Chemokines as new inflammatory players in the pathogenesis of epilepsy

Abstract

A large series of clinical and experimental studies supports a link between inflammation and epilepsy, indicating that inflammatory processes within the brain are important contributors to seizure recurrence and precipitation. Systemic inflammation can precipitate seizures in children suffering from epileptic encephalopathies, and hallmarks of a chronic inflammatory state have been found in patients with temporal lobe epilepsy. Research performed on animal models of epilepsy further corroborates the idea that seizures upregulate inflammatory mediators, which in turn may enhance brain excitability and neuronal degeneration. Several inflammatory molecules and their signaling pathways have been implicated in epilepsy. Among these, the chemokine pathway has increasingly gained attention. Chemokines are small cytokines secreted by blood cells, which act as chemoattractants for leukocyte migration. Recent studies indicate that chemokines and their receptors are also produced by brain cells, and are involved in various neurological disorders including epilepsy. In this review, we will focus on a subset of pro-inflammatory chemokines (namely CCL2, CCL3, CCL5, CX3CL1) and their receptors, and their increasingly recognized role in seizure control.

Autoimmune seizures and epilepsy

“…These events are followed by the induction of COX-2 and prostaglandins (PGE2), with upregulation of components of the complement system in the indicated cells (73). Subsequent changes include the production of chemokines and their receptors in neurons and activated astrocytes (69,74).…”

Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood‐brain barrier dysfunction and seizure progression

“…Until now, there has been ample evidence that the innate response plays a role during the development of TLE . More recently, the role of peripheral inflammation in TLE has come to attention, with a central role for the infiltration of leukocytes and/or activated circulating cytokines . However, their precise contribution to epileptogenesis and BBB dysfunction is still not understood.…”

“…1 More recently, the role of peripheral inflammation in TLE has come to attention, with a central role for the infiltration of leukocytes and/or activated circulating cytokines. 19 However, their precise contribution to epileptogenesis and BBB dysfunction is still not understood. We therefore studied the expression of various inflammatory markers of the innate and adaptive immune system in the epileptogenic human and rat hippocampus in relation to seizure activity and BBB dysfunction.…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…A dysregulated neuroinflammatory response has been suggested to play a pathogenic role in several central nervous system (CNS) diseases, including acute and chronic neurodegeneration, 1-3 and epilepsy. [4][5][6][7] Indeed, there are several examples in the literature showing that a persistent neuroinflammatory response in the injured brain may result in neuronal and glial cell dysfunction, alterations in bloodbrain barrier (BBB) homeostasis, or neuronal cell death. Inefficient anti-inflammatory control by endogenous resolving mechanisms may play a pivotal role in igniting persisting neuroinflammation.…”