Thapliyal Surabhi, Garg Nitika, Joshi Rupa, Chakrabarti Amitava, Medhi Bikash
Department of Pharmacology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
Department of Pharmacology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Ambala, India.
Basic Clin Neurosci. 2023 Sep-Oct;14(5):701-712. doi: 10.32598/bcn.2022.3904.1. Epub 2023 Sep 1.
Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods.
Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed.
The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14.
The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.
耐药性癫痫是一种尚未得到满足的医学状况，影响着30%的癫痫患者。已经开发了许多抗癫痫药物，但它们仅能缓解症状，并未针对潜在的发病机制。临床前模型为深入了解耐药性癫痫的模糊机制提供了机会。当前的动物模型存在需要纠正和验证的缺陷，以便发现新型抗癫痫药物。本研究旨在验证在两个不同时期的3种不同剂量的苯巴比妥。
以亚惊厥剂量（30毫克/千克/天/腹腔注射[IP]）给予雄性Wistar大鼠戊四氮28天以诱导点燃。此外，将点燃的大鼠分为以下四组：戊四氮对照组、戊四氮加苯巴比妥（20毫克/千克）、戊四氮加苯巴比妥40毫克/千克以及戊四氮加苯巴比妥（60毫克/千克）。在点燃后的第14天和第28天对它们进行评估。分析癫痫发作评分、氧化应激、苯巴比妥血浆水平以及海马神经元的组织病理学。
结果显示，戊四氮与苯巴比妥（40和60毫克/千克）联合使用在第14天显著降低了癫痫发作评分，显示出更高的抗氧化作用，并预防了神经元损伤，而在第28天，对点燃的大鼠长期给予戊四氮和苯巴比妥则观察到癫痫发作评分增加、氧化应激增加以及神经元死亡。此外，与第14天相比，在苯巴比妥治疗的第28天血液中的苯巴比妥水平显著升高。
采用40毫克/千克剂量苯巴比妥的改良方案在筛选难治性癫痫的抗癫痫药物方面可能具有巨大潜力。
