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

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

Research output: Contribution to journalArticle

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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) -cyclohexane-carboxylic acid methyl ester ( ATL-146e), a selective adenosine A2A 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 μg/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-α (TNF-α). 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-α 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-α during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.

Original languageEnglish (US)
Pages (from-to)994-998
Number of pages5
JournalJournal of vascular surgery
Volume35
Issue number5
DOIs
StatePublished - May 2002
Externally publishedYes

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Spinal Cord Ischemia
CD31 Antigens
Adenosine
Spinal Cord
Endothelial Cells
Reperfusion
Neoplasms
Rabbits
Reperfusion Injury
Spinal Cord Injuries
Staining and Labeling
Myelitis
Carboxylic Acids
ATL 146e
Serum
Constriction
Sodium Chloride
Paralysis
Laparotomy
Aorta

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-α and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia. / Cassada, David C.; Tribble, Curtis G.; Long, Stewart M.; Laubach, Victor E.; Kaza, Aditya K.; Linden, Joel; Nguyen, Bao Ngoc; Rieger, Jayson M.; Fiser, Steven M.; Kron, Irving L.; Kern, John A.

In: Journal of vascular surgery, Vol. 35, No. 5, 05.2002, p. 994-998.

Research output: Contribution to journalArticle

Cassada, David C. ; Tribble, Curtis G. ; Long, Stewart M. ; Laubach, Victor E. ; Kaza, Aditya K. ; Linden, Joel ; Nguyen, Bao Ngoc ; Rieger, Jayson M. ; Fiser, Steven M. ; Kron, Irving L. ; Kern, John A. / Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-α and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia. In: Journal of vascular surgery. 2002 ; Vol. 35, No. 5. pp. 994-998.
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title = "Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-α 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) -cyclohexane-carboxylic acid methyl ester ( ATL-146e), a selective adenosine A2A 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 μg/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-α (TNF-α). 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-α 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-α during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.",
author = "Cassada, {David C.} and Tribble, {Curtis G.} and Long, {Stewart M.} and Laubach, {Victor E.} and Kaza, {Aditya K.} and Joel Linden and Nguyen, {Bao Ngoc} and Rieger, {Jayson M.} and Fiser, {Steven M.} and Kron, {Irving L.} and Kern, {John A.}",
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T1 - Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-α and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia

AU - Cassada, David C.

AU - Tribble, Curtis G.

AU - Long, Stewart M.

AU - Laubach, Victor E.

AU - Kaza, Aditya K.

AU - Linden, Joel

AU - Nguyen, Bao Ngoc

AU - Rieger, Jayson M.

AU - Fiser, Steven M.

AU - Kron, Irving L.

AU - Kern, John A.

PY - 2002/5

Y1 - 2002/5

N2 - 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) -cyclohexane-carboxylic acid methyl ester ( ATL-146e), a selective adenosine A2A 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 μg/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-α (TNF-α). 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-α 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-α during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.

AB - 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) -cyclohexane-carboxylic acid methyl ester ( ATL-146e), a selective adenosine A2A 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 μg/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-α (TNF-α). 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-α 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-α during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.

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