Immune Mechanism of Epileptogenesis and Related Therapeutic Strategies

Abstract

Immunologic and neuroinflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources, it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. For this reason, we performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways involved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs.

Keywords: epilepsy; epileptogenesis; neuroimmunology; neuroinflammation; treatment.

Figure 1

Types of immunity acting at the level of the CNS. Created with www.Biorender.com (last access on 15 March 2022).

Figure 2

An outline of the processes underlying the activation of microglia. Created with www.Biorender.com (last access on 15 March 2022).

Figure 3

Some of the most important intracellular molecular pathways leading to epileptogenesis are shown. 1. -JAK-STAT pathway: proinflammatory cytokines (such as IL-10) set this pathway in motion. The phosphorylated STAT3 protein can alter gene expression to induce secretion of proinflammatory cytokines (IL-1β, IL-6, or TNF-α). 2. -TLR pathway can be activated by DAMPS or PAMPS. 3. -HMGB1 is produced by cell damage and activates the pathway through its interaction on RAGE-TLR4. 4. -TNFR can be activated by the release of TNF-α. The pathways activated by TLR, RAGE-TLR4, and TNFR converge in the activation of NF-κβ, which also modifies gene expression to induce the secretion of proinflammatory cytokines. Created with www.Biorender.com (last access on 15 March 2022).