TARGETING AUTOPHAGIC FLUX IMPAIRMENT AS A POTENTIAL DISEASE-MODIFYING STRATEGY IN TEMPORAL LOBE EPILEPSY

Temporal lobe epilepsy (TLE) often develops after a long latency period following an initial insult. Understanding the molecular mechanisms underlying this epileptogenic phase is crucial for developing preventive strategies. Increasing evidence suggests that autophagy, a key homeostatic cellular degradation process, may be involved in TLE pathophysiology.
The objectives of this study were: 1) to characterize the autophagy flux progression in different stages of epileptogenesis of the rat pilocarpine model of TLE, and 2) to evaluate the potential antiepileptogenic effect of the autophagy inducer spermidine.
Autophagy flux was analyzed at multiple stages of epileptogenesis – early latency, late latency, and the chronic phase – and was assessed by Western Blot analysis of key markers in the hippocampus. A cohort of animals was treated for a week with spermidine (25 mg/kg i.p.) immediately after status epilepticus (SE) and seizure frequency, and durations were monitored to evaluate disease-modifying effects.
Western blot analyses revealed a significant accumulation of autophagosomes in the hippocampus during the latency period and a reduced phosphorylation of proteins within the AMPK pathway, suggesting a blockade of the autophagic flux. Preliminary data from long-term seizure monitoring showed that spermidine-treated animals exhibit a reduced frequency of spontaneous recurrent seizures compared to controls.
Overall, these findings indicate an impairment of the autophagic flux during the latent phase of epileptogenesis and suggest that an early pharmacological induction of autophagy may exert a disease-modifying effect. Ongoing studies aim to identify the mechanism of flux inhibition and validate autophagy-related pathways as targets for epilepsy prevention.