Rotenone in Drug-Resistant Epilepsy Models: Powerful Tool or Problematic Paradigm?

The rotenone adjuvant kindling paradigm replicates key clinical features of drug-resistant epilepsy (DRE), including broad-spectrum pharmacoresistance, neuroinflammation, and oxidative stress, by combining mitochondrial complex I inhibition with pentylenetetrazol (PTZ) or corneal kindling. PTZ, a GABA_A receptor antagonist, induces seizures by reducing inhibitory neurotransmission and is widely used to model kindling and seizure susceptibility; in this paradigm, its repeated subconvulsive dosing facilitates progressive epileptogenesis and enhances network hyperexcitability. Rotenone-induced microglial activation and mitochondrial dysfunction further potentiate PTZ sensitivity, limiting the penetration and effectiveness of antiseizure drugs by promoting cytokine release, disrupting the blood-brain barrier, and overexpressing efflux transporters. In comparison to traditional DRE models, this paradigm's construct, face, and predictive validity are strengthened by its recapitulation of neuropsychiatric comorbidities and spontaneous recurrent seizures. Comparative findings suggest greater clinical relevance and improved suitability for evaluating mechanism-based therapies targeting mitochondrial dysfunction, GABAergic imbalance, and inflammatory signaling; however, concerns regarding systemic toxicity, mortality, and inter-animal variability remain important limitations. Overall, the rotenone adjuvant PTZ-kindling model represents a promising, though imperfect, translational platform for the development of novel therapies for DRE.