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

A review

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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 I2 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.

Abbreviations used in this paper:EPO = erythropoietin; mNSS = modified Neurological Severity Score; MWM = Morris water maze; SMD = standardized mean difference; STAIR = Stroke Therapy Academic Industry Roundtable; TBI = traumatic brain injury.

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 I2 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.

Systematic 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 treatment options for TBI because the translation of neuroprotective effects from preclinical studies to clinical practice has so far failed.17,23

Erythropoietin (EPO), a secreted 30-kD glycoprotein, is a multifunctional tissue-protecting agent that exerts antiapoptotic, antiinflammatory, antioxidative, angiogenic, and neurotrophic effects.7,38 Recently, several investigations have shown that EPO and its analogs provide substantial benefits to rodents after TBI.1,3–5,15,22 However, a pilot randomized trial in humans demonstrated that EPO does not reduce neuronal cell death compared with placebo, although TBI severity was worse in the EPO group, making it difficult to rule out a treatment effect.30 This discrepancy between animal and human studies might be due to bias in the conduct or reporting of animal experiments.39 Therefore, systematic reviews and meta-analyses can point to the cause of bias in animal experiments and provide a clear description of the circumstances under which the treatment is efficacious.

Some argue for the need to perform rigorous systematic reviews and meta-analyses of all available animal data before proceeding to clinical trials9,33 not only to reveal the specific conditions under which a drug can have neuroprotective effects but also to provide insights into potential limitations of the drug that may influence its clinical usefulness.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.

Methods

Literature Search

In October 2013 we searched 5 electronic databases (PubMed, Web of Science, MEDLINE, Embase, and Google Scholar) using the terms EPO (or erythropoietin) and TBI (or traumatic brain injury), limiting results to animal studies. Reference lists from the resulting research articles and reviews were used to identify further relevant publications.

Two investigators assessed the titles and abstracts of studies, and obtained copies of articles that described controlled studies of EPO or its analogs in animal models of TBI and that measured both lesion volume and neurobehavioral outcome. We included all studies in which neurobehavioral measurements were conducted not only after but also before TBI, thereby establishing a baseline for normal or pre-TBI function. Prespecified exclusion criteria were as follows: administration of any other neuroprotective agent in the treatment group, no control group, or data presented in duplicate by additional publications. Disagreements between investigators were resolved by consensus after discussion (Fig. 1).

Fig. 1.
Fig. 1.

Flowchart of TBI study search process.

Data Extraction

Two investigators extracted information about the included studies including animal species, type of TBI model, main experimental groups, method of EPO administration, and time of outcome assessment. Information about sample sizes and substances used as experimental and control treatments was also extracted. Disagreements between investigators were resolved by consensus after discussion.

We categorized neurobehavioral tests into 3 clinically meaningful categories: 1) modified Neurological Severity Score (mNSS) as a gross neurological deficit score; 2) the Morris water maze (MWM) for memory function; and 3) the foot-fault test for limb function. When neurobehavioral deficits were assessed at different times after TBI, only the 14th day was considered. Comparisons of neurobehavioral outcomes among studies were made considering cumulative EPO dose. In cases of missing data, we contacted the authors and requested the additional information. If data were only expressed graphically, numerical values were requested from the authors; if a response was not received, digital ruler software was used to estimate numerical values from the graphs. If required data were not presented or obtainable, the study was excluded from the meta-analysis.

Methodological Quality of Studies

The methodological quality of individual studies was assessed using an 8-point rating scale as previously described.13 One point was given for written evidence of each of the following criteria: presence of randomization; monitoring of physiological parameters; assessment of dose-response relationship; assessment of optimal treatment time window; blind measurements of outcomes; assessment of outcome on Days 1–3; assessment of outcome on Days 1–30; and combined measurement of lesion volume and neurobehavioral outcome. We also evaluated whether the preclinical EPO studies met the current Stroke Therapy Academic Industry Roundtable (STAIR) recommendations.12,26

Statistical Analysis

Results were calculated as the standardized mean difference ([SMD]; reported in units of standard deviation), which allows data measured on different scales to be merged, and 95% confidence intervals. The withinand between-study variation or heterogeneity was assessed using the Cochrane Q-statistic,10,35 with a significant Q-statistic (p < 0.10) indicating heterogeneity among studies. Heterogeneity was also quantified with the I2 metric, with higher values denoting a greater degree of heterogeneity (I2 0%–40%: no important heterogeneity; I2 30%–60%: moderate heterogeneity; I2 50%–90%: substantial heterogeneity; I2 75%–100%: considerable heterogeneity), and I2 values ≤ 50% indicate acceptable heterogeneity among studies.16

For studies comparing different doses and/or timing of drug administration with a single control group, we pooled data from all experimental groups to compare with the control group. Pooled effect size was estimated using fixed and random-effects models. When there was heterogeneity among studies, pooled effect size was estimated using a random-effects model.41,53 The presence of small study effects was investigated with funnel plots and Egger tests. For Egger tests, a p value of <0.10 was considered to indicate the presence of small study effects.10 Finally, we assessed the impact of several variables (type of EPO treatment, treatment dose, timing and duration of treatment, animal species) on the efficacy of EPO by using meta-regression when substantial or considerable heterogeneity existed. All statistical analyses were performed using Stata software (version 12.0).

Results

Description of Studies

We identified 290 studies (35 from PubMed, 94 from MEDLINE, 102 from Web of Science, 0 from Embase, and 59 from Google Scholar). On the basis of predefined criteria, 277 studies were excluded, leaving 13 studies2,15,25,29,43,45–52 for systematic review. One study2 was excluded from the meta-analysis because sample sizes were not stated, and we were unable to obtain this information from the authors. Another study15 was excluded because lesion volume was measured in cubic millimeters and MWM performance was measured in seconds. Therefore, the meta-analysis ultimately included 11 studies.25,29,43,45–52 Among the included studies (Table 1), treatment outcomes were measured for 1 to 90 days after TBI. Ten studies used rats, and 3 studies used mice. All studies assessed lesion volume and neurobehavioral function; 12 used the MWM to assess cognitive function, 7 used the mNSS to assess neurological function, and 9 used the foot-fault test to assess sensorimotor function.

