A Systematic Review and Meta-Analysis of Erythropoietin in Experimental Stroke

Jerndal, Mikael; Forsberg, Kalle; Sena, Emily S.; Macleod, Malcolm; O’Collins, Victoria; Lindén, Thomas; Nilsson, Michael; Howells, David W.

doi:10.1038/jcbfm.2009.267

Cited by 87 publications

(75 citation statements)

References 30 publications

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“…18 The tendency for lower-quality studies to overestimate intervention effects also exists in human trials 27 and meta-analyses of human stroke therapies. [19][20][21][22] That the reverse was true, with MSC higher-quality studies showing larger behavioral gains, increases confidence in their therapeutic translational potential. A significant favorable effect of MSCs was reported in 44 of the 46 studies and in 54 of the 62 treatment arms.…”

Section: Resultsmentioning

confidence: 94%

“…Third, the relationship between study quality and effect size was examined, because lower-quality preclinical stroke studies tend to overestimate efficacy. [18][19][20][21][22] Finally, the robustness of MSC efficacy was examined across clinical measures of interest such as dose and timing relative to stroke onset. Given the potential for MSCs as a restorative therapy, analyses were repeated using only preclinical studies that initiated MSC therapy 24 hours or more after stroke onset.…”

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confidence: 99%

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Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

et al. 2014

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Objectives:To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects.Methods: A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints.Results: Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral . intra-arterial . IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate . rat . mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs $24 hours poststroke; results were overall very similar. Conclusions:In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.

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Section: Resultsmentioning

confidence: 94%

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confidence: 99%

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

et al. 2014

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“…The lack of PI3K/ Akt/GSK-3b pathway activation could be explained by the use of lower rhEPO doses in our study when compared with previous ones. 19,28 In fact, only up to 1% of systemically administered rhEPO crosses the BBB in primates, 21 and poor penetration into the BBB is expected even when administering up to 10,000 IU/kg intravenously as single doses. 12 This poor crossing ratio suggests that high doses of systemically administered rhEPO are needed for direct neuron-protective purposes.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion

Ratilal

Arroja

Rocha

et al. 2014

JNS

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Object There is an unmet clinical need to develop neuroprotective agents for neurosurgical and endovascular procedures that require transient cerebral artery occlusion. The aim in this study was to explore the effects of a single dose of recombinant human erythropoietin (rhEPO) before middle cerebral artery (MCA) occlusion in a focal cerebral ischemia/reperfusion model. Methods Twenty-eight adult male Wistar rats were subjected to right MCA occlusion via the intraluminal thread technique for 60 minutes under continuous cortical perfusion monitoring by laser Doppler flowmetry. Rats were divided into 2 groups: control and treatment. In the treated group, rhEPO (1000 IU/kg intravenously) was administered 10 minutes before the onset of the MCA ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected, and animals were killed. The following parameters were evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron-specific enolase plasma levels, parenchyma histological features (H & E staining), Fluoro-Jade–positive neurons, p-Akt and total Akt expression by Western blot analysis, and p-Akt–positive nuclei by immunohistochemical investigation. Results Infarct volume and Fluoro-Jade staining of degenerating neurons in the infarct area did not vary between groups. The severity of neurological deficit (p < 0.001), amount of brain edema (78% reduction in treatment group, p < 0.001), and neuron-specific enolase plasma levels (p < 0.001) were reduced in the treatment group. Perivascular edema was histologically less marked in the treatment group. No variations in the expression or localization of p-Akt were seen. Conclusions Administration of rhEPO before the onset of 60-minute transient MCA ischemia protected the brain from this insult. It is unlikely that rhEPO pretreatment leads to direct neuronal antiapoptotic effects, as supported by the lack of Akt activation, and its benefits are most probably related to an indirect effect on brain edema as a consequence of blood-brain barrier preservation. Although research on EPO derivatives is increasing, rhEPO acts through distinct neuroprotective pathways and its clinical safety profile is well known. Clinically available rhEPO is a potential therapy for prevention of neuronal injury induced by transitory artery occlusion during neurovascular procedures.

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“…13,18 A systematic review and meta-analyses of the efficacy of EPO and its analogs in treating TBI in experimental animal studies have not yet been conducted. Therefore, our main objective was to systematically investigate whether the evidence from animal studies favors a beneficial effect of EPO in reducing lesion volume and improving neurobehavioral outcome after TBI.…”

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confidence: 99%

The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models

Peng

Xing²,

Yang³

et al. 2014

JNS

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S yStematic reviews and meta-analyses are fundamental tools used to interpret the effectiveness of a treatment across many studies. Recently, the need to conduct systematic reviews and meta-analyses of animal studies modeling clinically relevant problems has been highlighted. 9,13,36 In particular, systematic reviews of animal experiments will allow decisions regarding the design and conduct of subsequent clinical trials to be based on the entirety of the existing evidence that is synthesized in an unbiased manner. Moreover, systematic reviews permit a more objective appraisal of evidence than is allowed by the traditional narrative-style reviews that are more commonly associated with animal research. Traumatic brain injury (TBI), which is the leading cause of long-term disability in children and young adults worldwide, 11 causes a variety of cognitive, emotional, and behavioral problems that can occur either individually or in combination. 20,40 In the US, a case of TBI occurs every 15 seconds, resulting in 1.7 million new head injury victims per year. Each year, on average, these events are responsible for 50,000 deaths, leave 80,000 individuals with permanent disabilities, and cost more than US$77 billion. 34 However, there are no pharmacological treat- Object. Erythropoietin (EPO) shows promise as a neuroprotective agent in animal models of traumatic brain injury (TBI). However, clinical trials of the efficacy of EPO treatment in patients with TBI yield conflicting results. The authors conducted a systematic review and meta-analysis to assess the effect of EPO in experimental animal models of TBI, the goal being to inform the design of future clinical trials.Methods. The authors identified eligible studies by searching PubMed, Web of Science, MEDLINE, Embase, and Google Scholar in October 2013. Data were pooled using the random-effects model, and results were reported in terms of standardized mean difference. Statistical heterogeneity was examined using both I 2 and chi-square tests, and the presence of small study effects was investigated with funnel plots and Egger tests. In-depth analyses were performed for lesion volume and neurobehavioral outcome, and the studies' methodological quality was also evaluated.Results. Of a total of 290 studies, 13 found an effect of EPO on lesion volume and neurobehavioral outcome. Overall, the methodological quality of the studies was poor, and there was evidence of statistical heterogeneity among the publications as well as small-study effects. However, in-depth analyses showed statistically significant findings in favor of a beneficial effect of EPO after TBI.Conclusions. Despite limitations of this systematic review that may have influenced the findings, the authors conclude that EPO might be beneficial in treating experimental TBI in terms of reducing lesion volume and improving neurobehavioral outcome. However, this review also indicates that more well-designed and well-reported animal studies are needed. (http://thejns.org/doi/abs/10.3171/2014.6.JNS132577) KeY Wo...

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A Systematic Review and Meta-Analysis of Erythropoietin in Experimental Stroke

Cited by 87 publications

References 30 publications

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion

The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models

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