Neutrophil A(2A) adenosine receptor inhibits inflammation in a rat model of meningitis: Synergy with the type IV phosphodiesterase inhibitor, rolipram

Abstract

Bacterial meningitis is a disease worsened by neutrophil-induced damage in the subarachnoid space. In this study, the A(2A) adenosine receptors on human neutrophils were characterized, and the role of A(2A) 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 A(2A) selective antagonist, 125I-ZM241385 (B(max) = 843 receptors/neutrophil; K(D) = 0.125 nM). A selective A(2A) receptor agonist, WRC-0470 (2-cyclohexylmethylidene-hydrazinoadenosine; 0.03-1 μM), 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 μg/kg/h), with or without rolipram (0- 0.01 μg/kg/h), inhibited pleocytosis and reduced the lipopolysaccharide- induced increase in BBBP, indicative of decreased neutrophil-induced damage.