Mouse spinal cord compression injury is reduced by either activation of the adenosine A_2A receptor on bone marrow-derived cells or deletion of the A_2A receptor on non-bone marrow-derived cells

Activation of the adenosine A_2A receptor (A_2AR) 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_2AR 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_2AR 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_2AR -/- mice, and in wild type/knockout bone marrow chimera mice selectively lacking the A_2AR 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_2AR 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_2AR may be counterproductive. It may be possible to devise strategies to produce optimal spinal cord protection by exploiting temporal differences in A_2AR-mediated responses.