Published online before print February 13, 2003, doi: 10.1161/01.STR.0000057814.70180.17
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(Stroke. 2003;34:745.)
© 2003 American Heart Association, Inc.
Original Contributions |
Neuroprotective Effect of Granulocyte Colony–Stimulating Factor After Focal Cerebral Ischemia
From the Department of Neurology and the Department of Neuropathology (C.S.), University of Heidelberg, Heidelberg, Germany.
Correspondence to Clemens Sommer, MD, Laboratory of Neuropathology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. E-mail clemens.sommer{at}medizin.uni-ulm.de
Background and Purpose— The potential neuroprotective effect of the granulocyte colony–stimulating factor (G-CSF) after glutamate-induced excitotoxicity in cell culture and after focal cerebral ischemia in rats was studied. We hypothesized the existence of the G-CSF receptor (G-CSFR) as a main G-CSF effector on neurons, and immunohistochemistry, immunoblotting, and polymerase chain reaction were performed. The G-CSFR–mediated action was studied by activation of signal transducer(s) and activator(s) of transcription-3 (STAT3) in the periphery of the infarction.
Methods— Neuroprotection of various G-CSF concentrations on glutamate-induced excitotoxicity was studied in cell culture. In vivo, ischemia was induced by use of a suture occlusion model of the middle cerebral artery (90-minute occlusion) in the rat. Thirty minutes after the induction of ischemia, the animals (n=12 per group) received G-CSF at 60 µg/kg body wt IV for 90 minutes or vehicle (saline). Infarct volume was calculated on the basis of 2,3,5-triphenyltetrazolium chloride staining 24 hours after ischemia. Expression of the G-CSFR was studied by immunohistochemistry and verified by reverse transcription–polymerase chain reaction and immunoblotting. Expression of STAT3 was determined by immunohistochemistry.
Results— In cell culture, G-CSF exhibited a significant neuroprotective effect after glutamate-induced excitotoxicity (P<0.05). A G-CSF concentration of 10 ng/mL was maximally effective, resulting in a nearly complete protection. In vivo, G-CSF reduced infarct volume to 47% (132.0±112.7 mm3 versus 278.9±91.6 mm3 [P<0.05] in the control group). Immunohistochemistry, Western blotting, and reverse transcription–polymerase chain reaction revealed the existence of G-CSFRs in neurons and glial cells. Animals treated with G-CSF significantly upregulated STAT3 in the periphery of the infarction compared with control animals (P<0.05).
Conclusions— G-CSF achieved a significant neuroprotective effect in cell culture and after intravenous administration after stroke. Increased STAT3 expression in the penumbra of G-CSF–treated rats suggests mediation by G-CSFR.
Key Words: colony-stimulating factor, granulocyte • excitotoxicity • growth factors • ischemia • neuroprotection
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