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

Y. Li, R. J. Oskouian, Y. J. Day, J. M. Rieger, L. Liu, J. A. Kern, J. Linden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2029-2039
Number of pages11
JournalNeuroscience
Volume141
Issue number4
DOIs
StatePublished - 2006

Funding

We thank Melissa A. Marshall and Cynthia R. Frazier for their expert assistance with bone marrow transplants and radioligand binding assays. Supported by the Falk Medical Research Trust and NIH grant R01 HL37942.

Keywords

  • adenosine A receptor
  • bone marrow
  • inflammation
  • ischemia
  • reperfusion
  • spinal cord injury

ASJC Scopus subject areas

  • General Neuroscience

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