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.
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.


METHODS
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.


CONCLUSIONS
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.
Cassada
David C
DC
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Health Sciences Center, The University of Virginia Health System, Charlottesville, VA 22908, USA.
Tribble
Curtis G
CG
Long
Stewart M
SM
Laubach
Victor E
VE
Kaza
Aditya K
AK
Linden
Joel
J
Nguyen
Bao-Ngoc
BN
Rieger
Jayson M
JM
Fiser
Steven M
SM
Kron
Irving L
IL
Kern
John A
JA
D000818:Animals; D002196:Capillaries / Q000187:drug effects* / Q000503:physiopathology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects* / Q000502:physiology; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use*; D011817:Rabbits; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects* / Q000503:physiopathology; D020760:Spinal Cord Ischemia / Q000503:physiopathology* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000502:physiology
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011687:Purines; D014409:Tumor Necrosis Factor-alpha