title: Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke.
abstract: BACKGROUND
  Recovery of lost neurological function after stroke is limited and dependent on multiple mechanisms including inflammatory processes. Selective pharmacological modulation of inflammation might be a promising approach to improve stroke outcome.
  
  
  METHODS
  We used 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and potential allosteric agonist to CXCR7, administered to mice twice daily from day 2 after induction of photothrombosis (PT). In addition to functional outcome, the dynamics of post-stroke microglia response were monitored in vivo by 2-photon-laser-microscopy in heterozygous transgenic CX3CR1-green fluorescent protein (GFP) mice (CX3CR1(GFP/+)) and complemented with analyses for fractalkine (FKN) and pro-inflammatory cytokines.
  
  
  RESULTS
  We found a significantly enhanced recovery and modified microglia activation without affecting infarct size in mice treated with AMD3100 after PT. AMD3100 treatment significantly reduced the number of microglia in the peri-infarct area accompanied by stabilization of soma size and ramified cell morphology. Within the ischemic infarct core of AMD3100 treated wild-type mice we obtained significantly reduced levels of the endogenous CX3CR1 ligand FKN and the pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Interestingly, in CX3CR1-deficient mice (homozygous transgenic CX3CR1-GFP mice) subjected to PT, the levels of FKN were significantly lower compared to their wild-type littermates. Moreover, AMD3100 treatment did not induce any relevant changes of cytokine levels in CX3CR1 deficient mice.
  
  
  CONCLUSIONS
  After AMD3100 treatment, attenuation of microglia activation contributes to enhanced recovery of lost neurological function in experimental stroke possibly due to a depression of FKN levels in the brain. We further hypothesize that this mechanism is dependent on a functional receptor CX3CR1.
authors.affiliation: Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, S-22184, Lund, Sweden. helene.walter@uk-koeln.de.|Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany. helene.walter@uk-koeln.de.
authors.forename: Helene L
authors.initials: HL
authors.lastname: Walter
authors.affiliation: Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, S-22184, Lund, Sweden. g.h.van.der.maten@student.rug.nl.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: van der Maten
authors.affiliation: Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, S-22184, Lund, Sweden. ana.antunes@med.lu.se.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Antunes
authors.affiliation: Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, S-22184, Lund, Sweden. tadeusz.wieloch@med.lu.se.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
authors.affiliation: Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, S-22184, Lund, Sweden. karsten.ruscher@med.lu.se.
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
mesh_terms: D000818:Animals; D001596:Benzylamines; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000080027:Cyclams; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D018613:Microscopy, Confocal; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017785:Photons / Q000009:adverse effects; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*
chemical_list: C491049:Aif1 protein, mouse; D001596:Benzylamines; D002135:Calcium-Binding Proteins; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D023062:Receptors, Interleukin-8A; D049452:Green Fluorescent Proteins; C088327:plerixafor