Journal
NEUROPHARMACOLOGY
Volume 86, Issue -, Pages 203-211Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2014.06.029
Keywords
Caffeine; A(2A) adenosine receptor; A(1) adenosine receptor; Experimental autoimmune; encephalomyelitis; Multiple sclerosis; Therapeutic time window
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Funding
- National Natural Science Foundation of China [81371321]
- Zhejiang Provincial Special Funds [604161241]
- Ministry of Health of The People's Republic of China & Health Bureau of Zhejiang [WKJ2005-2-041]
- Wenzhou Science &Technology Bureau [H20100014]
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Chronic treatment with caffeine, the most widely consumed psychoactive drug and a non-selective antagonist of adenosine receptors, can protection against myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we investigated the mechanism underlying caffeine-mediated neuroprotection against EAE by determining the effective therapeutic time-window of caffeine and the involvement of adenosine A(2A) and A(1) receptor. We found that administration of caffeine during the effector phase (10 -> 20 days post-immunization, d.p.i., corresponding to appearance of neurological deficits) but not the induction phase (0 -> 10 d.p.i., before the appearance of ascending flaccid paralysis) significantly ameliorated EAE-induced neurobehavioral deficits, reduced the infiltration of inflammatory cells into the spinal cord and reduced the demyelination of spinal cord. Furthermore, genetic deletion of the A(2A)R exacerbated MOG-induced brain damage and caffeine administering to A(2A)R knockout mice reversed this EAE pathology by acting at non-A(2A)R target. The protective effect of chronic caffeine treatment was associated with up-regulation of brain A(1)R (but not A(2A)R). The identification of the effective therapeutic window of caffeine at the effector phase and clarification of non-A(2A)R target (likely A(1)R) in caffeine action in EAE models advance the therapeutic prospective that chronic caffeine consumption may attenuate brain damage in MS. (C) 2014 Elsevier Ltd. All rights reserved.
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