PPARα activation with fenofibrate confers hippocampal neuroprotection but lacks disease-modifying efficacy in chronic temporal lobe epilepsy.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) suppresses neuroinflammation and may interrupt epileptogenesis. We tested whether early intervention with the PPARα agonist fenofibrate exerts disease-modifying effects in the chronic phase of the lithium-pilocarpine model of temporal lobe epilepsy. Male Wistar rats received fenofibrate (100 mg/kg, i.p., daily for 15 days) initiated 1 h after status epilepticus. Outcomes were assessed 1-3 months later. Fenofibrate significantly attenuated neuronal loss in the dorsal CA1 subfield and ventral hilus of the hippocampus, partially reduced astrogliosis in the hilus, and decreased the proportion of amoeboid microglia in CA1. Behaviorally, fenofibrate prevented the TLE-induced reduction in risk-assessment exploration in the elevated plus maze, without affecting general locomotion or anxiety. Critically, fenofibrate did not alter the incidence of spontaneous recurrent seizures, interictal spike frequency, or the pathological reduction in delta and theta EEG power. It also failed to normalize the aberrant cortical response to pentylenetetrazol or reduce seizure severity. These findings demonstrate that early PPARα activation confers region-restricted neuroprotection and modest behavioral benefit, but does not suppress the core pathophysiological features of chronic epilepsy. The results dissociate neuroprotection from antiepileptogenesis and caution against assuming that anti-inflammatory interventions alone are sufficient for disease modification in temporal lobe epilepsy.