TABLE 1:

Characteristics of the 13 studies included in the systematic review*

Authors & YearAnimal Species & Sex (no.)Type of ModelDrug (treated/control)Main Experimental GroupsMethod of EPO AdministrationOutcome MeasuresTime of Measurement of OutcomeQuality Score
Grasso et al., 2007M SDRs (66)cryogenic cerebral injuryrhEPO/vehicle1) sham op; 2) TBI plus placebo; 3) TBI plus rhEPO1000 IU/kg rhEPO administered ip at 5 min after injury, & continued every 8 hrs up to 14 daysMWM test, brain edema, BBB integrity, lesion vol1–14 days2
Xiong et al., 2007young adult M & F C57BL/6 mice (56)CCI injuryrhEPO/sal1) M sal group; 2) M EPO group; 3) F sal group; 4) F EPO group; 5) sham group5000 U/kg body wt rhEPO administered ip at 6 hrs & at 3 & 7 days (total dosage 15,000 U/kg) after TBIMWM test, foot-fault test, lesion vol1–35 days4
Xiong et al., 2008adult M C57BL/6 mice (37)CCI injuryrhEPO/sal1) sal group; 2) EPO group; 3) sham group5000 U/kg body wt rhEPO administered ip at 6 hrs & at 3 & 7 days post-TBI (total dosage 15,000 U/kg)MWM test, foot-fault test, lesion vol1–35 days4
Zhang et al., 2009young adult M Wistar rats (25)CCI injuryEPO/sal1) sham group; 2) TBI + sal group; 3) TBI + EPO group; 4) TBI +EPO + hemodilution group5000 U/kg EPO administered ip at Days 1, 2, & 3 postinjurymNSS, foot-fault tests, MWM test, lesion vol1–35 days6
Xiong et al., 201046young adult M Wistar rats (25)CCI injuryEPO/sal1) sham group; 2) TBI + sal group; 3) TBI + EPOx1 group; 4) TBI +EPOx3 group5000 U/kg EPO administered ip at 1 day (EPOx1 group) or at Days 1, 2, & 3 (EPOx3 group) postinjurymNSS, foot-fault test, MWM test, lesion vol1–35 days8
Xiong et al., 201047young adult F EPOR-null & wild-type mice (72)CCI injuryEPO/sal1) sham group; 2) TBI + sal group; 3) TBI + EPO group5000 U/kg EPO administered ip at 6 hrs & 3 & 7 days postinjuryMWM test, foot-fault test, lesion vol1–35 days6
Zhang et al., 2010young adult M Wistar rats (24)CCI injuryEPO/sal1) sham control; 2) TBI + sal; 3) TBI + EPO5000 U/kg EPO administered ip at Days 1, 2, & 3 postinjurymNSS, foot-fault test, lesion vol1–35 days6
Meng et al., 2011young adult M Wistar rats (48)CCI injuryEPO/sal1) sham; 2) TBI/sal group; 3) TBI + EPO1K; 4) TBI + EPO3K; 5) TBI + EPO5K; 6) TBI + EPO7KEPO at doses of 0 (sal), 1000 (EPO1K), 3000 (EPO3K), 5000 (EPO5K), & 7000 (EPO7K) U/kg body wt was administered ip at 24, 48, & 72 hrs after TBImNSS, foot-fault test, MWM test, lesion vol1–35 days8
Ning et al., 2011young M Wistar rats (23)CCI injuryEPO/sal1) sal group; 2) EPO 6-hr group; 3) EPO 24-hr group5000 U/kg EPO in sal was administered ip at 6 hrs & at 1 & 2 days (EPO 6-hr group) or at 1, 2, & 3 days (EPO 24-hr group) postinjurymNSS, foot-fault test, MWM test, lesion vol1–90 days7
Xiong et al., 201148young adult M Wistar rats (32)CCI injuryCEPO/sal1) sham; 2) TBI + vehicle; 3) TBI + CEPO x 1; 4) TBI + CEPO x 350 μg/kg body wt CEPO administered ip at 6 hrs (for the CEPO x 1 group) or at 6, 24, & 48 hrs (for the CEPO x 3 group) after TBImNSS, foot-fault test, MWM test, lesion vol1–35 days6
Xiong et al., 201149young adult M Wistar rats (64)CCI injuryEPO/sal1) sham; 2) sal; 3) EPO + DMSO; 4) EPO + SU54165000 U/kg body wt EPO administered ip at 24, 48, & 72 hrs after TBImNSS, MWM test, lesion vol1–35 days5
Zhang et al., 2012young adult M Wistar rats (41) citsCCI injuryEPO/sal/Ara-C1) sham + sal group; 2) sham + Ara-C group; 3) TBI + sal + sal group; 4) TBI + sal + Ara-C group; 5) TBI + EPO + sal group; 6) TBI +EPO + Ara-C groupan optimal dose of 5000 U/kg body wt EPO administered ip at 24, 48, & 72 hrs after TBIMWM test, lesion vol1–35 days4
Anderson et al., 2013M SDRs (no. unclear)CCI injuryEPO/anakinra/vehicle1) sham; 2) TBI + EPO 2500 IU/kg; 3) TBI + anakinra at 100 mg/kg; 4) TBI + vehicle2500 IU/kg EPO administered ip 2, 12, 24, 36, 48, 60, & 72 hrs after CCI injurylocomotor placing task, rotarod test, MWM test, lesion vol1–30 days6

Two studies were excluded from the meta-analysis because lesion volume and MWM performance were measured using different increments (Grasso et al.) and sample sizes were not stated (Anderson et al.). BBB = blood-brain barrier; CCI = controlled cortical impact; CEPO = carbamylated EPO; DMSO = dimethyl sulfoxide; EPOR = EPO receptor; ip = intraperitoneally; rhEPO = recombinant human EPO; sal = saline; SDR, Sprague-Dawley rat; wt = weight.

