Pathophysiological Cascade of Events Leading to Epilepsy: Role of Inflammation

Abstract

Epileptogenesis is an alteration modification of the typical brain structure, yielding a brain drained by recurring seizures. Such a process is usually precipitated by neurodegeneration, disruption of blood-brain barrier (BBB), the amygdala, the glutamatergic system, oxidative stress, and epigenetic modification deoxyribonucleic acid (DNA). Since there is no efficient method yet, to modify or control this disorder's pathway due to its unclear pathology, novel therapeutic approaches are needed. The risk to develop epilepsy, aggravate the frequency of seizures have been strongly linked to peripheral inflammatory disorders in humans as well as animal studies, with the latter demonstrating a specific association between peripheral inflammatory bowel disorders and peripheral injection of the Toll‐like receptor 4 (TLR4) ligand lipopolysaccharide (LPS) and the increased seizer's frequency and their induced injuries. Understanding the exact function and role of the chemical mediators and receptors involved in the neuroinflammatory reaction could help elucidate their contribution to the pathogenesis of epilepsy. These inflammatory markers include interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), which are expressed in activated microglia and astrocytes; they trigger the complement system, nuclear factor-kappa b (NF-κB), cyclooxygenase-2 (COX-2), chemokines, and acute-phase proteins. The neural tissues and the endothelial layer of the BBB neurons are involved in these inflammatory reactions. The high-mobility-group Box 1 (HMGB1) fast release from microglia, neurons, and astrocytes after exposure to pro-convulsant insult and Toll-like receptor activation (TLR) signaling in astrocytes and neurons has been proven to be significantly involved in triggering brain inflammation and reducing the seizure threshold. The current review aims to determine the effect of anti-inflammatory drugs on the epilepsy foci rather than treating the symptoms. Such understanding could be the basis of developing a new treatment that could be effective for cases refractory to the current treatment.