Javaid Sana, Alqahtani Faleh, Parveen Abida, Ashraf Waseem, Rehman Zohabia, Anjum Syed Muhammad Muneeb, Ahmad Tanveer, Imran Imran
Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.
Department of Pharmacy, The Women University, Multan, Pakistan.
Epilepsia Open. 2025 Jun;10(3):669-681. doi: 10.1002/epi4.13141. Epub 2025 Apr 8.
Status epilepticus (SE) is a condition of neurological emergency, which precipitates various functional and morphological changes in the brain. Due to the risk of drug resistance associated with SE, this study aimed to evaluate a multitargeted approach to treat SE by combining clinically used antiseizure drugs.
In this study, we intraperitoneally administered tiagabine (TGB), levetiracetam (LEV), and perampanel (PER) alone and in combination as a duo and trio therapy after 30 min of SE in electrode-implanted male Sprague-Dawley rats subjected to lithium-pilocarpine-induced convulsive SE. The rats were monitored for SE-associated behavioral and electroencephalographic (EEG) changes. Moreover, at the end of the experiment, rats were sacrificed and brains were excised for biochemical and histopathological evaluation.
The control rats showed behavioral progression to the seizure of Stages 4-5 with 30-40 min of pilocarpine administration along with the appearance of uninterrupted fully blown epileptic spikes on EEG noted up to 2 h. The rats treated with TGB, LEV, and PER alone failed to provide behavioral and ictal attenuation. However, when combinations were tested, there was an improvement in seizure presentation while TGB + PER and LEV + PER also reversed SE-associated electrographic changes. However, the most prominent seizure attenuation was noted in rats receiving trio therapy with TGB, LEV, and PER. Moreover, the trio-treated rats demonstrated marked protection from SE-induced oxidative stress and morphological alterations in different regions of the brains.
We observed that intraperitoneal administration of TGB, LEV, and PER alone did not significantly alter the ictal activity recorded by EEG but pharmacological manipulation of acutely coadministered drugs caused a reduction of electrographic, biochemical, and histopathological eruptions providing preclinical evidence of a novel multitargeted combination treatment to ameliorate the acute SE.
This study investigates and compares the efficacy of mono- and polytherapy approach to counter the behavioral, electrographic, and histopathlogical manifestations of status epilepticus. The tiagabine as monotherapy was administered after 30 min of uninterrupted SE, and the outcomes were compared with levetiracetam and perampanel alone as well as their duo and trio combinations. We noted that combining the low doses of tiagabine, levetiracetam, and perampanel notably interrupted the seizure progression through distinct mechanism in rat model of status epilepticus. Thus, we conclude that this novel combination may be a promising multitargeted approach for management of status epilepticus.
癫痫持续状态（SE）是一种神经急症，可引发大脑各种功能和形态学变化。鉴于与SE相关的耐药风险，本研究旨在评估一种通过联合临床使用的抗癫痫药物来治疗SE的多靶点方法。
在本研究中，我们在锂-匹罗卡品诱导惊厥性SE的电极植入雄性Sprague-Dawley大鼠中，在SE发作30分钟后单独及以二联和三联疗法腹腔注射替加宾（TGB）、左乙拉西坦（LEV）和吡仑帕奈（PER）。监测大鼠与SE相关的行为和脑电图（EEG）变化。此外，在实验结束时，处死大鼠并取出大脑进行生化和组织病理学评估。
对照大鼠在给予匹罗卡品30 - 40分钟后出现行为进展至4 - 5期癫痫发作，同时在长达2小时的EEG上出现不间断的完全发作性癫痫棘波。单独用TGB、LEV和PER治疗的大鼠未能减轻行为和发作症状。然而，当测试联合用药时，癫痫发作表现有所改善，同时TGB + PER和LEV + PER也逆转了与SE相关的脑电图变化。然而，在接受TGB、LEV和PER三联疗法的大鼠中观察到最显著的癫痫发作减轻。此外，三联疗法治疗的大鼠在大脑不同区域表现出对SE诱导的氧化应激和形态学改变的显著保护作用。
我们观察到单独腹腔注射TGB、LEV和PER并未显著改变EEG记录的发作活动，但急性联合给药的药理学操作导致脑电图、生化和组织病理学发作减轻，为一种新型多靶点联合治疗改善急性SE提供了临床前证据。
本研究调查并比较了单药治疗和联合治疗方法对抗癫痫持续状态的行为、脑电图和组织病理学表现的疗效。在不间断SE发作30分钟后给予替加宾单药治疗，并将结果与单独使用左乙拉西坦和吡仑帕奈以及它们的二联和三联组合进行比较。我们注意到，在癫痫持续状态大鼠模型中，低剂量的替加宾、左乙拉西坦和吡仑帕奈联合使用通过不同机制显著中断了癫痫发作进程。因此，我们得出结论，这种新型联合疗法可能是一种有前景的治疗癫痫持续状态的多靶点方法。