Methodological Quality of Studies

The median quality score of included studies was 6 of 8 (range 2–8). Two studies25,46 had a score of 8, 1 study29 had a score of 7, and 5 studies2,47,48,51,52 had a score of 6. Animals were randomly allocated to treatment groups in 7 studies.2,25,29,46,47,51,52 Only 1 study15 did not report monitoring of physiological parameters (although the majority of the other studies only monitored body or rectal temperature). Only 3 studies25,46,48 assessed dose-response relationships, and 3 studies25,29,46 investigated the optimal time window for administering EPO. Four studies15,43,45,50 did not report that outcome measures were made by researchers who were blind to animal treatment. All 13 studies assessed treatment outcome at Days 1–3, and 12 studies2,25,29,43,45–52 also assessed outcome at Days 1–30. Overall, studies incompletely followed the STAIR recommendations (Table 2).

TABLE 2:

Fulfilled STAIR recommendations in preclinical EPO studies

STAIR RecommendationDescriptionSTAIR Criteria Met?
sample size calculationssample size calculation was not regularly reportedno
inclusion & exclusion criteriainclusion & exclusion criteria were not statedno
randomizationrandomization was reported in some studies3,24,28,42,43,47,48partially
allocation concealmentallocation concealment was not mentionedno
reporting of animals excluded from analysisreporting of animals excluded from analysis47 was done in some studiespartially
blinded assessment of outcomeblinded assessment of outcome was reported in some studiespartially
reporting potential conflicts of interest & study fundinginformation on whether a potential conflict of interest existed was given in all studiescompletely
dose response≥2 doses were investigated w/in 3 studies24,42,44partially
therapeutic window≥2 time points at which treatment was initiated were investigated24,28,42partially
outcome measuresmultiple end points, such as histological & behavioral outcomes, were investigatedcompletely
physiological monitoringonly 1 study15 didn't report monitoring of physiological parameterspartially
multiple speciestreatment efficacy was only investigated in rodents; efficacy in rabbits, gyrence-phalic primates, or cats as suggested has not been tested so farpartially
reproducibilityas shown by this meta-analysis, positive results of EPO & its analogs were replicated in independent laboratoriescompletely

Lesion Volume

Within 10 studies25,43,45–52 there were 17 comparisons (involving 264 animals) of lesion volume 35 days after TBI. Pooled analysis indicated that animals in the treatment groups had significantly reduced lesion volume compared with animals in the control groups (SMD = −1.715, 95% CI −2.359 to −1.071, p < 0.0001).

There was evidence of considerable heterogeneity among studies (χ2 = 76.27, df = 16 [p < 0.0001], I2 = 79.0%) and small study effects (Egger test bias coefficient = −4.08, 95% CI −10.0636 to −3.160554, p = 0.001) (Fig. 2).

Fig. 2.
Fig. 2.

Upper: Forest plot showing results from meta-analysis of lesion volume. Pooled analysis indicated that animals in the treatment groups had significantly reduced lesion volume compared with animals in the control groups (SMD = −1.715, 95% CI −2.359 to −1.071, p < 0.0001). Lower: Begg funnel plot of lesion volume. There was evidence of small study effects (Egger test bias coefficient = −4.08, 95% CI −10.0636 to −3.160554, p = 0.001). s.e. = standard error.

Foot-Fault Test

Nine studies25,29,43,45–48,51,52 evaluated sensorimotor function by using the foot-fault test 14 days after TBI. Pooled analysis indicated that animals in the treatment groups showed a significant improvement in sensorimotor function compared with animals in the control groups (overall: SMD = −2.813, 95% CI −3.15 to −2.473; forelimb: SMD = −3.153, 95% CI −3.635 to −2.670, p < 0.0001; hindlimb: SMD = −2.483, 95% CI −2.919 to −2.046, p < 0.0001).

There was acceptable heterogeneity among studies (overall: χ2 = 61.33, df = 33 [p = 0.002], I2 = 46.2%; forelimb: χ2 = 26.41, df = 16 [p = 0.049], I2 = 39.4%; hindlimb: χ2 = 27.75, df = 16 [p = 0.034], I2 = 42.3%); and small study effects for foot-fault test (Egger test bias coefficient = −4.88, p < 0.0001) (Fig. 3).

Fig. 3.
Fig. 3.

Upper: Forest plot showing results from meta-analysis of foot-fault test. Pooled analysis indicated that animals in the treatment groups showed a significant improvement in sensorimotor function compared with animals in the control groups (overall: SMD = −2.813, 95% CI −3.15 to −2.473; forelimb: SMD = −3.153, 95% CI −3.6385 to −2.670, p < 0.0001; hindlimb: SMD = −2.483, 95% CI −2.919 to −2.0546, p < 0.0001). Lower: Begg funnel plot of foot-fault test. There was evidence of small study effects (Egger test bias coefficient = −4.88, p < 0.0001).

The mNSS

Within 7 studies25,29,46,48,49,51,52 there were 13 comparisons (involving185 animals) of neurological function using the mNSS 14 days after TBI. Pooled analysis indicated that animals in the treatment groups had significantly lower mNSSs (that is, better neurological function) than animals in the control groups (SMD = −2.930; 95% CI −3.527 to −2.334, p < 0.0001).

There was acceptable heterogeneity among studies (χ2 = 22.66, df = 12 [p = 0.031], I2 = 47.0%) and small study effects (Egger test bias coefficient = −10.78, 95% CI −6.93247 to −4.581088, p < 0.0001) (Fig. 4).

Fig. 4.
Fig. 4.

Upper: Forest plot showing results from meta-analysis of mNSS. Pooled analysis indicated that animals in the treatment groups had significantly lower mNSSs (i.e., better neurological function) than animals in the control groups (SMD = −2.930, 95% CI −3.527 to −2.334, p < 0.0001). Lower: Begg funnel plot of mNSS. There was evidence of small study effects (Egger test bias coefficient = −10.78, 95% CI −6.93247 to −4.581088, p < 0.0001).

