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The Journal of Neuroscience, February 11, 2004, 24(6):1521-1529; doi:10.1523/JNEUROSCI.4271-03.2004

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 Previous Article

Neurobiology of Disease
A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Shigeki Tsutsui,1 Jurgen Schnermann,3 Farshid Noorbakhsh,1 Scot Henry,1 V. Wee Yong,1 Brent W. Winston,2 Kenneth Warren,4 and Christopher Power1

Departments of 1Clinical Neurosciences and 2 Critical Care Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, 3National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1370, and 4Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2B7, Canada

The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR-/-) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR+/+) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR-/- animals. In addition, spinal cords from A1AR-/- mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR+/+ animals. Macrophages from A1AR-/- animals exhibited increased expression of the proinflammatory genes, interleukin-1{beta}, and matrix metalloproteinase-12 on immune activation when matched with A1AR+/+ control cells. A1AR-/- macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR+/+ mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.

Key words: EAE; cytokines; MMPs; demyelination; adenosine amine congener; caffeine

Received Sep 18, 2003; revised December 15, 2003; accepted December 15, 2003.




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