表现出抗惊厥和抗氧化活性，抑制了点燃进程，并恢复了神经递质平衡。此外，曲美他嗪在癫痫发作期间对神经炎症表现出抗炎活性。
