Meta-Analysis of the Efficacy of Granulocyte-Colony Stimulating Factor in Animal Models of Focal Cerebral Ischemia

Abstract

Background and Purpose-Recent reports have described the efficacy of the hematopoietic growth factor granulocytecolony stimulating factor (G-CSF) in animal stroke models. Early clinical multicenter trials evaluating the effect of G-CSF in acute stroke and pilot clinical trials for the subacute phase are ongoing. To guide further development, a meta-analysis was performed to assess the effects of G-CSF on infarct size and sensorimotor deficits. Methods-Using electronic and manual searches of the literature, we identified studies describing the efficacy of G-CSF in animal models of focal cerebral ischemia. Two reviewers independently selected studies and extracted data on study quality, G-CSF doses, time of administration, and outcome measured as infarct volume and/or sensorimotor deficit. Data from all studies were pooled by meta-regression analyses. Results-Thirteen studies including 277 animals for infarct size calculation and 258 animals for assessment of sensorimotor deficit met the criteria for inclusion. Overall efficacy of G-CSF regarding infarct size reduction was 42%. Meta-regression analysis revealed a 0.8% (PϽ0.0001) decrease in infarct size per 1-g/kg increase in G-CSF dose when applied within the first 6 hours and a 2.1% (PϽ0.0001) decrease when applied later than 6 hours after induction of ischemia with a significant (Pϭ0.0004) greater infarct size reduction after delayed treatment. Sensorimotor deficits categorized into 3 subgroups improved between 24% and 40%. Conclusions-Our findings consolidate G-CSF as a drug that both reduces infarct size and enhances functional recovery.These effects are presumably dose dependent. In contrast to most other neuroprotectants, a beneficial outcome may also be achieved when treatment is delayed.

Multifunctional Actions of Approved and Candidate Stroke Drugs

“…112 Our meta-regression analysis revealed a clear doseresponse relationship of the efficacy of G-CSF. 112 When administered within the first 6 hours after the induction of ischemia, G-CSF reduced infarct sizes by 0.8% per 1 g/kg body weight and by 2.1% per 1 g/kg body weight when applied later than 6 hours. 112 Based on these promising preclinical studies, a number of clinical studies were initiated to test the efficacy of G-CSF in stroke patients.…”

“…[107][108][109][110][111] To obtain an overall impression of the efficacy of G-CSF in preclinical studies and to evaluate conditions under which maximum efficacy can be achieved, we performed a meta-analysis and meta-regression analysis of G-CSF in animal stroke models. 112 We showed that G-CSF reduced both infarct volumes and sensorimotor deficits. 112 Our meta-regression analysis revealed a clear doseresponse relationship of the efficacy of G-CSF.…”

“…112 We showed that G-CSF reduced both infarct volumes and sensorimotor deficits. 112 Our meta-regression analysis revealed a clear doseresponse relationship of the efficacy of G-CSF. 112 When administered within the first 6 hours after the induction of ischemia, G-CSF reduced infarct sizes by 0.8% per 1 g/kg body weight and by 2.1% per 1 g/kg body weight when applied later than 6 hours.…”

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

“…Numerous reports have described the efficacy of G-CSF in animal models of different neurological diseases including stroke (Schabitz et al, 2003;Schneider et al, 2005;KomineKobayashi et al, 2006;Solaroglu et al, 2006;Minnerup et al, 2008), Parkinson's disease (Cao et al, 2006;Meuer et al, 2006), and Alzheimer's disease (Tsai et al, 2007). These studies confirm G-CSF as a neurotrophic factor, and ascertained its role in neuroprotection and neuroregeneration relevant to the most prominent neurodegenerative diseases.…”

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

“…This former review observed a 0.8% reduction in infarct volume per 1 g/kg increase in G-CSF dose (Minnerup et al, 2008). However, it included fewer articles (13 publications), excluded studies appropriate for analysis (Hermann and Kilic, 2008;Sehara et al, 2007c;Taguchi et al, 2007) and found no evidence of publication bias.…”