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

Autor: Kaur A; Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India., Kaur A; Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India., Samriti; Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India., Goel RK; Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India. Electronic address: goelrkpup@gmail.com.
Jazyk: angličtina
Zdroj: Epilepsy research [Epilepsy Res] 2024 Nov; Vol. 207, pp. 107458. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1016/j.eplepsyres.2024.107458
Abstrakt: 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.
Competing Interests: Conflict of Interest No conflict of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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