Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats

Kong, TaeHo; Choi, Jung-Kyoung; Park, Hyeonseon; Choi, Byung Hyune; Snyder, Brian; Bukhari, Shefqat; Kim, Na-Kyeong; Huang, Xian; Park, Sora; Park, Hyung Chun; Ha, You Jung

doi:10.3171/2008.12.jns08172

Cited by 40 publications

(41 citation statements)

References 23 publications

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“…GM-CSF is actually shown to inhibit the expression of anti-apoptotic genes such as p53 and Bax in our previous study and others [9][10][11]13]. It is not clear, however, how GM-CSF could regulate apoptotic signals and inhibit the expression of apoptotic genes.…”

Section: Discussionmentioning

confidence: 76%

“…Otherwise, GM-CSF could block the apoptotic signals provoked by the PKC inhibition or activate independently the anti-apoptotic signals. We speculate that GM-CSF could act on rather common pathway(s) of apoptotic signals, because it inhibits many different types of apoptotic signals such as the PKC inhibitor, DNA damaging agent, growth factor withdrawal, hypoxia, mitochondrial damaging agent and glutamate-induced excitotoxicity [8][9][10][11]13].…”

Section: Discussionmentioning

confidence: 99%

“…In the rat models of CNS injuries mentioned above, GM-CSF was found to inhibit neuronal apoptosis [8,9,11].…”

Section: Introductionmentioning

confidence: 97%

“…[8][9][10][11]13]. In addition, GM-CSF decreases the expression of pro-apoptotic genes such as p53 and bax and increases that of antiapoptotic genes such as B cell lymphoma protein-2 (Bcl-2) and Bcl-xl in cultured cells and in animal model [9][10][11]13].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is also well known that the GM-CSF receptor is expressed on many neural cells types in the developing brain and in the mature central nervous system (CNS), and GM-CSF has neurotrophic and neurogenic activities [2][3][4][5][6]. Our group and others have demonstrated that GM-CSF have neuroprotective effects on cultured neuronal cells in vitro and in animal models of CNS injuries such as spinal cord injury (SCI), brain ischemic injury and Parkinson's disease [7][8][9][10][11][12][13]. In addition, we have shown that administration of GM-CSF and autologous bone marrow transplantation significantly induces recovery of acute SCI patients in phase I/II clinical trial [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

et al. 2010

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Recently, many studies have shown that granulocyte macrophage-colony stimulating factor (GM-CSF) has anti-apoptotic activity and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. This study investigated detailed mechanism of GM-CSF involved in its anti-apoptotic activity and regulation of Bcl-2 expression in neural progenitor cells (NPCs) as a model. NPCs were cultured from the brain of E13 ICR mouse. When NPCs were treated with staurosporine at 1 μM, apoptosis occurred in more than 30% of cells in TUNEL assay. However, apoptosis was significantly inhibited by pre-treatment with GM-CSF at 10 ng/ml. Under the same experimental condition, the expression of both Bcl-2 and Bcl-xl was clearly induced by GM-CSF regardless of staurosporine treatment in RT-PCR and Western blot analyses. GM-CSF was shown to induce the expression of Bcl-2 and Bcl-xl via Janus tyrosine kinase (JAK) but not via phosphatidylinositol 3-kinase (PI3K) or RAS-mitogen activated protein kinase kinase-1 (MEK-1) using specific signal pathway inhibitors. Further analyses showed that the expression of Bcl-2 and Bcl-xl was induced by GM-CSF via signal transducers and activators of transcription 5 (STAT5) and STAT3, respectively. In addition, JAK/STAT5-Bcl-2 pathway but not JAK/STAT3-Bcl-xl pathway was responsible for the anti-apoptotic activity of GM-CSF in NPCs in TUNEL assay. To our knowledge, this study is the first report that shows differential roles of Bcl-2 and Bcl-xl, and their regulation mechanism involved in the anti-apoptotic activity of GM-CSF in NPCs.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

“…In the rat models of CNS injuries mentioned above, GM-CSF was found to inhibit neuronal apoptosis [8,9,11].…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

et al. 2010

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Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke

Bath

Sprigg

England

2013

Cochrane Database of Systematic Reviews

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Toll‐like receptor 4 contributes to poor outcome after intracerebral hemorrhage

Sansing

Harris

Welsh

et al. 2011

Annals of Neurology

161

153

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Objective Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which perihematomal inflammation contributes to neuronal injury and functional disability. Histologically, the region becomes infiltrated with neutrophils and activated microglia followed by neuronal loss but little is known about the immune signals that coordinate these events. This study aimed to determine the role of Toll-like receptor 4 (TLR4) in the innate immune response after ICH and its impact on neurobehavioral outcome. Methods Transgenic mice incapable of TLR4 signaling and wild-type controls were subjected to striatal blood injection to model ICH. The perihematomal inflammatory response was then quantified by immunohistochemistry, whole brain flow cytometry, and PCR. The critical location of TLR4 signaling was determined by blood transfer experiments between genotypes. Functional outcomes were quantified in all cohorts using the cylinder and open field tests. Results TLR4-deficient mice had markedly decreased perihematomal inflammation, associated with reduced recruitment of neutrophils and monocytes, fewer microglia, and improved functional outcome by day 3 after ICH. Moreover, blood transfer experiments revealed that TLR4 on leukocytes or platelets within the hemorrhage contributes to perihematomal leukocyte infiltration and the neurological deficit. Interpretation Together, these data identify a critical role for TLR4 signaling in perihematomal inflammation and injury and indicate this pathway may be a target for therapeutic intervention.

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Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats

Cited by 40 publications

References 23 publications

Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke

Toll‐like receptor 4 contributes to poor outcome after intracerebral hemorrhage

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