Microglial activation is inhibited by selective anti-seizure medications.

Objective: To investigate the anti-inflammatory properties of anti-seizure medications (ASMs) administered to patients with drug-resistant epilepsy (DRE) and the role of sodium channels in microglial activation.

Material: Primary microglia monocultures from mice brains.

Treatment: Microglia were activated with 10 μg/mL lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C) and pre- (45 min ASM then 2 h ASM plus stimulus) or post- (2 h stimulus then 24 h only ASM) treated with ASMs. Microglia were treated with cannabidiol (10 μM), stiripentol (250 μM), fenfluramine (50 μM), phenytoin (8 and 40 μM), cenobamate (300 and 900 μM), or the small molecule sodium channel blocker GS967 (10 and 30 μM). The sodium channel modulators tetrodotoxin (1 μM), µ-conotoxin KIIIA (1 μM), and β-pompilidotoxin (0.5 μM) were also applied.

Methods: Microglia activation was quantified through measurements of Ptgs2 (Cox2), Tnf-α, and Ifn-β induction by RT-qPCR and of cell morphology by immunocytochemistry. Expression of sodium channels in microglia was studied using PCR, RT-qPCR, immunohisto- and immunocytochemistry. Mann Whitney test and the Kruskal-Wallis test with Dunn's multiple comparisons post-test were used.

Results: ASMs have a differential effect on microglial activation. Uniquely, cenobamate inhibited the induction of Ifn-β and made the cells less amoeboid. The voltage gated sodium channel Na_v1.2 is expressed by microglial cells and its expression levels change with microglial inflammatory response. Toxins that block sodium channels modulated microglial activation.

Conclusions: ASMs, applied to patients with DRE, have a differential ability to reduce microglial activation and pro-inflammatory microglial morphology in vitro. Moreover, sodium channel blockage modulates inflammation through microglia activation. Taken together these results suggest, that further investigation of patient's immune response to ASMs could be important.