Beneficial Effects of Hematopoietic Growth Factor Therapy in Chronic Ischemic Stroke in Rats (original) (raw)
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Romanian Journal of Neurology, 2009
The hematopoietic growth factors (HGF) have been known for 20 years, named for their role in the proliferation, differentiation and survival of hematopoietic progenitor cells. They (erythropoietin, G-CSF and GM-CSF) have been used many years in clinical practice in oncological and hematological pathology. Recent studies suggest that HGF have also important non-hematopoietic functions in the central nervous system. HGF and their receptors are expressed by neurons in many brain regions and are up-regulated after focal ischemia, indicating an autocrin protective response of the injured brain. The neuroprotective function of HGF has been suggested by the effect of decreasing infarct volumes in different experimental models in rodents and has been attributed to their anti-apoptotic activity (by activating several protective pathways, PI3K/Akt being the most important). Moreover, HGF induces neurogenesis and angiogenesis, possible the substrate of improving recovery post-stroke. There is ...
Circulation, 2004
Background— Stroke is a leading cause of death and disability worldwide; however, no effective treatment currently exists. Methods and Results— Rats receiving subcutaneous granulocyte colony-stimulating factor (G-CSF) showed less cerebral infarction, as evaluated by MRI, and improved motor performance after right middle cerebral artery ligation than vehicle-treated control rats. Subcutaneous administration of G-CSF enhanced the availability of circulating hematopoietic stem cells to the brain and their capacity for neurogenesis and angiogenesis in rats with cerebral ischemia. Conclusions— G-CSF induced increases in bone marrow cell mobilization and targeting to the brain, reducing the volume of cerebral infarction and improving neural plasticity and vascularization.
Journal of Cerebral Blood Flow & Metabolism, 2005
Growth factors possess neuroprotective and neurotrophic properties in vitro, but few have been extensively studied in vivo after stroke. In the present study, we investigated the potential functional benefits of granulocyte colony-stimulating factor (G-CSF) administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received G-CSF (50 lg/kg, subcutaneously) or vehicle (saline) at the onset of reperfusion. Granulocyte colony-stimulating factor-treated mice killed at 48 hours after MCAO revealed a 445% reduction (Po0.05) in lesion volume. In terms of body weight recovery, and in tests of motor (grid test and rotarod) and cognitive ability (water maze), MCAO significantly worsened the outcome in vehicletreated mice as compared with shams (Po0.05). However, G-CSF treatment was beneficial as, compared with vehicle, this significantly improved weight recovery and motor ability. This effect was most apparent on the water maze where G-CSF-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate long-term beneficial effects of a single dose of G-CSF administered on reperfusion, and illustrate the need to further investigate the mechanisms of G-CSF action.
Stroke a Journal of Cerebral Circulation, 2011
Background and Purpose-Enhancing collateral artery growth is a potent therapeutic approach to treat cardiovascular ischemic disease from occlusive artery. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has gained attention for its ability to promote arteriogenesis, ameliorating brain damage, by the mechanisms involving monocyte upregulation. However, the recent clinical study testing its efficacy in myocardial ischemia has raised the question about its safety. We tested alternative colony-stimulating factors for their effects on collateral artery growth and brain protection. Methods-Brain hypoperfusion was produced by occluding the left common carotid artery in C57/BL6 mice. After the surgery, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, or GM-CSF (100 g/kg/day) was administered daily for 5 days. The angioarchitecture for leptomeningeal anastomoses and the circle of Willis were visualized after the colony-stimulating factor treatment. Circulating blood monocytes and Mac-2-positive cells in the dorsal surface of the brain were determined. A set of animals underwent subsequent ipsilateral middle cerebral artery occlusion and infarct volume was assessed. Results-Granulocyte colony-stimulating factor as well as GM-CSF promoted leptomeningeal collateral growth after common carotid artery occlusion. Both granulocyte colony-stimulating factor and GM-CSF increased circulating blood monocytes and Mac-2-positive cells in the dorsal brain surface, suggesting the mechanisms coupled to monocyte upregulation might be shared. Infarct volume after middle cerebral artery occlusion was reduced by granulocyte colony-stimulating factor, similarly to GM-CSF. Macrophage colony-stimulating factor showed none of theses effects. Conclusions-Granulocyte colony-stimulating factor enhances collateral artery growth and reduces infarct volume in a mouse model of brain ischemia, similarly to GM-CSF. (Stroke. 2011;42:770-775.
Translational Stroke Research
Granulocyte-colony-stimulating factor (G-CSF) functions both as a neuroprotectant and a stimulator of autologous bone marrow stem cell release. Therefore, administration of G-CSF should improve the outcome of stroke. Here, we examine the safety of using G-CSF to treat acute ischemic stroke using a randomized controlled trial involving 20 adult patients presenting with ischemia in the carotid region within 48 h of onset. The experimental group (n = 10) received subcutaneous G-CSF injections (10 mg kg−1 day−1) in addition to conventional therapy for 5 days. The primary outcome was motor function as measured by the modified Rankin Scale 180 days post-stroke. Safety was evaluated according to the frequency of hemorrhagic transformation of infarctions and serious adverse events. Only six patients in the experimental group completed full course of treatment, while four patients (three in the control and one in the experimental group) were lost to follow-up. We found the experimental and control groups did not differ significantly in either neurological impairment or degree of disability/dependence at 180 days post-stroke. We conclude that while adding G-CSF (10 mg kg−1 day−1) to acute ischemic stroke therapy for 5 days is safe, its efficacy remains unproven.
Blood, 2008
Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)-expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival and functional outcome.
Journal of Cerebral Blood Flow and Metabolism, 2006
Cerebral ischemia induces the expression of several growth factors and cytokines, which protect neurons against ischemic insults. Recent studies showed that granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for the antiapoptotic cascade. The current study was designed to assess the neuroprotective mechanisms of G-CSF in ischemia/ reperfusion injury using bone marrow chimera mice known to express enhanced green fluorescent protein (EGFP). Mice were subjected to ischemia/reperfusion and divided into two groups: those treated with G-CSF (G-CSF group) and vehicle (control group) (n ¼ 35 in each group). Immunohistochemistry and immunoblotting for antiapoptotic protein, nitrotyrosine, and inducible nitrate oxide synthase (iNOS) were performed. G-CSF significantly reduced stroke volume (34%, Po0.006). G-CSF upregulated Stat3, pStat3, and Bcl-2 (Po0.05), and suppressed iNOS and nitrotyrosine expression. In EGFP chimera mice, G-CSF decreased the migration of Iba-1/EGFP-positive bone marrow-derived monocytes/macrophages and increased intrinsic microglia/macrophages at ischemic penumbra (Po0.05), suggesting that bone marrow-derived monocytes/macrophages are not involved in G-CSF-induced reduction of ischemic injury size. Our study indicated that G-CSF exerts a neuroprotective effect through the direct activation of antiapoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia.