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

Gibson, Claire L.; Bath, Philip M.W.; Murphy, Seán

doi:10.1038/sj.jcbfm.9600033

Cited by 156 publications

(92 citation statements)

References 55 publications

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“…Although the administration of G-CSF significantly improved the early neurological outcome, this beneficial effect can be mediated not only by caspase-altering mechanisms but also may involve other mechanisms such as the inhibition of the inflammatory response, as shown previously (Gibson et clearly demonstrated the long-term benefits using the same dose of G-CSF (50μg/kg) on both motor and cognitive outcome up to 3 weeks after an experimental stroke (Gibson et al, 2005a). The dose (Schedule A) used in the present study is a pharmacological dose that has already been shown to cause neuroprotection in previous experimental studies (Gibson et al, 2005b;Gibson et al, 2005a;Schneider et al, 2005). Moreover, this dose is also in the range of G-CSF doses that has been used in human clinical trials (Gabrilove et al, 1988).…”

Section: Discussionmentioning

confidence: 77%

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

et al. 2006

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We investigated the molecular mechanisms of the anti-apoptotic properties of Granulocyte-Colony Stimulating Factor (G-CSF) on neurons and whether G-CSF affects glial cell survival following focal cerebral ischemia in rats. Sprague-Dawley rats were subjected to a transient 90min middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Rats were treated with either a single dose of G-CSF (50 μg/kg, subcutaneously) at the onset of reperfusion or G-CSF (50 μg/kg body weight, subcutaneously) was administered starting at the onset of reperfusion and followed by the administration of the same dose per day for an additional 2 days. Brains were harvested either 24hrs, 72hrs or 2 weeks after reperfusion for assays of infarct volume, immunohistological studies and Western Blot analysis for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Pim-1, bcl-2, Bax, cytochrome c, cellular inhibitor of apoptosis protein 2 (cIAP2), and cleaved caspase-3 levels. G-CSF significantly reduced infarct volume and ameliorated the early neurological outcome. G-CSF treatment significantly up-regulated pSTAT3, Pim-1, bcl-2 expression, and down-regulated cytochrome c release to the cytosol, Bax translocation to the mitochondria, and cleaved caspase-3 levels in neurons. The activation of the STAT3 pathway was accompanied by increased cIAP2 expression in glial cells. After MCAO, G-CSF treatment increased both neuronal and glial survival by effecting different anti-apoptotic pathways which reflects the multifactorial actions of this drug. These changes were associated with remarkable improvement in tissue preservation and behavioral outcome. KeywordsApoptosis; Bcl-2; Glia; Pim-1; STAT; Stroke Granulocyte-Colony Stimulating Factor (G-CSF) is a member of the hematopoietic growth factor family, which orchestrates the proliferation, differentiation, and survival of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Demetri and Griffin, 1991). It has been widely used in clinical practice for the treatment of such conditions as neutropenia, associated with cytotoxic therapy. NIH Public AccessHowever, growing evidence has suggested that G-CSF also has important non-hematopoietic functions in other tissues including the central nervous system (CNS). Recent studies have shown the presence of the G-CSF-receptor (G-CSFR) in a wide variety of cells in the brain, including neurons and glial cells (Schneider et al., 2005). G-CSF and its receptor are coexpressed in neurons and are upregulated in response to neural injury, suggesting an autrocrine protective signalin...

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Section: Discussionmentioning

confidence: 77%

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

et al. 2006

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“…Numerous studies have demonstrated G-CSF induced improvements of motor functions after experimental ischemia or other neurological diseases. Interestingly, many of these studies used the rotarod to assess basic motor function (Gibson et al, 2005;Park et al, 2005;Schneider et al, 2005Schneider et al, , 2006. The rotarod is a practicable and easily quantifiable test, in which animals maintain balance on a rotating rod.…”

Section: Discussionmentioning

confidence: 99%

The Role of Granulocyte-Colony Stimulating Factor (G-CSF) in the Healthy Brain: A Characterization of G-CSF-Deficient Mice

Diederich¹,

Sevimli²,

Dörr³

et al. 2009

J. Neurosci.

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Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that controls proliferation and differentiation of neural stem cells. Although recent studies have begun to explore G-CSF-related mechanisms of action in various disease models, little is known about its function in the healthy brain. In the present study, the effect of G-CSF deficiency on memory formation and motor skills was investigated. The impact of G-CSF deficiency on the structural integrity of the hippocampus was evaluated by analyzing the generation of doublecortin-expressing cells, the amount of bromodeoxyurine-labeled cells, the dendritic complexity in hippocampal neurons, the binding densities of NMDA and GABA A receptors and the induction of long-term potentiation (LTP). G-CSF deficiency caused a disruption in memory formation and in the development of motor skills. These impairments were associated with reduced ligand binding densities of NMDA receptors in hippocampal subfields CA3 and the dentate gyrus. The reduced excitation was potentiated by increased ligand binding densities of GABA A receptors resulting in a relative shift in favor of inhibition and impaired behavioral performance. These alterations were accompanied by impaired induction of LTP in the CA1 region. Moreover, G-CSF deficiency led to decreased dendritic complexity in hippocampal neurons in the dentate gyrus and the CA1 region. G-CSF deficiency also caused a reduction of neuronal precursor cells in the dentate gyrus. These findings confirm G-CSF as an essential neurotrophic factor, and point to a role in the proliferation, differentiation and functional integration of neural cells necessary for the structural and functional integrity of the hippocampal formation.

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“…Data on vital status was available in 6 studies (Gibson et al, 2005a;Schabitz et al, 2003;Schneider et al, 2005;Sevimli et al, 2009;Six et al, 2003;Yanqing et al, 2006); G-CSF reduced the odds of dying almost 4-fold (OR 0.27, 95% CI 0.14 to 0.51, p<0.0001).…”

Section: Survivalmentioning

confidence: 99%

“…Impairment was measured at various time points post stroke (1, 2, 3, 7, 14, 21 and 35 days); beneficial effects of G-CSF were seen at all times but there was no correlation between reduction in impairment and time to measurement (r s = 0.37, p=0.47). G-CSF increased time that animals stayed on a Rotarod (Gibson et al, 2005a;Lee et al, 2005;Schneider et al, 2006;Sevimli et al, 2009) (table 3) at 1 and 5 weeks post ischaemia. Similarly, improvements were seen in limb function as assessed by limb placement tests at 1 and 4 weeks post stroke.…”

Section: Motor Impairmentmentioning

confidence: 99%

“…The majority of included studies were randomised (Gibson et al, 2005a;Gibson et al, 2005b;Han et al, 2008;Komine-Kobayashi et al, 2006;Lan et al, 2008;Lee et al, 2005;Schabitz et al, 2003;Schneider et al, 2005; Yanqing et al, 2006;Zhao et al, 2007c) and although each study varied in G-CSF dose regimen, only one study specifically addressed the optimal time window of drug administration (Lee et al, 2005). One study assessed dose response (Taguchi et al 2007).…”

Section: Study Qualitymentioning

confidence: 99%

See 1 more Smart Citation

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: A systematic review

England

Gibson

Bath

2009

Brain Research Reviews

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

Cited by 156 publications

References 55 publications

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

The Role of Granulocyte-Colony Stimulating Factor (G-CSF) in the Healthy Brain: A Characterization of G-CSF-Deficient Mice

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: A systematic review

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