Guanabenz Prevents d-Galactosamine/Lipopolysaccharide-Induced Liver Damage and Mortality

Abstract

Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-α) expression. Consequently, drugs interfering with eIF2α phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2α phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti-inflammatory activity by increasing in vitro interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the d-galactosamine (d-galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF-α production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure.

Guanabenz modulates microglia and macrophages during demyelination

“…Therapeutic Gz attenuates EAE symptoms. We first employed Gz in EAE models to investigate its potential to dampen inflammation within the CNS, since it has been shown to exert anti-inflammatory effects in other contexts [7][8][9][10] . Monophasic EAE was induced in 8-10-week-old female C57BL/6 mice using MOG , and motor dysfunction was assessed daily using a disease score measure of 0 (no deficits) through 5 (death).…”

“…Some immunomodulatory effects were also observed, with fewer immune cells present in the spinal cord of EAE animals administered Gz daily 6 . There have since been reports that Gz exerts anti-inflammatory activity in other pathological settings such as latent Toxoplasma gondii infection 7 , d -Galactosamine/LPS-induced liver damage 8 , and a toxin-induced model of systemic lupus erythematosus (SLE) 9 . In vitro work has demonstrated that Gz directly downregulates pro-inflammatory genes in LPS-stimulated primary macrophages and dendritic cells 8 , 10 .…”

“…There have since been reports that Gz exerts anti-inflammatory activity in other pathological settings such as latent Toxoplasma gondii infection 7 , d -Galactosamine/LPS-induced liver damage 8 , and a toxin-induced model of systemic lupus erythematosus (SLE) 9 . In vitro work has demonstrated that Gz directly downregulates pro-inflammatory genes in LPS-stimulated primary macrophages and dendritic cells 8 , 10 . Taken together, it is possible that Gz exerts anti-inflammatory effects to a greater extent than previously investigated in models of MS.…”

Tectorigenin protects against experimental fulminant hepatic failure by regulating the TLR4/mitogen‐activated protein kinase and TLR4/nuclear factor‐κB pathways and autophagy

“…The sections were stained with hematoxylin–eosin, and representative images of nonconsecutive free‐selection 200× histological fields were captured using a digital slice scanning equipment (NanoZoomer 2.0RS). Hematoxylin–eosin stained livers were evaluated by a single pathologist in a blinded fashion on the reported semiquantitative scale (Perego et al, ).…”

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells

“…TNF-α is recognized as a critical inflammatory mediator in the pathogenesis of inflammation and infection-related diseases; moreover, its toxicity may directly damage hepatocytes (31). High amounts of circulating pro-inflammatory TNFα, the characteristic manifestation of FHF, ultimately induce multiple organ failure (32). TNF-α, via binding TNF receptor on the surface of hepatocytes as an exocellular death signal, can stimulate inner oxidative stress and initiate the apoptotic pathway, which triggers more extensive hepatocyte death and a serious inflammatory response (33).…”