title: Chronic caffeine treatment protects against experimental autoimmune encephalomyelitis in mice: therapeutic window and receptor subtype mechanism.
abstract: 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 A2A and A1 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 A2AR exacerbated MOG-induced brain damage and caffeine administering to A2AR knockout mice reversed this EAE pathology by acting at non-A2AR target. The protective effect of chronic caffeine treatment was associated with up-regulation of brain A1R (but not A2AR). The identification of the effective therapeutic window of caffeine at the effector phase and clarification of non-A2AR target (likely A1R) in caffeine action in EAE models advance the therapeutic prospective that chronic caffeine consumption may attenuate brain damage in MS.
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China.
authors.forename: Tan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China.
authors.forename: Na-na
authors.initials: NN
authors.lastname: Xi
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China.
authors.forename: Xiao-feng
authors.initials: XF
authors.lastname: Shang
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China; Department of Neurology, Boston University School of Medicine, USA. Electronic address: chenjf@bu.edu.
authors.forename: Jiang-fan
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical University, PR China. Electronic address: zhengry1949@163.com.
authors.forename: Rong-yuan
authors.initials: RY
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002110:Caffeine / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002110:Caffeine
keywords: A(1) adenosine receptor; A(2A) adenosine receptor; Caffeine; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Therapeutic time window