The MWM Test

Within 10 included trials,25,29,43,45–50,52 there were 18 comparisons (involving 296 animals) of spatial learning and memory deficits performed using the MWM 35 days after TBI. Pooled analysis indicated that animals in the treatment groups significantly improved spatial learning performance (that is, greater percentage of time spent in the correct quadrant) compared with animals in the control groups (SMD = 3.933; 95% CI 3.355–4.512, p < 0.0001).

There was acceptable heterogeneity among studies (χ2 = 32.55, df = 17 [p = 0.013], I2 = 47.8%) and small study effects (Egger test bias coefficient = 10.13 (95% CI 3.710158–5.675137, p < 0.0001) (Fig. 5).

Fig. 5.
Fig. 5.

Upper: Forest plot showing results from meta-analysis of MWM test. Pooled analysis indicated that animals in the treatment groups showed significantly improved spatial learning (i.e., greater percentage of time spent in the correct quadrant) compared with animals in the control groups (SMD = 3.933, 95% CI 3.355–4.512, p < 0.0001). Lower: Begg funnel plot of MWM test. There was evidence of small study effects (Egger test bias coefficient = 10.13, 95% CI 3.710158–5.675137, p < 0.0001).

Meta-Regression Analysis

A multicovariate, random-effects regression model considering EPO treatment type, dose, timing and duration, and animal species explained 89.99% of the variance6 in the effects of EPO on lesion volume among 10 studies25,43,45–52 (Table 3).

TABLE 3:

Meta-regression analysis*

_ESCoefficientSEtp > |t|95% CI
treatment dose–0.73186480.4506005–1.620.130–1.7136390.2499093
type of EPO treatment–1.8839730.7043093–2.670.020–3.418531–0.3494147
timing & duration of treatment0.55222690.75540.730.479–1.0936482.198102
animal species–1.7440210.345596–5.050.000–2.49701–0.9910316
_cons4.5405932.5144511.810.096–0.937926110.01911

Residual maximum likelihood estimate of between-study variance, τ2 = 0.2108; % residual variation due to heterogeneity, I2_res = 40.76%; proportion of between-study variance explained as adjusted R2 = 89.99%; joint test for all covariates Model F(4,12) = 9.42, with Knapp-Hartung modification probably > F = 0.0011. _cons = constant; _ES = effect size; _res = residual; t = test for coefficient.

Discussion

It is important to assess the benefits of candidate neuroprotective drugs by considering both histopathological and functional outcome.37 We present the first systematic review and meta-analysis of the efficacy of EPO and its analogs in treating animal models of TBI. Although small study effects and statistical heterogeneity were present among studies, we found that EPO and its analogs potentially exert neuroprotective effects in terms of reducing lesion volume and improving neurobehavioral outcome after TBI. These findings extend previous systematic reviews of controlled trials in animal models, which report that progesterone and beta-2 receptor antagonists also exert neuroprotective effects against TBI.13,19

Critical appraisal of the methodological quality of studies is an essential part of systematic reviews.27,28,31 We assessed methodological quality in accordance with previously described standards for preclinical development of neuroprotective drugs13 that were established by a panel of expert stroke researchers to address the failure of many clinical trials of these drugs for acute ischemic stroke.14,24,41,42 Overall, we found that the methodological quality of the included EPO/TBI studies was poor; many failed to accurately report randomization of group assignment, blinded assessment of outcome, investigation of the optimal time window for treatment, and determination of a dose-response relationship, which are important issues that are generally required in clinical studies.39 Moreover, none of the included studies reported calculations of optimal sample size or criteria for inclusion/exclusion. Also, EPO treatment efficacy in rabbits, cats, or gyrencephalic primates has not yet been tested and should be considered in future studies.

This systematic review has some limitations. First, our objective was to assess the overall efficacy of EPO and its analogs, and we did not undertake analyses to investigate the presence of dose-response relationships or effects related to the timing of drug administration, such as those performed in a previously published study.19 It should also be noted that our pooling of all doses may lead to an underestimation of treatment efficacy, assuming the existence of a true dose-response relationship.

Second, publication bias, which is considered a potential threat to the validity of all systematic reviews of experimental studies, should also be considered. Although we made an extensive effort to identify all relevant published and unpublished studies, we were only able to include data that were published in some form; hence our analysis did not take unpublished data into account. Because studies with negative results are less likely to be published, our results may overstate overall effect size. The funnel plots and the Egger tests suggest the possibility of publication bias or other small-study biases, consistent with that observed in previous systematic reviews of animal studies.19,32

Third, nonpublication of studies serves to limit available information on the effect of treatment under certain testing conditions, such as specific doses or timing of treatment. Extracting multiple pieces of information from a single publication has the potential to introduce bias into systematic reviews because the results were generated by the same investigators. As found in this review, the existence of true heterogeneity should be considered as a potential explanation.

Fourth, there were differences among studies in terms of animal species, physiological parameters, methods of drug administration, and experimental protocols. We used regression analysis to explore sources of variation in the effect of EPO on lesion volume. Unfortunately, it was not possible to judge accurately whether the relationships we observed were independent of these factors, which also led to statistical heterogeneity and made the analysis less reliable.

Fifth, although a fundamental assumption is that the results of animal studies, if performed well enough, will predict effects in humans, promising neuroprotective drugs previously identified as effective in animal TBI models have failed in Phase II or III clinical trials.45

Finally, there were several instances in which numerical data were not readily available and had to be derived from graphs. Although we enlarged the graphs, and data were independently extracted by 2 investigators, this technique can be imprecise. Therefore, our findings should be interpreted carefully.

