title: CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents.
abstract: The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A₁R). We show that, in the presence of the A₁R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A₁R⁻/⁻ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1⁻/⁻ and cx3cr1(GFP/GFP) mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1⁻/⁻ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1⁻/⁻ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygen-glucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosine-dependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.
authors.affiliation: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Cipriani
authors.forename: Pia
authors.initials: P
authors.lastname: Villa
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chece
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lauro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Paladini
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.forename: Carlo
authors.initials: C
authors.lastname: Perego
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Eusebi
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D054428:Chemokine CX3CL1 / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000517:prevention & control; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D009474:Neurons / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D019707:Receptors, Chemokine / Q000172:deficiency; D018047:Receptors, Purinergic P1 / Q000172:deficiency; D014970:Xanthines / Q000627:therapeutic use
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D018047:Receptors, Purinergic P1; D014970:Xanthines; D049452:Green Fluorescent Proteins; C051360:1,3-dipropyl-8-cyclopentylxanthine; D005947:Glucose
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