Selective blockade of mglu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in mice

BACKGROUND/AIMS: mGlu5 metabotropic glutamate receptor antagonists protect rat hepatocytes against hypoxic death. Here, we have examined whether mGlu5 receptor antagonists are protective against liver damage induced by oxidative stress. METHODS: Toxicity of isolated hepatocytes was induced by tert-butylhydroperoxide (t-BuOOH) after pretreatment with the mGlu5 receptor antagonists, MPEP, SIB-1757 and SIB-1893. The effect of these drugs was also examined in mice challenged with toxic doses of acetaminophen. RESULTS: Addition of tBuOOH (0.5 mM) to isolated hepatocytes induced cell death (70+/-5% at 3 h). Addition of MPEP or SIB-1893 to hepatocytes reduced both the production of reactive oxygen species (ROS) and cell toxicity induced by t-BuOOH (tBuOOH=70+/-5%; tBuOOH+MPEP=57+/-6%; tBuOOH+SIB-1893=40+/-4%). In mice, a single injection of acetaminophen (300 mg/kg, i.p.) induced centrilobular liver necrosis, which was detectable after 24 h. MPEP (20 mg/kg, i.p.) substantially reduced liver necrosis and the production of ROS, although it did not affect the conversion of acetaminophen into the toxic metabolite, N-acetylbenzoquinoneimine. MPEP, SIB-1893 and SIB-1757 (all at 20 mg/kg, i.p.) also reduced the increased expression and activity of liver iNOS induced by acetaminophen. CONCLUSIONS: We conclude that pharmacological blockade of mGlu5 receptors might represent a novel target for the treatment of drug-induced liver damage

Significance of Tumor Microenvironment on the Genesis of: Interstitial Fluid, Angiogenesis, Haemostatic/Haemorheologic Abnormalities. Pathogenesis and Therapeutic Aspects

Solid tumours tend to have e more acidic and hypoxic microenvironment then normal tissue. This hostile microenvironment results from a disparity between oxygen supply and demand of the tumor tissue. Overcoming hypoxia tumor induces e new vascular supply. This new vasculature is however inefficient and chaotic. It perpetuates the factors that have stimulated its induction. This review focuses on these processes and peculiarly on angiogenesis, tumor vascular morphology, hypoxia, pH, and the metabolic-vascular events induced or following rumour tissue heating. The various mechanisms that either modulate tumor micrenvironments blood perfusion during hyperthermia are described, providing also the many clinical modalities that may enhance or sensitize cancer cells to heat