Unraveling the Inflammatory Enigma: Is Neuroinflammation a Culprit or Consequence in Pharmacoresistant Epilepsy?

BACKGROUND

Approximately 30% of epilepsy patients develop pharmacoresistant epilepsy (PRE), characterized by persistent seizures refractory to antiseizure medications (ASMs). While neuroinflammation is implicated in both epileptogenesis and treatment failure, its precise temporal contribution remains unclear. This study aimed to delineate the distinct roles of acute versus chronic neuroinflammation in seizure susceptibility and the maintenance of drug resistance.

METHODS

Male Sprague-Dawley rats received acute inflammatory priming via systemic (intraperitoneal) or intracranial (hippocampal) lipopolysaccharide (LPS) administration prior to lithium-pilocarpine-induced status epilepticus (SE). Rats were subsequently classified as PRE or pharmacosensitive epilepsy (PSE) based on their response to two sequentially administered ASMs. Outcomes were assessed using video-EEG monitoring, hippocampal cytokine profiling (IL-6 and TNF-α), histopathological analysis of neuronal damage, and peripheral inflammatory markers.

RESULTS

Acute inflammatory priming significantly lowered the threshold for SE induction (P < 0.05); however, it did not increase the proportion of PRE (P > 0.05). In contrast, established PRE was characterized by sustained hippocampal neuroinflammation, with markedly elevated IL-6 and TNF-α levels compared to PSE and control groups, alongside severe neuronal loss.

CONCLUSION

These findings reveal a temporal dissociation in the roles of neuroinflammation: acute inflammation acts as a potent initiator of epileptogenesis, whereas chronic, sustained inflammation coincides with the drug-resistant phenotype. This study refines the prevailing view of neuroinflammation from a static pathogenic factor to a dynamic, phase-dependent modulator, supporting the rationale for stage-targeted strategies in PRE. Notably, putative mechanisms linking inflammation to resistance, such as impaired efferocytosis, warrant future experimental validation.