From insult to hyperexcitability: pharmacological targeting of MyD88 and JAK/STAT3 pathways in epilepsy.

Neuroinflammation is hypothesized to be a fundamental driver of epileptogenesis, potentially contributing to the transformation of the healthy brain into a state prone to spontaneous recurrent seizures. This manuscript explores the pivotal roles of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) in modulating neuronal excitability and structural plasticity. We delineate how the activation of the NLRP3 inflammasome and the P2×7 receptor pathway leads to the maturation of IL-1β, which subsequently triggers the MyD88 and PI3K/AKT/mTOR cascades. These pathways collectively enhance NMDA receptor activity and glutamate release while suppressing GABAergic inhibition, establishing a cycle of neuronal hyperexcitability. Furthermore, we examine the systemic and local impacts of IL-6 signaling mediated through the JAK/STAT3 pathway. Beyond acute synaptic effects, IL-6 contributes to chronic pathology by inducing gliosis, hindering hippocampal neurogenesis, and promoting blood-brain barrier leakage via CCL2 production. These multi-level disruptions not only facilitate seizure activity but also contribute to the cognitive and behavioral comorbidities often observed in epilepsy. By synthesizing current understanding of these signaling axes, this review highlights the therapeutic potential of targeting specific cytokine receptors, such as the IL-1 receptor antagonist, to intercept the epileptogenic process. Understanding these neuroinflammatory benchmarks is essential for developing disease-modifying treatments that move beyond symptomatic seizure control toward true prevention of epilepsy.