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.
Activation of the adenosine A(2A) receptor (A(2A)R) 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 A(2A)R 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 A(2A)R only on bone marrow-derived cells but retaining receptors on other tissues including blood vessels. Paradoxically, reduced spinal cord injury is also noted in A(2A)R -/- mice, and in wild type/knockout bone marrow chimera mice selectively lacking the A(2A)R on non-bone marrow-derived cells, or in mice treated with the A(2A) 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 A(2A)R 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 A(2A) agonist-mediated protection. We conclude that A(2A) 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 A(2A)R may be counterproductive. It may be possible to devise strategies to produce optimal spinal cord protection by exploiting temporal differences in A(2A)R-mediated responses.
Li
Y
Y
Department of Medicine, University of Virginia Health System, MR5 Box 801394, Charlottesville, VA 22908, USA.
Oskouian
R J
RJ
Day
Y-J
YJ
Rieger
J M
JM
Liu
L
L
Kern
J A
JA
Linden
J
J
D058908:Adenosine A2 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism*; D013117:Spinal Cord Compression / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics
C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D010880:Piperidines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385