Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke

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'-[1,4-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 (cx3cr1gfp/+) 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. conclusion: 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. © walter et al.