Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke.
Research output: Contribution to journal › Article
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 CX(3)CR1-green fluorescent protein (GFP) mice (CX(3)CR1(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 CX(3)CR1 ligand FKN and the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-6. Interestingly, in CX(3)CR1-deficient mice (homozygous transgenic CX(3)CR1-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 CX(3)CR1 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 CX(3)CR1.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Journal||Journal of Neuroinflammation|
|Publication status||Published - 2015|
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