Mouse spinal cord compression injury is reduced by either activation of the adenosine A2A receptor on bone marrow–derived cells or deletion of the A2A receptor on non-bone marrow–derived cells

• Published in: Neuroscience 2006, Vol.141 (4), p.2029-2039
• Main Authors: Li, Y., Oskouian, R.J., Day, Y.-J., Rieger, J.M., Liu, L., Kern, J.A., Linden, J.
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Agonists; adenosine A2A receptor; Analysis of Variance; Animals; Biological and medical sciences; bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Transplantation - methods; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Female; Fundamental and applied biological sciences. Psychology; inflammation; ischemia; Mice; Mice, Knockout; Motor Activity - drug effects; Motor Activity - physiology; Myelin Sheath - pathology; Piperidines - chemistry; Piperidines - pharmacology; Radioligand Assay - methods; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; reperfusion; Spinal Cord Compression - metabolism; Spinal Cord Compression - pathology; Spinal Cord Compression - physiopathology; Spinal Cord Compression - therapy; spinal cord injury; Time Factors; Triazines - pharmacokinetics; Triazoles - pharmacokinetics; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2006.05.014

Activation of the adenosine A2A receptor (A2AR) at the time of reperfusion has been shown to reduce ischemia–reperfusion injury in peripheral tissues and spinal cord. In this study we show that treating mice with the A2AR agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester for four days beginning before or just after the onset of reperfusion after compression-induced spinal cord injury rapidly (within 1 day) and persistently (>42 days) reduces locomotor dysfunction and spinal cord demyelination. Protection is abolished in knockout/wild type bone marrow chimera mice selectively lacking the A2AR only on bone marrow–derived cells but retaining receptors on other tissues including blood vessels. Paradoxically, reduced spinal cord injury is also noted in A2AR −/− mice, and in wild type/knockout bone marrow chimera mice selectively lacking the A2AR on non-bone marrow–derived cells, or in mice treated with the A2A antagonist, 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol. The greatest protection is seen in knockout/wild type bone marrow chimera mice treated with 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester, i.e. by activating the A2AR in mice expressing the receptor only in bone marrow–derived cells. The data suggest that inflammatory bone marrow–derived cells are the primary targets of A2A agonist-mediated protection. We conclude that A2A agonists or other interventions that inhibit inflammation during and after spinal cord ischemia may be effective in reducing spinal cord injury in patients, but excessive or prolonged stimulation of the A2AR may be counterproductive. It may be possible to devise strategies to produce optimal spinal cord protection by exploiting temporal differences in A2AR-mediated responses.