Identifying key regulators of the immune/inflammatory response for developing anticonvulsive and antiepileptogenic approaches

Abstract

Epilepsy therapy is based on drugs that treat the symptoms, seizures, rather than the disease. There are no treatments for modifying the course of the disease, improving prognosis. Another unmet need is the absence of biomarkers able to identify patients at risk of developing epilepsy or with a progressive disease. Among the potential pathways for attaining these unmet needs, we focused on neuroinflammation since it is a pathological process occurring in experimental epileptogenesis and in human epilepsy. Interleukin-1β (IL-1β)/IL-1Receptor type 1 (IL-1R1) and High Mobility Group Box 1 (HMGB1)/Toll-like Receptor 4 (TLR4) axes are key initiators of neuroinflammation following epileptogenic injuries. Experimental and clinical evidence showed that endogenous anti-inflammatory mechanisms are not efficiently activated in epileptogenic tissue. Among these mechanisms, we focused on specialized mediators driving the process of “resolution of inflammation”. We demonstrated that induction of pro-resolving response is delayed during epileptogenesis compared to activation of neuroinflammation. Based on this, we studied the antiepileptogenic and disease-modifying effects of two pharmacological strategies aimed at (1) anticipating and boosting resolution of neuroinflammation by enhancing pro-resolving mechanisms and (2) blocking the neuroinflammatory response with a combined anti-inflammatory treatment targeting IL-1β/IL-1R1 and HMGB1/TLR4 pathways. (1) The pro-resolving treatment decreased neuroinflammation, ameliorated cognitive deficits and reduced spontaneous seizure frequency and duration; (2) the combined anti-inflammatory treatment prevented disease progression. The role of HMGB1 and its isoforms was investigated in epileptogenesis and drug-resistance. In two animal models of epileptogenesis the pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset, and prospectively identified animals that developed the disease. Moreover, the combined anti-inflammatory approach prevented disease progression and the increase in HMGB1 isoforms in blood during epileptogenesis. In conclusion, pro-resolving and anti-inflammatory treatments have disease-modifying effects and HMGB1 isoforms are potential mechanistic biomarkers for epileptogenesis, underlying the need of validation in prospective clinical studies.