Neutrophil A2A adenosine receptor inhibits inflammation in a rat model of meningitis: synergy with the type IV phosphodiesterase inhibitor, rolipram.
Bacterial meningitis is a disease worsened by neutrophil-induced damage in the subarachnoid space. In this study, the A2A adenosine receptors on human neutrophils were characterized, and the role of A2A receptors on the trafficking of leukocytes to the cerebrospinal fluid and on blood-brain barrier permeability (BBBP) was assessed in a rat meningitis model. Neutrophils bind the A2A selective antagonist, 125I-ZM241385 (Bmax=843 receptors/neutrophil; KD=0.125 nM). A selective A2A receptor agonist, WRC-0470 (2-cyclohexylmethylidene-hydrazinoadenosine; 0.03-1 microM), alone and synergistically with the type IV phosphodiesterase inhibitor, rolipram, increased neutrophil [cAMP]i and reduced cytokine-enhanced neutrophil adherence, superoxide release, and degranulation. These effects of WRC-0470 were reversed by ZM241385 (100 nM). In a lipopolysaccharide-induced rat meningitis model, WRC-0470 (0-0.9 microgram/kg/h), with or without rolipram (0-0.01 microgram/kg/h), inhibited pleocytosis and reduced the lipopolysaccharide-induced increase in BBBP, indicative of decreased neutrophil-induced damage.
Sullivan
G W
GW
Cardiology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. gws3u@virginia.edu
Linden
J
J
Buster
B L
BL
Scheld
W M
WM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D007964:Leukocytosis; D016920:Meningitis, Bacterial / Q000276:immunology*; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D016897:Respiratory Burst; D020889:Rolipram / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014227:Triazines / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C097270:ZM 241385; D013481:Superoxides; D000242:Cyclic AMP; D020889:Rolipram; D000241:Adenosine; C101949:binodenoson