Endogenous brain protection by granulocyte-colony stimulating factor after ischemic stroke

• Published in: Experimental neurology 2009-06, Vol.217 (2), p.328-335
• Main Authors: Sevimli, Sevgi, Diederich, Kai, Strecker, Jan-Kolja, Schilling, Matthias, Klocke, Rainer, Nikol, Sigrid, Kirsch, Friederike, Schneider, Armin, Schäbitz, Wolf-Rüdiger
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cytoprotection - drug effects; Cytoprotection - physiology; Disease Models, Animal; Enzyme Activation - drug effects; Enzyme Activation - physiology; Female; G-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - deficiency; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Immunohistochemistry; Ischemic brain injury; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; MMP-9; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Reverse Transcriptase Polymerase Chain Reaction; Stroke - drug therapy; Stroke - pathology; Stroke - physiopathology; Stroke recovery; Up-Regulation - drug effects; Up-Regulation - physiology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2009.03.018

Several lines of evidence have demonstrated beneficial effects of the hematopoietic factor G-CSF in experimental stroke. A conclusive demonstration of this effect in G-CSF deficient mice is, however, lacking. We therefore investigated the effect of G-CSF deficiency on infarct volumes, functional recovery, mRNA and protein expression of the matrix metalloproteinase 9 (MMP-9) after stroke. Furthermore we tested the efficacy of G-CSF substitution in G-CSF deficient animals to prevent the potential consequences of G-CSF deficiency. In the present study experimental stroke was induced in female non-treated wildtype (wt), G-CSF deficient mice and G-CSF substituted G-CSF deficient mice followed by assessment of infarct volumes, neurological outcome and sensorimotor function. In addition, immunohistochemistry and real-time PCR of the peri-ischemic area were performed. G-CSF deficient mice showed increased infarct volumes, whereas G-CSF substituted mice had a remarkable reduction in lesion size compared to wt mice. These findings are accompanied by an improvement in neurological and sensorimotor function. G-CSF deficiency resulted in an upregulation of MMP-9 in the direct peri-ischemic tissue. Treatment with G-CSF suppressed the upregulation of MMP-9. Taken together, G-CSF deficiency clearly resulted in enlarged infarct volumes, and worsened neurological outcome. G-CSF substitution abolished these negative effects, led to significant reduced lesion volumes, and improved neurological outcome. G-CSF mediated suppression of MMP-9 further demonstrates that endogenous G-CSF plays a significant role in brain protective mechanisms. We have shown for the first time that endogenous G-CSF is required for brain recovery mechanisms after stroke.