Luzindole attenuates LPS/d-galactosamine-induced acute hepatitis in mice

Abstract

Melatonin is a well-documented hormone that plays central roles in the regulation of sleep–wake cycles. There is cumulative evidence to suggest that melatonin is also a pleiotropic regulator of inflammation, and luzindole has been widely used as a melatonin receptor antagonist. This study investigated the potential effects of luzindole on LPS/d-galactosamine (d-GalN)-induced acute hepatitis. The results indicated that treatment with luzindole alleviated histological damage in the liver, reduced the level of transaminases in plasma and improved the survival of LPS/d-GalN-exposed mice. Treatment with luzindole also suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 in LPS/d-GalN-exposed mice. In addition, treatment with luzindole inhibited the activation of caspase-3, -8 and -9, and suppressed the cleavage of caspase-3 and poly(ADP-ribose) polymerase. Therefore, treatment with luzindole attenuates LPS/d-GalN-induced acute liver injury, suggesting that luzindole might have potential value for the intervention of inflammation-based hepatic disorders.

Melatonin Attenuates Sepsis-Induced Small-Intestine Injury by Upregulating SIRT3-Mediated Oxidative-Stress Inhibition, Mitochondrial Protection, and Autophagy Induction

“…Competitive melatonin receptor antagonist luzindole (MT1/MT2-nonselective) and 4-phenyl-2-propionamidotetralin (4P-PDOT, MT2-selective) was i.p. injection at a dose of 40 mg/kg and 1.0 mg/kg dissolved in 10% DMSO (diluted with edible oil; the dose of luzindole ( 36 ) and 4P-PDOT ( 37 ) was chosen based on previous literature and our preliminary experiment. The benefit effect of melatonin on SIRT1 activation was considerably blocked by luzindole ( 36 ) and slightly blocked by 4P-PDOT in small intestine 8 h following sepsis ( Figure 3A ).…”

“…injection at a dose of 40 mg/kg and 1.0 mg/kg dissolved in 10% DMSO (diluted with edible oil; the dose of luzindole ( 36 ) and 4P-PDOT ( 37 ) was chosen based on previous literature and our preliminary experiment. The benefit effect of melatonin on SIRT1 activation was considerably blocked by luzindole ( 36 ) and slightly blocked by 4P-PDOT in small intestine 8 h following sepsis ( Figure 3A ). In addition, the benefit effect of melatonin on SIRT3 activation was considerably blocked by MT1/MT2-nonselective antagonist luzindole but was not blocked by MT2-selective antagonist 4P-PDOT in small intestine 8 h following sepsis ( Figure 3B ).…”

Antioxidant and Anti-Inflammatory Effects of Bischofia javanica (Blume) Leaf Methanol Extracts through the Regulation of Nrf2 and TAK1

“…When co-exposed to LPS and D-Gal, animals develop lethal liver injury mimicking hepatitis [ 35 ]. The inflammatory cytokines and ROS produced by LPS in the injured liver led to high levels of liver enzymes such as AST and ALT in serum [ 36 , 37 , 38 , 39 ]. Therefore, serum levels of AST and ALT in an LPS/D-Gal-induced acute hepatitis mouse model were measured to evaluate the anti-inflammatory effect of MBJ in vivo.…”

Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to LPS/Galactosamine Liver Injury and Protection by Betaine Administration

“…Betaine can prevent/protect against apoptosis induced by an array of agents [ 24 , 46 , 47 , 48 ]. Strategies increasing the anti-apoptotic armamentarium of hepatocytes have been shown to beneficially impact the outcome of fulminant hepatic failure [ 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. In this study, we show that betaine is also effective in protecting against LPS-GalN-induced apoptosis in RD mice.…”

“…We believe that betaine pretreatment prevents SAM depletion and thereby prevents the hypomethylation of ribosomal RNA induced by GalN treatment and the “priming” of hepatocytes to subsequent damage [ 67 , 68 ]. While many agents have been used to ameliorate LPS/GalN liver damage [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 69 , 70 , 71 , 72 ], betaine is inexpensive, bioavailable [ 73 , 74 ], and has no consistent relation with cancer, cardiovascular risk, or risk factors [ 75 ], making it a safe therapeutic.…”