To improve the transition from animal experiments to human clinical trials, future animal studies should report full methodological details to allow others to reproduce and validate their results and to enable more accurate reviews and meta-analyses, which would further scientific progress. Researchers are strongly encouraged to consult and follow the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines when designing studies and writing up results, which is considered an important step forward in improving scientific reporting standards for animal research.8,21

Also, this systematic review focuses only on the overall effect of EPO on long-term outcomes following TBI, largely due to insufficient data regarding other short-term outcomes such as brain edema and blood-brain barrier permeability, which were reported in only one of the included studies.15 Moreover, most included studies used the controlled cortical impact injury model of TBI to investigate the effect of EPO; therefore, these limited results might be inadequate for predicting the treatment response in patients. With that in mind, prior to making any clinical practice recommendations, more appropriate and standardized experimental studies are needed to better evaluate the impact of this promising pharmacological intervention for TBI.

Conclusions

Despite its limitations, this systematic review and meta-analysis show that EPO and analogs can reduce lesion volume and improve neurobehavioral outcomes in animal models of TBI. However, without rigorous, robust, and detailed preclinical evaluation, it is unlikely that novel neuroprotective drugs will prove effective when tested in large, time-consuming, and expensive human clinical trials. Thus, more well-designed and well-reported experimental animal studies are needed.

Disclosure

This work was financially supported by the Young Scientists Fund of the National Natural Science Foundation of China (Grant Nos. 81303074 and 81303098). The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Huang, Peng. Acquisition of data: Peng, Xing, Yang, Y Wang, W Wang. Analysis and interpretation of data: Peng, Yang, Y Wang, W Wang. Drafting the article: Huang, Peng, Y Wang. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Huang. Statistical analysis: W Wang. Study supervision: Huang, Xing.

References

  • 1

    Akdemir Ozisik POruckaptan HOzdemir Geyik PMisirlioglu MSargon MFKilinc K: Effect of erythropoietin on brain tissue after experimental head trauma in rats. Surg Neurol 68:5475552007

    • Search Google Scholar
    • Export Citation
  • 2

    Anderson GDPeterson TCVonder Haar CKantor EDFarin FMBammler TK: Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model. Front Pharmacol 4:1292013

    • Search Google Scholar
    • Export Citation
  • 3

    Bouzat PFrancony GThomas SValable SMauconduit FFevre MC: Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative. Crit Care Med 39:209921052011

    • Search Google Scholar
    • Export Citation
  • 4

    Brines MLGhezzi PKeenan SAgnello Dde Lanerolle NCCerami C: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526105312000

    • Search Google Scholar
    • Export Citation
  • 5

    Cherian LGoodman JCRobertson C: Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther 322:7897942007

    • Search Google Scholar
    • Export Citation
  • 6

    Colditz GABrewer TFBerkey CSWilson MEBurdick EFineberg HV: Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271:6987021994

    • Search Google Scholar
    • Export Citation
  • 7

    Cotena SPiazza OTufano R: The use of erythtropoietin in cerebral diseases. Panminerva Med 50:1851922008

  • 8

    Danos ODavies KLehn PMulligan R: The ARRIVE guidelines, a welcome improvement to standards for reporting animal research. J Gene Med 12:5595602010

    • Search Google Scholar
    • Export Citation
  • 9

    Dirnagl U: Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab 26:146514782006

  • 10

    Egger MSmith GDSchneider MMinder C: Bias in metaanalysis detected by a simple, graphical test. BMJ 315:6296341997

  • 11

    Feigin VLTheadom ABarker-Collo SStarkey NJMcPherson KKahan M: Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol 12:53642013

    • Search Google Scholar
    • Export Citation
  • 12

    Fisher MFeuerstein GHowells DWHurn PDKent TASavitz SI: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:224422502009

    • Search Google Scholar
    • Export Citation
  • 13

    Gibson CLGray LJBath PMMurphy SP: Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131:3183282008

    • Search Google Scholar
    • Export Citation
  • 14

    Gibson CLGray LJMurphy SPBath PM: Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26:110311132006

    • Search Google Scholar
    • Export Citation
  • 15

    Grasso GSfacteria AMeli FFodale VBuemi MIacopino DG: Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182:991052007

    • Search Google Scholar
    • Export Citation
  • 16

    Higgins JPTGreen S: Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 Cochrane Collaboration2011. (http://handbook.cochrane.org/) [Accessed June 4 2014]

    • Search Google Scholar
    • Export Citation
  • 17

    Janowitz TMenon DK: Exploring new routes for neuroprotective drug development in traumatic brain injury. Sci Transl Med 2:27rv12010

  • 18

    Jerndal MForsberg KSena ESMacleod MRO'Collins VELinden T: A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 30:9619682010

    • Search Google Scholar
    • Export Citation
  • 19

    Ker KPerel PBlackhall K: Beta-2 receptor antagonists for traumatic brain injury: a systematic review of controlled trials in animal models. CNS Neurosci Ther 15:52642009

    • Search Google Scholar
    • Export Citation
  • 20

    Kersel DAMarsh NVHavill JHSleigh JW: Psychosocial functioning during the year following severe traumatic brain injury. Brain Inj 15:6836962001

    • Search Google Scholar
    • Export Citation
  • 21

    Kilkenny CBrowne WJCuthill ICEmerson MAltman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e10004122010

    • Search Google Scholar
    • Export Citation
  • 22

    Lu DMahmood AQu CGoussev ASchallert TChopp M: Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 22:101110172005

    • Search Google Scholar
    • Export Citation
  • 23

    Lu JFrerich JMTurtzo LCLi SChiang JYang C: Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury. Proc Natl Acad Sci U S A 110:10747107522013

    • Search Google Scholar
    • Export Citation
  • 24

    Macleod MRO'Collins THorky LLHowells DWDonnan GA: Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 25:7137212005

    • Search Google Scholar
    • Export Citation
  • 25

    Meng YXiong YMahmood AZhang YQu CChopp M: Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. Laboratory investigation. J Neurosurg 115:5505602011

