2018 年 10 巻 1 号 p. 22-32
Purpose: To elucidate the effects of antiepileptic drugs (AEDs) on microglial cytokine production, polarization, and morphology.
Methods: MG6, an immortalized mouse microglial cell line, was stimulated with lipopolysaccharides (LPS) and the levels of pro-inflammatory cytokines were measured by enzyme linked immunosorbent assay, quantitative polymerase chain reaction (q-PCR), and intracellular staining using flow cytometry. M1 and M2 signatures of microglia after polarization were assessed using quantitative PCR and flow cytometry. Primary microglia prepared from CX3CR1-GFP mice were used to study the effects of AEDs on microglial morphology.
Results: Valproic acid (VPA) or gabapentin (GBP) augmented LPS-induced interleukin-6 (IL-6) production, while phenobarbital (PB) suppressed it. Tumor necrosis factor α (TNFα) production was enhanced by VPA, but was suppressed by PB and GBP. Levetiracetam did not alter cytokine production. It was difficult to assess the effects of water-insoluble AEDs because dimethyl sulfoxide solvent markedly suppressed IL-6 production. The mechanism of altered IL-6 production by AEDs was independent of their transcription or extracellular release. VPA augmented microglial M1 polarization. AEDs did not substantially affect the expression of microglial surface markers and had limited effect on the morphology of primary microglia.
Discussion: Although VPA increased microglial production of pro-inflammatory cytokines, partly due to augmented M1 polarization, most of the AEDs tested in the present study had neither beneficial nor adverse effects on inflammation in clinical practice.
