Neuroprotective Effect of Granulocyte Colony–Stimulating Factor After Focal Cerebral Ischemia

Abstract

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 (nϭ12 per group) received G-CSF at 60 g/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 (PϽ0.05). 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% (132.0Ϯ112.7 mm 3 versus 278.9Ϯ91.6 mm 3 [PϽ0.05] 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 (PϽ0.05). Conclusions-G-CSF

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

“…Along with other growth factors (Schabitz et al, 2001(Schabitz et al, , 2003, G-CSF has been previously reported to reduce lesion volume after ischemia in mice (Six et al, 2003) and the rat (Schabitz et al, 2003). In these studies, 50 or 60 mg/kg G-CSF was administered via a single subcutaneous injection, and their findings formed the basis for the present study.…”

“…In vitro studies have shown that G-CSF protects neurons against glutamateinduced neurotoxicity (Schabitz et al, 2003). The main actions of G-CSF are mediated via binding to a G-CSF receptor, present on hematopoietic, neuronal and glial cells (Schabitz et al, 2003).…”

“…In vitro studies have shown that G-CSF protects neurons against glutamateinduced neurotoxicity (Schabitz et al, 2003). The main actions of G-CSF are mediated via binding to a G-CSF receptor, present on hematopoietic, neuronal and glial cells (Schabitz et al, 2003). Once activated, the G-CSF receptor can activate proteins such as STAT3 (Shuai, 2000), which in turn activate antiapoptotic proteins such as bcl-2 (Fukada et al, 1996).…”

“…After focal cerebral ischemia, G-CSF administration has been shown to result in significant decreases in lesion volume, both in mice (Six et al, 2003) and the rat (Schabitz et al, 2003). However, these studies have only looked at short-term effects, giving little indication of whether lesion development was prevented or simply delayed.…”

Granulocyte–Colony Stimulating Factor Promotes Liver Repair and Induces Oval Cell Migration and Proliferation in Rats

“…This expression is induced by ischemia, and both counteracts neuronal degeneration and contributes to long-term plasticity after damage. 28,29 Similarly, G-CSF administration after myocardial infarction in mice induces G-CSFR expression in cardiomyocytes and results in the prevention of cardiac remodeling. 30 Regarding the BMC contribution to liver regeneration, our study shows that the number of BM-derived hepatic cells in G-CSF-treated animals was increased up to 6-fold, as compared with the controls.…”