    • Search Google Scholar
    • Export Citation
  • 26

    Minnerup JHeidrich JRogalewski ASchäbitz WRWellmann J: The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke 40:311331202009

    • Search Google Scholar
    • Export Citation
  • 27

    Moher DCook DJEastwood SOlkin IRennie DStroup DF: Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 354:189619001999

    • Search Google Scholar
    • Export Citation
  • 28

    Moja LPTelaro ED'Amico RMoschetti ICoe LLiberati A: Assessment of methodological quality of primary studies by systematic reviews: results of the metaquality cross sectional study. BMJ 330:10532005

    • Search Google Scholar
    • Export Citation
  • 29

    Ning RXiong YMahmood AZhang YMeng YQu C: Erythropoietin promotes neurovascular remodeling and longterm functional recovery in rats following traumatic brain injury. Brain Res 1384:1401502011

    • Search Google Scholar
    • Export Citation
  • 30

    Nirula RDiaz-Arrastia RBrasel KWeigelt JAWaxman K: Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial. Crit Care Res Pract 2010:2098482010

    • Search Google Scholar
    • Export Citation
  • 31

    Oxman ADGuyatt GH: Guidelines for reading literature reviews. CMAJ 138:6977031988

  • 32

    Perel PRoberts ISena EWheble PBriscoe CSandercock P: Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334:1972007

    • Search Google Scholar
    • Export Citation
  • 33

    Pound PEbrahim SSandercock PBracken MBRoberts I: Where is the evidence that animal research benefits humans?. BMJ 328:5145172004

    • Search Google Scholar
    • Export Citation
  • 34

    Prins MGreco TAlexander DGiza CC: The pathophysiology of traumatic brain injury at a glance. Dis Model Mech 6:130713152013

  • 35

    Sacks HSBerrier JReitman DAncona-Berk VAChalmers TC: Meta-analyses of randomized controlled trials. N Engl J Med 316:4504551987

    • Search Google Scholar
    • Export Citation
  • 36

    Sandercock PRoberts I: Systematic reviews of animal experiments. Lancet 360:5862002

  • 37

    Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:275227581999

    • Search Google Scholar
    • Export Citation
  • 38

    Velly LPellegrini LGuillet BBruder NPisano P: Erythropoietin 2nd cerebral protection after acute injuries: a double-edged sword?. Pharmacol Ther 128:4454592010

    • Search Google Scholar
    • Export Citation
  • 39

    Wardlaw JMWarlow CPSandercock PADennis MSLindley RI: Neuroprotection disappointment yet aGAIN. Lancet 356:5972000. (Letter)

  • 40

    Washington PMForcelli PAWilkins TZapple DNParsadanian MBurns MP: The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J Neurotrauma 29:228322962012

    • Search Google Scholar
    • Export Citation
  • 41

    Willmot MGibson CGray LMurphy SBath P: Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review. Free Radic Biol Med 39:4124252005

    • Search Google Scholar
    • Export Citation
  • 42

    Willmot MGray LGibson CMurphy SBath PM: A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide 12:1411492005

    • Search Google Scholar
    • Export Citation
  • 43

    Xiong YLu DQu CGoussev ASchallert TMahmood A: Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. Laboratory investigation. J Neurosurg 109:5105212008

    • Search Google Scholar
    • Export Citation
  • 44

    Xiong YMahmood AChopp M: Animal models of traumatic brain injury. Nat Rev Neurosci 14:1281422013

  • 45

    Xiong YMahmood ALu DQu CGoussev ASchallert T: Role of gender in outcome after traumatic brain injury and therapeutic effect of erythropoietin in mice. Brain Res 1185:3013122007

    • Search Google Scholar
    • Export Citation
  • 46

    Xiong YMahmood AMeng YZhang YQu CSchallert T: Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. Laboratory investigation. J Neurosurg 113:5986082010

    • Search Google Scholar
    • Export Citation
  • 47

    Xiong YMahmood AQu CKazmi HZhang ZGNoguchi CT: Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J Neurotrauma 27:2052152010

    • Search Google Scholar
    • Export Citation
  • 48

    Xiong YMahmood AZhang YMeng YZhang ZGQu C: Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury. Laboratory investigation. J Neurosurg 114:5495592011

    • Search Google Scholar
    • Export Citation
  • 49

    Xiong YZhang YMahmood AMeng YQu CChopp M: Erythropoietin mediates neurobehavioral recovery and neurovascular remodeling following traumatic brain injury in rats by increasing expression of vascular endothelial growth factor. Transl Stroke Res 2:6196322011

    • Search Google Scholar
    • Export Citation
  • 50

    Zhang YChopp MMahmood AMeng YQu CXiong Y: Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury. Exp Neurol 235:3363442012

    • Search Google Scholar
    • Export Citation
  • 51

    Zhang YXiong YMahmood AMeng YLiu ZQu C: Sprouting of corticospinal tract axons from the contralateral hemisphere into the denervated side of the spinal cord is associated with functional recovery in adult rat after traumatic brain injury and erythropoietin treatment. Brain Res 1353:2492572010

    • Search Google Scholar
    • Export Citation
  • 52

    Zhang YXiong YMahmood AMeng YQu CSchallert T: Therapeutic effects of erythropoietin on histological and functional outcomes following traumatic brain injury in rats are independent of hematocrit. Brain Res 1294:1531642009

    • Search Google Scholar
    • Export Citation
  • 53

    Zhou JBYang JK: Angiotensin-converting enzyme gene polymorphism is associated with proliferative diabetic retinopathy: a meta-analysis. Acta Diabetol 47:Suppl 11871932010

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Wei Huang, Ph.D., Institute of Integrated Medicine, Xiangya Hospital, Central South University, No. 87 Xiangya Rd., Changsha, Hunan Province 410008, PR China. email: huangweidavid@aliyun.com.

Please include this information when citing this paper: published online July 18, 2014; DOI: 10.3171/2014.6.JNS132577.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flowchart of TBI study search process.

