Protective effect of an adenosine kinase inhibitor in septic shock.
Adenosine exhibits potent anti-inflammatory activities but its therapeutic use is limited by cardiovascular side effects. Inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (EC 2.7.1.20), were evaluated for their ability to enhance endogenous adenosine production. One novel adenosine kinase inhibitor, GP-1-515, was studied in two models of septic shock to assess its protective effects. GP-1-515 significantly decreased mortality in mice that received a lethal i.v. injection of endotoxin. The beneficial effect was accompanied by decreased neutrophil accumulation in the lungs and was reversed by an adenosine receptor antagonist, implying that the effects were mediated by endogenous adenosine. Plasma levels of TNF-alpha, but not IL-1 alpha or IL-6, were lower in the GP-1-515-treated animals. In a second model of sepsis, GP-1-515 increased survival in bacterial peritonitis in rats. The mechanism of action in both models was likely multifactorial, including adenosine-mediated inhibition of neutrophil adhesion, cytokine production, and oxygen radical generation. Adenosine kinase inhibitors have potent anti-inflammatory effects in vitro and in vivo and represent a novel therapeutic approach to the treatment of inflammatory diseases.
Firestein
G S
GS
Gensia, Inc., San Diego, CA 92121.
Boyle
D
D
Bullough
D A
DA
Gruber
H E
HE
Sajjadi
F G
FG
Montag
A
A
Sambol
B
B
Mullane
K M
KM
D000241:Adenosine / Q000378:metabolism; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001424:Bacterial Infections / Q000517:prevention & control; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010538:Peritonitis / Q000517:prevention & control; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology*; D012772:Shock, Septic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D018076:DNA, Complementary; D008070:Lipopolysaccharides; D012263:Ribonucleosides; D014409:Tumor Necrosis Factor-alpha; C087698:GP 1-515; D000248:Adenosine Kinase; D000241:Adenosine