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Purpose The present study, conducted in rats, investigated whether propofol attenuates lipopolysaccharide (LPS)-triggered liver dysfunction via regulation of tumor necrosis factor (TNF)-[alpha] production in activated Kupffer cells. Methods Rats received LPS (500 [mu]g/kg) under Urethane[TM] sedation (1 g/kg) in combination with propofol (5 mg/kg/h) or Intralipid[TM] from 1 h before to 6 h after LPS administration. Some rats were treated with 10 mg/kg gadolinium chloride (GdCl.sub.3) to induce Kupffer cell depletion. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), TNF-[alpha] mRNA and protein expression, caspase-3 activation and apoptosis were evaluated in hepatocytes. Immunofluorescence staining revealed expression of the pan-macrophage marker CD68 as well as TNF-[alpha] in Kupffer cells. Results ALT and AST serum levels increased approximately four-fold in LPS-exposed rats compared with Intralipid[TM]-treated rats at 6 h after LPS administration, whereas propofol and GdCl.sub.3 reduced the LPS-induced increases. LPS simultaneously augmented TNF-[alpha] expression in Kupffer cells, followed by increased caspase-3 activity and apoptosis in hepatocytes. Immunofluorescence staining and immunoblotting assay showed that TNF-[alpha] expression in Kupffer cells was inhibited by propofol and GdCl.sub.3, resulting in a reduction of caspase-3 activity and apoptosis in LPS-treated rat hepatocytes. Conclusions Propofol (5 mg/kg/h) attenuated LPS-triggered liver dysfunction via inhibition of TNF-[alpha] production in activated Kupffer cells. These results suggest that propofol is capable of inhibiting inflammation-induced liver dysfunction in vivo., Author(s): Jiazheng Li[sup.1] , Nobuhisa Kandatsu[sup.1] , Guo-Gang Feng[sup.2] , Jia-Zhen Jiang[sup.1] , Lei Huang[sup.3] , Hiroyuki Kinoshita[sup.1] , Shoshiro Okada[sup.2] , Yoshihiro Fujiwara[sup.1] Author Affiliations: (1) Department of Anesthesiology, [...]

Abstract Background Domoic acid (DA) is an excitatory amino acid analogue of kainic acid (KA) that acts via activation of glutamate receptors to elicit a rapid and potent excitotoxic response, resulting in neuronal cell death. Recently, DA was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in vitro. We have reported that WDR35, a WD-repeat protein, may mediate apoptosis in several animal models. In the present study, we administered DA to rats intraperitoneally, then used liquid chromatography/ion trap tandem mass spectrometry (LC-MS/MS) to identify and quantify DA in the brains of the rats and performed histological examinations of the hippocampus. We further investigated the potential involvement of glutamate receptors, ROS, p38 MAPK, and WDR35 in DA-induced toxicity in vivo. Results Our results showed that intraperitoneally administered DA was present in the brain and induced neurodegenerative changes including apoptosis in the CA1 region of the hippocampus. DA also increased the expression of WDR35 mRNA and protein in a dose- and time-dependent manner in the hippocampus. In experiments using glutamate receptor antagonists, the AMPA/KA receptor antagonist NBQX significantly attenuated the DA-induced increase in WDR35 protein expression, but the NMDA receptor antagonist MK-801 did not. In addition, the radical scavenger edaravone significantly attenuated the DA-induced increase in WDR35 protein expression. Furthermore, NBQX and edaravone significantly attenuated the DA-induced increase in p38 MAPK phosphorylation. Conclusion In summary, our results indicated that DA activated AMPA/KA receptors and induced ROS production and p38 MAPK phosphorylation, resulting in an increase in the expression of WDR35 in vivo.