Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-alpha and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia.

Abstract

OBJECTIVE:

Inflammation is likely a major contributor to spinal cord reperfusion injury after aortic reconstruction. Systemic 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL-146e), a selective adenosine A(2A) agonist, has been shown to reduce paralysis after spinal cord ischemia. We hypothesized that ATL-146e reduces cytokine production during spinal cord reperfusion, curtailing inflammation and decreasing spinal cord capillary platelet-endothelial cell adhesion molecule-1 (PECAM-1) expression.

STUDY DESIGN:

New Zealand White rabbits sustained spinal cord ischemia with 45-minute cross-clamping of the infrarenal aorta. One group of animals received intravenous ATL-146e at 0.06 microg/kg/min for 3 hours during reperfusion, beginning after 30 minutes of ischemia. A second group received saline solution vehicle alone for 3 hours, serving as an ischemic control. A third group served as sham-operated animals, undergoing laparotomy with anesthesia. Serum was assayed with enzyme-linked immunosorbent assay for tumor necrosing factor-alpha (TNF-alpha). Animals were allowed to recover for 48 hours and were evaluated for hind-limb motor function with the Tarlov (0 to 5) scoring system. At necropsy, animals from each group yielded spinal cords for immunohistochemical staining for PECAM-1. Data are expressed as mean +/- standard error of the mean, with statistical analysis with Student t test and Kruskal-Wallis nonparametric test.

RESULTS:

Markedly improved Tarlov scores were seen in rabbits with ATL-146e (P <.001) during spinal cord reperfusion as compared with ischemic control animals. A significant reduction was found in TNF-alpha in the sera of rabbits with ATL-146e infusion (P <.01) as compared with ischemic control animals. Significantly reduced endothelial PECAM-1 staining intensity (P <.05) was seen in microscopic spinal cord sections from rabbits with ATL-146e.

CONCLUSION:

ATL-146e, an adenosine A(2A) agonist, reduces spinal cord reperfusion injury. The mechanism of the protection may involve a reduction in circulating TNF-alpha during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.

• Authors: David C Cassada, Curtis G Tribble, Stewart M Long, Victor E Laubach, Aditya K Kaza, Joel Linden, Bao-Ngoc Nguyen, Jayson M Rieger, Steven M Fiser, Irving L Kron, John A Kern
• Journal: Journal of vascular surgery (J Vasc Surg) Vol. 35 Issue 5 Pg. 994-8 (May 2002) ISSN: 0741-5214 [Print] United States
• PMID: 12021717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATL 146e
• Cyclohexanecarboxylic Acids
• Platelet Endothelial Cell Adhesion Molecule-1
• Purines
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Capillaries (drug effects, physiopathology)
• Cyclohexanecarboxylic Acids (pharmacology, therapeutic use)
• Disease Models, Animal
• Platelet Endothelial Cell Adhesion Molecule-1 (drug effects, physiology)
• Purines (pharmacology, therapeutic use)
• Rabbits
• Reperfusion Injury (physiopathology, prevention & control)
• Spinal Cord (blood supply, drug effects, physiopathology)
• Spinal Cord Ischemia (physiopathology, therapy)
• Tumor Necrosis Factor-alpha (drug effects, physiology)