Kaur Navjot, Singh Tanveer, Kumar Sandeep, Goel Rajesh Kumar
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
Epilepsy Behav. 2017 Jul;72:8-16. doi: 10.1016/j.yebeh.2017.04.004. Epub 2017 May 29.
Most of the clinically available antiepileptic drugs have only antiseizure effects and are reported unable to prevent epileptogenesis. In the past decade, several drugs underwent clinical trials for management of epileptogenesis, but none of the drugs tested was found effective. One of the major lacunas is availability of appropriate preclinical approaches to delineate mechanisms of epileptogenesis. Thus, the present study attempts to suggest a neurochemistry based approach for safe management of epileptogenesis. The altered neurochemical milieu in amygdala, cortex and hippocampus areas of the mice brain in naïve, kindled and kindling resistant animals has been delineated. The endogenous natural antiepileptogenic neurochemical defense mechanism observed in kindling resistant animals may uncover neurochemical mechanisms of epileptogenesis and in turn suggest us novel interventions for safe management of epileptogenesis. The kindling epileptogenesis was carried out in two month old male Swiss albino mice by administering subconvulsive pentylenetetrazole (35mg/kg; i.p.) at an interval of 48±2h for 42days. 2h after the last pentylenetetrazole injection, the animals were subjected to behavioral evaluations. Four hours after behavioral evaluation, all animals were euthanized and discrete parts of brain (amygdala, cortex and hippocampus) were harvested for neurochemical analysis. Results revealed that 60% of animals responded to kindling as observed with decreased seizure threshold, while the rest were found resistant. The kindled animals were found to be associated with anxiety, depression and cognitive impairment; while in kindling resistant animals no such behavioral deficits were observed. The neurochemical analysis revealed that in kindled animals altered glutamate-GABA neurotransmission, and decreased taurine, glycine, d-serine, monoamine levels with elevated indoleamine 2,3-dioxygenase activity were observed, which may be convicted for progression of kindling epileptogenesis. However, in kindling resistant animals elevated GABA, taurine, tryptophan, serotonin, glycine, and d-serine levels with decreased indoleamine 2,3-dioxygenase activity were observed as natural endogenous antiepileptogenic mechanisms, which may be foreseen as safe pharmacological targets for management of epileptogenesis.
大多数临床上可用的抗癫痫药物仅具有抗惊厥作用，据报道无法预防癫痫发生。在过去十年中，几种药物进行了治疗癫痫发生的临床试验，但所测试的药物均未发现有效。其中一个主要缺陷是缺乏合适的临床前方法来描述癫痫发生的机制。因此，本研究试图提出一种基于神经化学的方法来安全管理癫痫发生。已描绘了未点燃、点燃和抗点燃动物小鼠大脑杏仁核、皮层和海马区中改变的神经化学环境。在抗点燃动物中观察到的内源性天然抗癫痫发生神经化学防御机制可能揭示癫痫发生的神经化学机制，进而为我们提供安全管理癫痫发生的新干预措施。通过以48±2小时的间隔腹腔注射亚惊厥剂量的戊四氮（35mg/kg）持续42天，在2月龄雄性瑞士白化小鼠中进行点燃癫痫发生实验。在最后一次戊四氮注射后2小时，对动物进行行为评估。行为评估4小时后，对所有动物实施安乐死，并采集大脑的离散部分（杏仁核、皮层和海马）进行神经化学分析。结果显示，60%的动物对点燃有反应，表现为癫痫阈值降低，而其余动物则被发现具有抗性。发现点燃动物伴有焦虑、抑郁和认知障碍；而在抗点燃动物中未观察到此类行为缺陷。神经化学分析显示，在点燃动物中观察到谷氨酸 - γ-氨基丁酸神经传递改变，牛磺酸、甘氨酸、D-丝氨酸、单胺水平降低以及吲哚胺2,3-双加氧酶活性升高，这可能与点燃癫痫发生的进展有关。然而，在抗点燃动物中观察到γ-氨基丁酸、牛磺酸、色氨酸、5-羟色胺、甘氨酸和D-丝氨酸水平升高以及吲哚胺2,3-双加氧酶活性降低，这是天然的内源性抗癫痫发生机制，可被视为管理癫痫发生的安全药理学靶点。
