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

Journal of Neuroinflammation

Karsten Ruscher²  Tadeusz Wieloch²  Ana Rita Antunes²  Gerlinde van der Maten²  Helene L Walter¹ 

[1]Department of Neurology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany

[2]Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, Lund, S-22184, Sweden

关键词: Stroke recovery;    Microglia;    Inflammation;    Fractalkine;    Cytokine;    CX3CR1;    Chemokine receptor;   

Others  :  1137617
DOI  :  10.1186/s12974-014-0232-1

 received in 2014-08-13, accepted in 2014-12-27,  发布年份 2015

【 摘 要 】

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.

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.

【 授权许可】

   
2015 Walter et al.; licensee BioMed Central.

【 图 表 】

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