Rehman Zohabia, Farooq Talha, Javaid Sana, Ashraf Waseem, Fawad Rasool Muhammad, Samad Noreen, Tariq Maryam, Muhammad Muneeb Anjum Syed, Sivandzade Farzane, Alotaibi Faisal, Alqahtani Faleh, Imran Imran
Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
Department of Pharmacy, The Women University, Multan 60000, Pakistan.
Saudi Pharm J. 2022 May;30(5):494-507. doi: 10.1016/j.jsps.2022.03.003. Epub 2022 Mar 10.
The pentylenetetrazol (PTZ)-induced kindling model acts through the antagonism of central GABA receptors and is one of the most widely used experimental animal models to study the characteristics of seizure development, behavioral manifestations and evaluation of antiseizure effects of existing and new drug candidates.
In the current study, we investigated the impact of chronically administered levetiracetam (50 mg/kg) and sodium selenite (Sod.Se: 0.25 and 0.5 mg/kg) alone and in combination during the kindling process (21 days) in rats. Moreover, the behavioral changes (through the integration of a wide array of behavioral tests) and markers of oxidative stress in isolated brain homogenates were assessed in PTZ- kindled rats.
The outcomes from the fully kindled rats revealed the increased seizure score and severity over time with marked behavioral deficits. However, the animals treated with the selected dose of LEV alone showed partial protection from epileptogenesis and amelioration (P < 0.05) of anxiety-like behavior (open filed, light/dark, elevated plus maze tests), cognitive impairment (y-maze, novel object recognition and water maze tests) and depression (sucrose preference test). Moreover, combining the LEV with sodium selenite resulted in a significant neuroprotective effect in comparison to monotherapy by reducing the disease progression and ameliorating behavioral outcomes. The combination of Sod.Se in a dose-dependent manner with LEV produced additive effects as maximum animals remained seizure-free compared to kindled rats (P < 0.05). The attenuation of PTZ induced oxidative stress was evident from the reduced malondialdehyde and elevated superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) level with P < 0.05, as compared to control epileptic rats. These observed results of combination therapy might be due to the antioxidant and neuroprotective properties of Sod.Se, thus augmenting the seizure-modifying potentials of levetiracetam.
Overall, the current findings support the prominence of combining the Sod.Se with LEV, over monotherapy to deal with prevailing challenges of drug resistance and neuropsychiatric sufferings common in epileptic patients.
戊四氮（PTZ）诱导的点燃模型通过拮抗中枢γ-氨基丁酸（GABA）受体发挥作用，是研究癫痫发作发展特征、行为表现以及评估现有和新候选药物抗癫痫作用最广泛使用的实验动物模型之一。
在本研究中，我们调查了在大鼠点燃过程（21天）中单独及联合长期给予左乙拉西坦（50mg/kg）和亚硒酸钠（Sod.Se：0.25和0.5mg/kg）的影响。此外，在PTZ点燃的大鼠中评估了行为变化（通过一系列行为测试综合评估）以及离体脑匀浆中的氧化应激标志物。
完全点燃大鼠的结果显示，随着时间推移癫痫发作评分和严重程度增加，伴有明显的行为缺陷。然而，单独用选定剂量的左乙拉西坦治疗的动物表现出对癫痫发生的部分保护作用，并且焦虑样行为（旷场试验、明暗试验、高架十字迷宫试验）、认知障碍（Y迷宫试验、新物体识别试验和水迷宫试验）及抑郁（蔗糖偏好试验）有所改善（P<0.05）。此外，与单一疗法相比，左乙拉西坦与亚硒酸钠联合使用可通过减缓疾病进展和改善行为结果产生显著的神经保护作用。Sod.Se与左乙拉西坦以剂量依赖方式联合使用产生相加效应，因为与点燃大鼠相比，大多数动物保持无癫痫发作（P<0.05）。与对照癫痫大鼠相比，丙二醛减少，超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽过氧化物酶（GPx）水平升高（P<0.05），表明PTZ诱导的氧化应激得到减轻。联合治疗的这些观察结果可能归因于Sod.Se的抗氧化和神经保护特性，从而增强了左乙拉西坦的癫痫发作调节潜力。
总体而言，目前的研究结果支持将Sod.Se与左乙拉西坦联合使用优于单一疗法，以应对癫痫患者中常见的耐药性和神经精神痛苦等普遍挑战。
