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

Walter, Helene L; van der Maten, Gerlinde LU ; Antunes, Ana LU ; Wieloch, Tadeusz LU and Ruscher, Karsten LU (2015) In Journal of Neuroinflammation 12(24). p.1-15
Abstract
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
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in
Journal of Neuroinflammation
volume
12
issue
24
pages
1 - 15
publisher
BioMed Central
external identifiers
  • pmid:25881123
  • scopus:84924280793
ISSN
1742-2094
DOI
10.1186/s12974-014-0232-1
language
English
LU publication?
yes
id
5e9cdab0-0622-45c6-9883-1dcd6c3cfd7b (old id 5341629)
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http://www.ncbi.nlm.nih.gov/pubmed/25881123?dopt=Abstract
date added to LUP
2015-05-05 17:19:27
date last changed
2017-08-13 03:55:00
@article{5e9cdab0-0622-45c6-9883-1dcd6c3cfd7b,
  abstract     = {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.},
  author       = {Walter, Helene L and van der Maten, Gerlinde and Antunes, Ana and Wieloch, Tadeusz and Ruscher, Karsten},
  issn         = {1742-2094},
  language     = {eng},
  number       = {24},
  pages        = {1--15},
  publisher    = {BioMed Central},
  series       = {Journal of Neuroinflammation},
  title        = {Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke.},
  url          = {http://dx.doi.org/10.1186/s12974-014-0232-1},
  volume       = {12},
  year         = {2015},
}