Al-Shorbagy Muhammad Y, Wadie Walaa, El-Tanbouly Dalia M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates.
Front Pharmacol. 2021 Oct 8;12:735165. doi: 10.3389/fphar.2021.735165. eCollection 2021.
Mitochondrial oxidative status exerts an important role in modulating glia-neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (-ERK1/2) and p-AMP-activated protein kinase (-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost -ERK1/2 and -AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.
线粒体氧化状态在癫痫发生过程中调节胶质细胞与神经元的相互作用方面发挥着重要作用。曲美他嗪（TMZ）是一种著名的抗缺血药物，已显示出对包括癫痫在内的多种神经退行性疾病具有潜在的治疗前景。然而，其抗癫痫潜力背后的确切机制尚未完全阐明。在此，研究了TMZ对锂/匹罗卡品（Li/PIL）诱导癫痫发作大鼠海马体中线粒体氧化损伤以及谷氨酸稳态破坏的影响。动物腹腔注射3 mEq/kg LiCl，20小时后腹腔注射匹罗卡品（单次腹腔注射；150 mg/kg）以诱导癫痫发作，有或没有TMZ预处理（25 mg/kg；腹腔注射），连续五天。观察癫痫发作评分和发作潜伏期。记录线粒体氧化还原状态以及ATP和解偶联蛋白2。此外，揭示了谷氨酸稳态。目前的研究结果表明，TMZ可降低Li/PIL诱导的癫痫发作评分和潜伏期。它改善了线粒体氧化还原状态，维持了能量产生机制，并减少了反应性星形胶质细胞，表现为海马组织中胶质纤维酸性蛋白免疫染色区域减少。此外，它调节磷酸化细胞外信号调节激酶（-ERK1/2）和磷酸化AMP激活蛋白激酶（-AMPK）信号通路，以反映已证实的抗凋亡作用。因此，它上调了星形胶质细胞谷氨酸转运体的mRNA表达，并降低了升高的谷氨酸水平。当前研究表明，TMZ具有强大的抗癫痫和神经保护潜力。这些作用与其调节线粒体氧化还原状态、增强-ERK1/2和-AMPK信号通路以及恢复海马体中谷氨酸稳态的能力有关。
