Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

Abstract

BackgroundPeripheral-type benzodiazepine receptor (PBR) expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL)-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB), p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT)3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect.MethodsCultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting.ResultsMidazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase), SP600125 (an inhibitor of SAPK/JNK), and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3). However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2). Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB.ConclusionThese results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS.

Resveratrol Prevents Ammonia Toxicity in Astroglial Cells

“…These cytokines have a major role in initiating a cascade of activation of other cytokines and growth factor in inflammatory response [73]. TNF-α is synthesized mainly by microglia and astrocytes, and has several important functions in the CNS, including astrocytes activation and glutamatergic gliotransmission [30], [73], [74]. Recent studies show that proinflammatory cytokines are increased in HE [75], [76], may be used as a marker for encephalopathy grade.…”

“…This enzyme is very sensitive to oxidative stress, and it has been hypothesized to play an important role in the pathogenesis of ammonia neurotoxicity [23]. The C6 cell line are widely used to study astrocytic functions such as glutamate metabolism (glutamate uptake, GS activity and glutathione production), S100B secretion, oxidative and inflammatory responses [24], [25], [26], [27], [28], [29], [30].…”

Septic encephalopathy: does inflammation drive the brain crazy?

“…81 This seems to be a specific effect, as propofol has no such protective effect in vitro. 82 Thus, if systemic and brain inflammation leads to delirium, it is expected that BZ could improve delirium in the critically ill patient.…”

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

“…Recent study has demonstrated that astrocytic activation, maturation, and differentiation are involved in the expression of central type benzodiazepine receptors coupled to GABA A receptors in astrocytes. Furthermore, Hiroki et al has demonstrated that midazolam inhibits IL-1b-induced IL-6 release through the JAK/STAT3 pathway suppression in C6 glioma cells [21]. However, the cytoprotective effect of midazolam on brain astrocytes has not been fully disclosed.…”