Chapter 4 – Ictogenic and Epileptogenic Mechanisms of Neuroinflammation: Insights From Animal Models

Neuroinflammation is a hallmark of human epileptogenic foci in various pharmacoresistant forms of epilepsy. Increasing experimental evidence has shown that neuroinflammation is not a bystander phenomenon of the diseased brain tissue, but it contributes to neuronal hyperexcitability underlying seizure generation. Several of the molecules that constitute the inflammatory milieu in the epileptogenic areas can activate signaling pathways in neurons and glia that result in pathologic modifications of cell function. These pathways include rapid posttranslational changes in voltage-gated and receptor-coupled ion channels, mostly mediated by activation of protein kinases, and transcriptional regulation of genes involved in synaptic transmission and plasticity. These nonconventional modes of action highlight the neuromodulatory role of inflammatory molecules, which differs from their classic functions as mediators of immune activation during infections. In this chapter, we will review cell sources and targets of inflammatory mediators in epilepsy and their impact on glial and neuronal functions. We will report the up-to-date evidence supporting their neuromodulatory role and discuss how these mechanisms can be harnessed to characterize and validate targets for novel therapeutics, which may prevent or control pharmacoresistant seizures.