A Novel Adenosine Precursor 2′,3′-Cyclic Adenosine Monophosphate Inhibits Formation of Post-surgical Adhesions

BACKGROUND: Intraperitoneal adenosine reduces abdominal adhesions. However, because of the ultra-short half-life and low solubility of adenosine, optimal efficacy requires multiple dosing. AIM: Here, we compared the ability of potential adenosine prodrugs to inhibit post-surgical abdominal adhesions after a single intraperitoneal dose. METHODS: Abdominal adhesions were induced in mice using an electric toothbrush to damage the cecum. Also, 20 μL of 95 % ethanol was applied to the cecum to cause chemically induced injury. After injury, mice received intraperitoneally either saline (n = 18) or near-solubility limit of adenosine (23 mmol/L; n = 12); 5′-adenosine monophosphate (75 mmol/L; n = 11); 3′-adenosine monophosphate (75 mmol/L; n = 12); 2′-adenosine monophosphate (75 mmol/L; n = 12); 3′,5′-cyclic adenosine monophosphate (75 mmol/L; n = 19); or 2′,3′-cyclic adenosine monophosphate (75 mmol/L; n = 20). After 2 weeks, adhesion formation was scored by an observer blinded to the treatments. In a second study, intraperitoneal adenosine levels were measured using tandem mass spectrometry for 3 h after instillation of 2′,3′-cyclic adenosine monophosphate (75 mmol/L) into the abdomen. RESULTS: The order of efficacy for attenuating adhesion formation was: 2′,3′-cyclic adenosine monophosphate > 3′,5′-cyclic adenosine monophosphate ≈ adenosine > 5′-adenosine monophosphate ≈ 3′-adenosine monophosphate ≈ 2′-adenosine monophosphate. The groups were compared using a one-factor analysis of variance, and the overall p value for differences between groups was p < 0.000001. Intraperitoneal administration of 2′,3′-cAMP yielded pharmacologically relevant levels of adenosine in the abdominal cavity for >3 h. CONCLUSION: Administration of 2′,3′-cyclic adenosine monophosphate into the surgical field is a unique, convenient and effective method of preventing post-surgical adhesions by acting as an adenosine prodrug.