A novel adenosine precursor 2',3'-cyclic adenosine monophosphate inhibits formation of post-surgical adhesions

Abstract

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.

Fig. 1

Bar graph shows the adhesion scores of mice treated with a single intraperitoneal dose of the indicated treatment. Each compound was administered into the peritoneal cavity at a concentration that was approximately the limit of solubility for that compound (23 mmol/L for adenosine and 75 mmol/L for all other purines). Values are means and SEMs

Fig. 2

Line graphs illustrate the relationship between time (1–180 min) after administration into the peritoneal cavity of 2′,3′-cAMP (1 mL of a 75 mmol/L solution) and concentrations of 2′,3′-cAMP, 2′-AMP and 3′-AMP. Values are means and SEMs

Fig. 3

Line graphs illustrate the relationship between time (1–180 min) after administration into the peritoneal cavity of 2′,3′-cAMP (1 mL of a 75 mmol/L solution) and concentrations of adenosine, inosine and hypoxanthine. The level of hypoxanthine at 1-min post-administration was below the assay’s detection limit (<DL). Values are means and SEMs