Effects of hypnotic bromovalerylurea on microglial BV2 cells

Abstract

An old sedative and hypnotic bromovalerylurea (BU) has anti-inflammatory effects. BU suppressed nitric oxide (NO) release and proinflammatory cytokine expression by lipopolysaccharide (LPS)-treated BV2 cells, a murine microglial cell line. However, BU did not inhibit LPS-induced nuclear translocation of nuclear factor-κB and subsequent transcription. BU suppressed LPS-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1). The Janus kinase 1 (JAK1) inhibitor filgotinib suppressed the NO release much more weakly than that of BU, although filgotinib almost completely prevented LPS-induced STAT1 phosphorylation. Knockdown of JAK1, STAT1, or IRF1 did not affect the suppressive effects of BU on LPS-induced NO release by BV2 cells. A combination of BU and filgotinib synergistically suppressed the NO release. The mitochondrial complex I inhibitor rotenone, which did not prevent STAT1 phosphorylation or IRF1 expression, suppressed proinflammatory mediator expression less significantly than BU. BU and rotenone reduced intracellular ATP (iATP) levels to a similar extent. A combination of rotenone and filgotinib suppressed NO release by LPS-treated BV2 cells as strongly as BU. These results suggest that anti-inflammatory actions of BU may be attributable to the synergism of inhibition of JAK1/STAT1-dependent pathways and reduction in iATP level.

Comparison of the detrimental features of microglia and infiltrated macrophages in traumatic brain injury: A study using a hypnotic bromovalerylurea

“…BU has marked antiinflammatory effects on microglia (Higaki et al, ) and macrophages (Kikuchi et al, ), and the effects that are at least partly attributable to suppressive effects on ATP synthesis (Kawasaki et al, ). In this study, the effects of BU on cell metabolism were investigated in primary microglial cells (Figure ) and alveolar macrophages (Supporting Information Figure S1) using the Seahorse Mito‐Stress Test, which assesses Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) (Figure a) (Banh et al, ; Garaude et al, ).…”

“…BU inhibits CCL2 expression by lipopolysaccharide (LPS)‐treated peritoneal macrophages (Kikuchi et al, ) and proinflammatory activation of microglia (Higaki et al, ). The antiinflammatory effects were at least partly attributable to its suppressive effects on mitochondrial ATP production (Kawasaki et al, ). In this study using a rat stab‐wound TBI model, BU produced marked long‐term amelioration of neurological deficits while reducing brain tissue loss.…”

Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

“…It reduced tissue loss and improved cognitive function in a rat stab-wound brain injury model [70]. The anti-inflammatory effect of BU on LPS-treated primary microglia is as strong as that of Dex [136]. BU does not inhibit the nuclear translocation of NFκB but suppresses the phosphorylation of JAK1-STAT1 and the expression of IRF1 [135].…”

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

“…Although BU does not suppress LPS-induced NFkB translocation into nuclei, its inhibitory effects are exerted at the transcriptional level. BU inhibited ATP synthesis in mitochondria; this may be related to its anti-inflammatory effects [10,96] . Moreover, BU inhibits Janus kinase 1 activity, thus suppressing the phosphorylation of STAT1 and the subsequent expression of IRF1 [43] .…”

“…It is not prescribed currently because of its weak actions as a hypnotic/sedative compared with newer agents such as benzodiazepines and also due to dependency. Recently, it has been found to have strong anti-inflammatory effects [10,43,96,97] . The effects of BU on LPS-treated primary rat microglia are as strong as those of Dex [43] .…”