Effects of antiepileptic drugs on microglial properties

Abstract

Purpose:To elucidate the effects of antiepileptic dr ugs (AEDs) on micr oglial cytokine pr oduction, polarization, and morphology. Methods: MG6, an immor talized mouse micr oglial 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: Valpr oic 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 incr eased micr oglial pr oduction of pr o-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.

Interdependence of neural network dysfunction and microglial alterations in Alzheimer’s disease-related models

“…However, we cannot exclude that LEV affects genes, morphological parameters or functions of microglia/macrophages that we did not measure. LEV has been shown to affect some properties of immortalized microglial cell lines ( Shima et al., 2018 ; Itoh et al., 2019 ), although it should be noted that such cell lines differ from primary microglia in many respects, including in their responses to LPS stimulation ( Butovsky et al., 2014 ; Das et al., 2016 ). For the following reasons we also consider it most likely that the effects of tau reduction on inflammation-related gene expression resulted indirectly from the modulation of neuronal activities.…”

Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy

“…In vitro studies on microglial cells as mediators of inflammation have demonstrated that topiramate, a second generation AED, decreased the release of IL-1β, IL-6 and TNF-α [ 144 ] . Other AEDs such as levetiracetam, gabapentin, and phenobarbital showed slight modification in cytokine production [ 145 ] . The first generation AED valproic acid, was shown to increase IL-6 and TNF-α production in LPS-induced microglial cells [ 145 ] , which contrasts with in vivo results where TNF-α and IL-1β were decreased after valproic acid treatment [ 143 ] .…”

“…Other AEDs such as levetiracetam, gabapentin, and phenobarbital showed slight modification in cytokine production [ 145 ] . The first generation AED valproic acid, was shown to increase IL-6 and TNF-α production in LPS-induced microglial cells [ 145 ] , which contrasts with in vivo results where TNF-α and IL-1β were decreased after valproic acid treatment [ 143 ] . It was also demonstrated that the AED levetiracetam suppressed neuroinflammation and phagocytosis in a pilocarpine induced SE model [ 143 ] .…”