Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke.

Abstract

After stroke, brain inflammation in the ischemic hemisphere hampers brain tissue reorganization and functional recovery. Housing rats in an enriched environment (EE) dramatically improves recovery of lost neurologic functions after experimental stroke. We show here that rats housed in EE after stroke induced by permanent occlusion of the middle cerebral artery (pMCAO), showed attenuated levels of proinflammatory cytokines in the ischemic core and the surrounding peri-infarct area, including a significant reduction in the stroke-induced chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor-1 (CXCL12). To mimic beneficial effects of EE, we studied the impact of inhibiting CXCL12 action on functional recovery after transient MCAO (tMCAO). Rats treated with the specific CXCL12 receptor antagonist 1-[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclo-tetradecan (AMD3100) showed improved recovery compared with saline-treated rats after tMCAO, without a concomitant reduction in infarct size. This was accompanied by a reduction of infiltrating immune cells in the ischemic hemisphere, particularly cluster of differentiation 3-positive (CD3(+)) and CD3(+)/CD4(+) T cells. Spleen atrophy and delayed death of splenocytes, induced by tMCAO, was prevented by AMD3100 treatment. We conclude that immoderate excessive activation of the CXCL12 pathway after stroke contributes to depression of neurologic function after stroke and that CXCR4 antagonism is beneficial for the recovery after stroke.

• Authors: Karsten Ruscher, Enida Kuric, Yawei Liu, Helene L Walter, Shohreh Issazadeh-Navikas, Elisabet Englund, Tadeusz Wieloch
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 33 Issue 8 Pg. 1225-34 (Aug 2013) ISSN: 1559-7016 [Electronic] United States
• PMID: 23632969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzylamines
• Chemokine CXCL12
• Cyclams
• Heterocyclic Compounds
• Receptors, CXCR4
• DNA
• plerixafor

Topics

• Animals
• Atrophy
• Benzylamines
• Blotting, Western
• Brain (pathology)
• Brain Ischemia (immunology, physiopathology)
• Chemokine CXCL12 (antagonists & inhibitors, physiology)
• Cyclams
• DNA (biosynthesis, genetics)
• DNA Fragmentation
• Down-Regulation
• Environment
• Flow Cytometry
• Fluorescent Antibody Technique
• Heterocyclic Compounds (therapeutic use)
• Immunohistochemistry
• Ischemic Attack, Transient (pathology)
• Male
• Middle Cerebral Artery (physiology)
• Rats
• Rats, Inbred SHR
• Receptors, CXCR4 (biosynthesis, genetics)
• Recovery of Function
• Signal Transduction (physiology)
• Spleen (pathology)
• Stroke (drug therapy, physiopathology)