  • View in gallery

    Upper: Forest plot showing results from meta-analysis of lesion volume. Pooled analysis indicated that animals in the treatment groups had significantly reduced lesion volume compared with animals in the control groups (SMD = −1.715, 95% CI −2.359 to −1.071, p < 0.0001). Lower: Begg funnel plot of lesion volume. There was evidence of small study effects (Egger test bias coefficient = −4.08, 95% CI −10.0636 to −3.160554, p = 0.001). s.e. = standard error.

  • View in gallery

    Upper: Forest plot showing results from meta-analysis of foot-fault test. Pooled analysis indicated that animals in the treatment groups showed a significant improvement in sensorimotor function compared with animals in the control groups (overall: SMD = −2.813, 95% CI −3.15 to −2.473; forelimb: SMD = −3.153, 95% CI −3.6385 to −2.670, p < 0.0001; hindlimb: SMD = −2.483, 95% CI −2.919 to −2.0546, p < 0.0001). Lower: Begg funnel plot of foot-fault test. There was evidence of small study effects (Egger test bias coefficient = −4.88, p < 0.0001).

  • View in gallery

    Upper: Forest plot showing results from meta-analysis of mNSS. Pooled analysis indicated that animals in the treatment groups had significantly lower mNSSs (i.e., better neurological function) than animals in the control groups (SMD = −2.930, 95% CI −3.527 to −2.334, p < 0.0001). Lower: Begg funnel plot of mNSS. There was evidence of small study effects (Egger test bias coefficient = −10.78, 95% CI −6.93247 to −4.581088, p < 0.0001).

  • View in gallery

    Upper: Forest plot showing results from meta-analysis of MWM test. Pooled analysis indicated that animals in the treatment groups showed significantly improved spatial learning (i.e., greater percentage of time spent in the correct quadrant) compared with animals in the control groups (SMD = 3.933, 95% CI 3.355–4.512, p < 0.0001). Lower: Begg funnel plot of MWM test. There was evidence of small study effects (Egger test bias coefficient = 10.13, 95% CI 3.710158–5.675137, p < 0.0001).

References

  • 1

    Akdemir Ozisik POruckaptan HOzdemir Geyik PMisirlioglu MSargon MFKilinc K: Effect of erythropoietin on brain tissue after experimental head trauma in rats. Surg Neurol 68:5475552007

    • Search Google Scholar
    • Export Citation
  • 2

    Anderson GDPeterson TCVonder Haar CKantor EDFarin FMBammler TK: Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model. Front Pharmacol 4:1292013

    • Search Google Scholar
    • Export Citation
  • 3

    Bouzat PFrancony GThomas SValable SMauconduit FFevre MC: Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative. Crit Care Med 39:209921052011

    • Search Google Scholar
    • Export Citation
  • 4

    Brines MLGhezzi PKeenan SAgnello Dde Lanerolle NCCerami C: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526105312000

    • Search Google Scholar
    • Export Citation
  • 5

    Cherian LGoodman JCRobertson C: Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther 322:7897942007

    • Search Google Scholar
    • Export Citation
  • 6

    Colditz GABrewer TFBerkey CSWilson MEBurdick EFineberg HV: Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271:6987021994

    • Search Google Scholar
    • Export Citation
  • 7

    Cotena SPiazza OTufano R: The use of erythtropoietin in cerebral diseases. Panminerva Med 50:1851922008

  • 8

    Danos ODavies KLehn PMulligan R: The ARRIVE guidelines, a welcome improvement to standards for reporting animal research. J Gene Med 12:5595602010

    • Search Google Scholar
    • Export Citation
  • 9

    Dirnagl U: Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab 26:146514782006

  • 10

    Egger MSmith GDSchneider MMinder C: Bias in metaanalysis detected by a simple, graphical test. BMJ 315:6296341997

  • 11

    Feigin VLTheadom ABarker-Collo SStarkey NJMcPherson KKahan M: Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol 12:53642013

    • Search Google Scholar
    • Export Citation
  • 12

    Fisher MFeuerstein GHowells DWHurn PDKent TASavitz SI: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:224422502009

    • Search Google Scholar
    • Export Citation
  • 13

    Gibson CLGray LJBath PMMurphy SP: Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131:3183282008

    • Search Google Scholar
    • Export Citation
  • 14

    Gibson CLGray LJMurphy SPBath PM: Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26:110311132006

    • Search Google Scholar
    • Export Citation
  • 15

    Grasso GSfacteria AMeli FFodale VBuemi MIacopino DG: Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182:991052007

    • Search Google Scholar
    • Export Citation
  • 16

    Higgins JPTGreen S: Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 Cochrane Collaboration2011. (http://handbook.cochrane.org/) [Accessed June 4 2014]

    • Search Google Scholar
    • Export Citation
  • 17

    Janowitz TMenon DK: Exploring new routes for neuroprotective drug development in traumatic brain injury. Sci Transl Med 2:27rv12010

  • 18

    Jerndal MForsberg KSena ESMacleod MRO'Collins VELinden T: A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 30:9619682010

    • Search Google Scholar
    • Export Citation
  • 19

    Ker KPerel PBlackhall K: Beta-2 receptor antagonists for traumatic brain injury: a systematic review of controlled trials in animal models. CNS Neurosci Ther 15:52642009

    • Search Google Scholar
    • Export Citation
  • 20

    Kersel DAMarsh NVHavill JHSleigh JW: Psychosocial functioning during the year following severe traumatic brain injury. Brain Inj 15:6836962001

    • Search Google Scholar
    • Export Citation
  • 21

    Kilkenny CBrowne WJCuthill ICEmerson MAltman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e10004122010

    • Search Google Scholar
    • Export Citation
  • 22

    Lu DMahmood AQu CGoussev ASchallert TChopp M: Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 22:101110172005

    • Search Google Scholar
    • Export Citation
  • 23

    Lu JFrerich JMTurtzo LCLi SChiang JYang C: Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury. Proc Natl Acad Sci U S A 110:10747107522013

