Modelling Epilepsy Associated Alzheimer’s Disease Through Mitochondrial Complex-I Inhibition: Neurochemical and Therapeutic Perspectives

Alzheimer’s disease (AD) is comorbid condition in epilepsy. Mitochondrial dysfunction serves as a common disease mechanism. This study aimed to develop a new mouse of epilepsy-associated AD by inhibiting mitochondrial complex-I and exploring neurochemistry to identify therapeutic targets. Swiss albino mice were divided into naïve, corneal kindled (CK), and rotenone corneal kindled (RCK) groups. CK underwent epileptogenesis by using 6 Hz corneal kindling model (15 mA, 20 V, 6-Hz, 3 s for 15 days), while RCK underwent both epileptogenesis and mitochondrial dysfunction via rotenone administration (2.5 mg/kg, i.p daily). RCK mice exhibited generalised tonic-clonic seizures, cognitive deficits, oxidative stress, and Aβ/tau deposition. Neurochemical analysis showed increased glutamate, kynurenine, and reduced GABA, taurine, monoamines, antioxidants, and acetylcholinesterase activity. The RCK model replicates construct and face validity of both epilepsy and AD, may serve as a new model to investigate shared disease mechanisms and associated altered neurotransmitter as therapeutic approach.