Preventive administration of ornithine alpha-ketoglutarate improves intestinal mucosal repair after transient ischemia in rats.

ABSTRACT

OBJECTIVES: To investigate whether the preventive enteral administration of a polyamine precursor, such as ornithine alpha-ketoglutaiate (OKG), has a beneficial effect on the repair process of the intestinal mucosa after transient mesenteric vascular occlusion. DESIGN: A controlled laboratory study. SETTING: A research laboratory facility at the Research Institute for Digestive Cancer. SUBJECTS: Male Wistar rats, weighing 330 to 350 g, housed individually in plastic cages under standardized conditions (23 degrees C, 73 degrees F, 60% relative humidity, 12-hr light and 12-hr dark cycles). INTERVENTIONS: Intragastrically, 1.5 or 17 hrs before surgery, animals received either distilled water (water group), or an amino acid solution of either OKG (1 g/kg) or L-lysine (0.68 g/kg) in distilled water under isonitrogenous conditions. Intestinal ischemia was produced in anesthetized rats by occluding the superior mesenteric artery for 90 mins with a microbulldog clamp. At the end of the ischemic period, the clamp was removed, allowing reperfusion, and the abdomen was closed. MEASUREMENTS AND MAIN RESULTS: At 0, 4, and 24 hrs after ischemia/reperfusion, the midjejuno-ileum was resected. Intestinal morphology, polyamine content, and hydrolase activities were determined. In all groups at the end of the ischemic period, the villi were dismantled with preservation of the crypts. Rats treated with OKG exhibited a restoration of short villi by 4 hrs after ischemia/reperfusion. In other groups, the villi remained extensively denuded. By 24 hrs, only rats treated with OKG showed a complete recovery of normal mucosal architecture. The amount of the polyamines, putrescine, and spermidine were significantly enhanced by 4 hrs after ischemia/reperfusion in the mucosa of rats treated with OKG, as compared with the two other groups. At a functional level, sucrase and aminopeptidase activities remained significantly higher by 4 hrs of ischemia/reperfusion in rats treated with OKG as compared with rats receiving water or lysine. By 24 hrs, hydrolase activities were normalized in rats treated with OKG, whereas an important deficit in hydrolase activities remained in rats receiving either water or lysine. CONCLUSIONS: OKG administration to rats did not prevent ischemic damage of the intestinal mucosa, but it accelerated the repair of the mucosa during reperfusion. OKG favored the restitution of normal villus architecture and the functional recovery of the intestinal mucosa. We hypothesized that OKG-triggered metabolites might mediate the restitution process and contribute to the healing of the intestinal mucosa by minimizing cell injury and by promoting the replacement of injured cells.