Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity

• DOI: 10.1016/j.ejphar.2012.04.030
• Publication Date: 2012-04-21T22:17:33Z
• Authors: Van P. Dam; Jennifer L. Scott; Anthony Ross; Robert T. Kinobe
• Keywords: Inflammation; 0301 basic medicine; Cystathionine gamma-Lyase; Glycine; 610; Sulfides; 620; Anti-Bacterial Agents; Rats; 3. Good health; Rats, Sprague-Dawley; Necrosis; 03 medical and health sciences; Alkynes; Animals; Female; Kidney Diseases; Hydrogen Sulfide; Lipid Peroxidation; Gentamicins

Clinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, intracellular oxidative stress and heightened inflammation have been implicated. Hydrogen sulphide is an endogenously produced signal transduction molecule with strong anti-inflammatory, anti-apoptotic and cytoprotective properties. In several models of inflammatory disease however, tissue damage has been associated with increased activity of cystathionine gamma-lyase, biosynthesis of hydrogen sulphide and activation of leukocytes. The aim of this study was to determine effects of inhibiting hydrogen sulphide biosynthesis by DL-propargyl glycine (an irreversible inhibitor of cystathionine gamma-lyase) on inflammation, necrosis and renal function, following treatment with gentamicin in rats. Adult female Sprague-Dawley rats were divided into six groups and treated with; physiological saline, sodium hydrosulphide, DL-propargyl glycine, gentamicin, a combination of gentamicin and sodium hydrosulphide, or gentamicin and DL-propargyl glycine respectively. Gentamicin-induced histopathological changes including inflammatory cell infiltration and tubular necrosis were attenuated by co-administering gentamicin with DL-propargyl glycine (P<0.05 compared to saline controls and P<0.05 compared to gentamicin only). Similarly, DL-propargyl glycine caused a significant reduction (P<0.05) in lipid peroxidation, production of superoxide and the activation of tumour necrosis factor-alpha in gentamicin-treated animals. These data show that protective effects of DL-propargyl glycine might be related at least in part, to the reduced inflammatory responses observed in animals treated with both gentamicin and DL-propargyl glycine. Thus, enzyme systems involved in hydrogen sulphide biosynthesis may offer a viable therapeutic target in alleviating the nephrotoxic effects of gentamicin.