Attenuation of mitochondrial refractory epilepsy in rotenone corneal kindling model of drug resistance by idebenone: An approach to bypass mitochondrial complex I

IF 2 4区医学 Q3 CLINICAL NEUROLOGY Epilepsy Research Pub Date : 2024-10-05 DOI:10.1016/j.eplepsyres.2024.107458

Arshbir Kaur, Arvinder Kaur, Samriti, Rajesh Kumar Goel

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Abstract

Objective

To assess the potential of bypassing mitochondrial complex I with idebenone to overcome drug resistance in a Rotenone corneal kindling (RCK) mouse model of mitochondrial refractory epilepsy.

Material and method

Resistance was developed by administering rotenone 2.5 mg/kg intraperitoneally once and corneal kindling twice daily. The kindling development took 15 days, and pre-treatment resistance validation was carried out with five different antiseizure drugs: pregabalin, levetiracetam, valproate, lamotrigine, and phenytoin. The treatment drug, Idebenone (IDB) was given at doses of 10, 20, and 40 mg/kg intraperitoneally for 10 days. The post-treatment resistance validation was evaluated with same standard drugs in same order along with other parameters assessment, such as NAD(P)H: quinone oxidoreductase 1 (NQO1), ATP, GSH, and TBARS.

Results

The pre-treatment resistance validation shows an inability of standard drugs to attenuate seizure scores by rotenone kindling, justifying the development of drug resistance. IDB successfully abolished the resistance developed in RCK model. IDB elevated the levels of ATP and NQO1 and showed antioxidant activity by elevating GSH and attenuating TBARS.

Conclusion & future direction

IDB have successfully elevated the level of ATP, NQO1 in RCK model, hence proving the complex I bypass hypothesis. Thus, IDB can be the drug of choice for mitochondrial epilepsies involving drug refractoriness as adjuvant with anticonvulsant drugs.

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依地美酮可减轻鱼藤酮角膜点燃耐药模型中的线粒体难治性癫痫：绕过线粒体复合体 I 的方法

材料与方法通过腹腔注射鱼藤酮 2.5 毫克/千克，每天 1 次，角膜点燃 2 次，产生耐药性。角膜点燃过程历时 15 天，治疗前用五种不同的抗癫痫药物：普瑞巴林、左乙拉西坦、丙戊酸钠、拉莫三嗪和苯妥英进行耐药性验证。治疗药物艾地苯醌（IDB）的剂量分别为 10、20 和 40 毫克/千克，腹腔注射 10 天。结果治疗前的耐药性验证表明，标准药物无法减轻鱼藤酮点燃的癫痫发作评分，这证明耐药性的产生是有道理的。IDB 成功消除了 RCK 模型中产生的耐药性。IDB 提高了 ATP 和 NQO1 的水平，并通过提高 GSH 和降低 TBARS 显示出抗氧化活性。因此，IDB 可以作为抗惊厥药物的辅助药物，用于治疗涉及药物难治性的线粒体癫痫。

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来源期刊

Epilepsy Research 医学-临床神经学

CiteScore

0.10

自引率

4.50%

发文量

143

审稿时长

62 days

期刊介绍： Epilepsy Research provides for publication of high quality articles in both basic and clinical epilepsy research, with a special emphasis on translational research that ultimately relates to epilepsy as a human condition. The journal is intended to provide a forum for reporting the best and most rigorous epilepsy research from all disciplines ranging from biophysics and molecular biology to epidemiological and psychosocial research. As such the journal will publish original papers relevant to epilepsy from any scientific discipline and also studies of a multidisciplinary nature. Clinical and experimental research papers adopting fresh conceptual approaches to the study of epilepsy and its treatment are encouraged. The overriding criteria for publication are novelty, significant clinical or experimental relevance, and interest to a multidisciplinary audience in the broad arena of epilepsy. Review articles focused on any topic of epilepsy research will also be considered, but only if they present an exceptionally clear synthesis of current knowledge and future directions of a research area, based on a critical assessment of the available data or on hypotheses that are likely to stimulate more critical thinking and further advances in an area of epilepsy research.