    • Search Google Scholar
    • Export Citation
  • 24

    Macleod MRO'Collins THorky LLHowells DWDonnan GA: Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 25:7137212005

    • Search Google Scholar
    • Export Citation
  • 25

    Meng YXiong YMahmood AZhang YQu CChopp M: Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. Laboratory investigation. J Neurosurg 115:5505602011

    • Search Google Scholar
    • Export Citation
  • 26

    Minnerup JHeidrich JRogalewski ASchäbitz WRWellmann J: The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke 40:311331202009

    • Search Google Scholar
    • Export Citation
  • 27

    Moher DCook DJEastwood SOlkin IRennie DStroup DF: Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 354:189619001999

    • Search Google Scholar
    • Export Citation
  • 28

    Moja LPTelaro ED'Amico RMoschetti ICoe LLiberati A: Assessment of methodological quality of primary studies by systematic reviews: results of the metaquality cross sectional study. BMJ 330:10532005

    • Search Google Scholar
    • Export Citation
  • 29

    Ning RXiong YMahmood AZhang YMeng YQu C: Erythropoietin promotes neurovascular remodeling and longterm functional recovery in rats following traumatic brain injury. Brain Res 1384:1401502011

    • Search Google Scholar
    • Export Citation
  • 30

    Nirula RDiaz-Arrastia RBrasel KWeigelt JAWaxman K: Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial. Crit Care Res Pract 2010:2098482010

    • Search Google Scholar
    • Export Citation
  • 31

    Oxman ADGuyatt GH: Guidelines for reading literature reviews. CMAJ 138:6977031988

  • 32

    Perel PRoberts ISena EWheble PBriscoe CSandercock P: Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334:1972007

    • Search Google Scholar
    • Export Citation
  • 33

    Pound PEbrahim SSandercock PBracken MBRoberts I: Where is the evidence that animal research benefits humans?. BMJ 328:5145172004

    • Search Google Scholar
    • Export Citation
  • 34

    Prins MGreco TAlexander DGiza CC: The pathophysiology of traumatic brain injury at a glance. Dis Model Mech 6:130713152013

  • 35

    Sacks HSBerrier JReitman DAncona-Berk VAChalmers TC: Meta-analyses of randomized controlled trials. N Engl J Med 316:4504551987

    • Search Google Scholar
    • Export Citation
  • 36

    Sandercock PRoberts I: Systematic reviews of animal experiments. Lancet 360:5862002

  • 37

    Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:275227581999

    • Search Google Scholar
    • Export Citation
  • 38

    Velly LPellegrini LGuillet BBruder NPisano P: Erythropoietin 2nd cerebral protection after acute injuries: a double-edged sword?. Pharmacol Ther 128:4454592010

    • Search Google Scholar
    • Export Citation
  • 39

    Wardlaw JMWarlow CPSandercock PADennis MSLindley RI: Neuroprotection disappointment yet aGAIN. Lancet 356:5972000. (Letter)

  • 40

    Washington PMForcelli PAWilkins TZapple DNParsadanian MBurns MP: The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J Neurotrauma 29:228322962012

    • Search Google Scholar
    • Export Citation
  • 41

    Willmot MGibson CGray LMurphy SBath P: Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review. Free Radic Biol Med 39:4124252005

    • Search Google Scholar
    • Export Citation
  • 42

    Willmot MGray LGibson CMurphy SBath PM: A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide 12:1411492005

    • Search Google Scholar
    • Export Citation
  • 43

    Xiong YLu DQu CGoussev ASchallert TMahmood A: Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. Laboratory investigation. J Neurosurg 109:5105212008

    • Search Google Scholar
    • Export Citation
  • 44

    Xiong YMahmood AChopp M: Animal models of traumatic brain injury. Nat Rev Neurosci 14:1281422013

  • 45

    Xiong YMahmood ALu DQu CGoussev ASchallert T: Role of gender in outcome after traumatic brain injury and therapeutic effect of erythropoietin in mice. Brain Res 1185:3013122007

    • Search Google Scholar
    • Export Citation
  • 46

    Xiong YMahmood AMeng YZhang YQu CSchallert T: Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. Laboratory investigation. J Neurosurg 113:5986082010

    • Search Google Scholar
    • Export Citation
  • 47

    Xiong YMahmood AQu CKazmi HZhang ZGNoguchi CT: Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J Neurotrauma 27:2052152010

    • Search Google Scholar
    • Export Citation
  • 48

    Xiong YMahmood AZhang YMeng YZhang ZGQu C: Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury. Laboratory investigation. J Neurosurg 114:5495592011

    • Search Google Scholar
    • Export Citation
  • 49

    Xiong YZhang YMahmood AMeng YQu CChopp M: Erythropoietin mediates neurobehavioral recovery and neurovascular remodeling following traumatic brain injury in rats by increasing expression of vascular endothelial growth factor. Transl Stroke Res 2:6196322011

    • Search Google Scholar
    • Export Citation
  • 50

    Zhang YChopp MMahmood AMeng YQu CXiong Y: Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury. Exp Neurol 235:3363442012

    • Search Google Scholar
    • Export Citation
  • 51

    Zhang YXiong YMahmood AMeng YLiu ZQu C: Sprouting of corticospinal tract axons from the contralateral hemisphere into the denervated side of the spinal cord is associated with functional recovery in adult rat after traumatic brain injury and erythropoietin treatment. Brain Res 1353:2492572010

    • Search Google Scholar
    • Export Citation
  • 52

    Zhang YXiong YMahmood AMeng YQu CSchallert T: Therapeutic effects of erythropoietin on histological and functional outcomes following traumatic brain injury in rats are independent of hematocrit. Brain Res 1294:1531642009

    • Search Google Scholar
    • Export Citation
  • 53

    Zhou JBYang JK: Angiotensin-converting enzyme gene polymorphism is associated with proliferative diabetic retinopathy: a meta-analysis. Acta Diabetol 47:Suppl 11871932010

    • Search Google Scholar
    • Export Citation

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