losartan-potassium and Brain-Injuries--Traumatic

Neuroprotective drugs have been used to prevent secondary brain injury in patients with traumatic brain injury; however, the optimal medication remains questionable. We performed a Bayesian network meta-analysis to evaluate the safety and efficacy of different medications with known neuroprotective properties in this group of patients.. Several databases were searched to identify any eligible trials comparing pharmacological components with confirmed neuroprotective mechanisms. Bayesian network meta-analysis was performed to combine direct and indirect evidence. The surface under the cumulative ranking curve was obtained to determine the ranking probability of the treatment agents for each outcome. The primary outcome was all-cause mortality.. A total of 23 trials comprising 4,325 participants were identified. The pooled relative risk (RR) showed administration of erythropoietin (RR: 0.68; 95% CrI: 0.50-0.93) and propranolol (RR: 0.43; 95% CrI: 0.20-0.85) decreased all-cause mortality compared with placebo. We also found erythropoietin (RR: 1.55; 95% CrI: 1.03-2.35), propranolol (RR: 1.52; 95% CrI: 1.05-2.20), and progesterone (RR: 1.47; 95% CrI: 1.03-2.10) showed better efficacy in functional recovery.. Overall, erythropoietin and propranolol were associated with reduced mortality in adults with traumatic brain injury. These treatment agents were also associated with improved functional outcomes.

Topics: Adult; Bayes Theorem; Brain Injuries, Traumatic; Erythropoietin; Humans; Network Meta-Analysis; Neuroprotective Agents; Propranolol

The aim of this meta-analysis was to review the scientific literature published until April 18, 2021, to summarize existing knowledge on the efficacy and safety of erythropoietin (EPO) for traumatic brain injury (TBI).. This systematic review followed PRISMA guidelines. Randomized controlled trials (RCTs) reporting on the efficacy and safety of EPO in the treatment of TBI were systematically searched in relevant electronic databases according to a pre-designed search strategy. The primary outcomes are the mortality; and secondary outcomes are the good functional outcome (GFO) and adverse events (AEs).. A total of 10 RCTs involving 2,402 participants fulfilled the inclusion criteria. The results showed that there is a significant difference in terms of the mortality (RR = 0.67, 95% CI = 0.54-0.84, P = 0.0003) and seizure rate (RR = 0.52, 95% CI = 0.29-0.96, P = 0.04) between the EPO groups compared to those in the control groups. However, compared with the control groups, the GFO in the EPO groups was not statistically significant (RR = 1.18, 95% CI = 0.93-1.48, P = 0.17).. Findings of the present meta-analysis suggest that the use of EPO could reduce mortality rate in patients with TBI, without increasing the incidence of AEs. EPO has potential research and application value in the treatment of TBI.

Topics: Brain Injuries, Traumatic; Erythropoietin; Humans; Incidence; Seizures

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Erythropoietin (EPO) has been shown to be beneficial in traumatic brain injury (TBI). We have attempted to quantitatively synthesize the findings of current randomized controlled trials (RCTs) in this meta-analysis and analyzed the need for further trials using trial sequential analysis (TSA).. A systematic search was performed in PubMed, the Cochrane Library databases, and Google Scholar for RCTs until December 2019 evaluating the role of EPO in patients with TBI. Seven RCTs were finally included in the quantitative analysis. TSA was done to evaluate the need for further studies.. The pooled estimate demonstrated that EPO significantly reduced mortality at 6 months (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.43-0.97; P = 0.04) but not in hospital mortality (OR, 0.84; 95% CI, 0.31-2.32; P = 0.74). There was no significant difference in the rate of favorable outcomes with EPO (OR, 1.58; 95% CI, 0.84-2.99; P = 0.16). The rate of deep vein thrombosis (RD, -0.02; 95% CI, -0.06 to 0.02; P =0.41) was also not found to be significantly different in the 2 groups. TSA showed that the accrued information is insufficient to make any definitive conclusions.. EPO seems to be beneficial in terms of reducing 6-month mortality, however, its effect on in-hospital mortality, neurologic outcomes, and risk of deep vein thrombosis fails to reach statistical significance. TSA suggests a need for large trials to evaluate the role of EPO in patients with TBI in a more systematic way.

Topics: Brain Injuries, Traumatic; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Outcome after traumatic brain injury (TBI) varies largely and degree of immune activation is an important determinant factor. This meta-analysis evaluates the efficacy of drugs with anti-inflammatory properties in improving neurological and functional outcome. The systematic search following PRISMA guidelines resulted in 15 randomized placebo-controlled trials (3734 patients), evaluating progesterone, erythropoietin and cyclosporine. The meta-analysis (15 studies) showed that TBI patients receiving a drug with anti-inflammatory effects had a higher chance of a favorable outcome compared to those receiving placebo (RR = 1.15; 95% CI 1.01-1.32, p = 0.041). However, publication bias was indicated together with heterogeneity (I

Topics: Age Factors; Anti-Inflammatory Agents; Brain Injuries, Traumatic; Cyclosporine; Erythropoietin; Humans; Progesterone; Treatment Outcome

Recent studies regarding the effects of erythropoietin (EPO) for treating traumatic brain injury (TBI) have been inconsistent. This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess the safety and efficacy of EPO for TBI patients at various follow-up time points.. A literature search was performed using PubMed, Web of Science, MEDLINE, Embase, Google Scholar and the Cochrane Library for RCTs studying EPO in TBI patients published through March 2019. Non-English manuscripts and non-human studies were excluded. The assessed outcomes include mortality, neurological recovery and associated adverse effects. Dichotomous variables are presented as risk ratios (RR) with a 95% confidence interval (CI).. A total of seven RCTs involving 1197 TBI patients (611 treated with EPO, 586 treated with placebo) were included in this study. Compared to the placebo arm, treatment with EPO did not improve acute hospital mortality or short-term mortality. However, there was a significant improvement in mid-term (6 months) follow-up survival rates. EPO administration was not associated with neurological function improvement. Regarding adverse effects, EPO treatment did not increase the incidence of thromboembolic events or other associated adverse events.. This meta-analysis indicates a slight mortality benefit for TBI patients treated with EPO at mid-term follow-up. EPO does not improve in-hospital mortality, nor does it increase adverse events including thrombotic, cardiovascular and other associated complications. Our analysis did not demonstrate a significant beneficial effect of EPO intervention on the recovery of neurological function. Future RCTs are required to further characterize the use of EPO in TBI.

Topics: Adult; Brain Injuries, Traumatic; Erythropoietin; Humans; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic

The objective of this study is to assess the effectiveness of erythropoietin (EPO) on mortality, neurological outcomes, and adverse event in the treatment of traumatic brain injury (TBI).. We searched databases including PubMed, OVID, and the Cochrane Library from inception until October 18, 2019 for randomized controlled trials (RCTs) to compare EPO treatment group and placebo in patients with TBI. Two authors independently processed the data and evaluated the quality of inclusion studies. Statistical analysis was performed with heterogeneity test with. Seven RCTs accounting for 1180 patients were included after meeting the inclusion criteria. Compared with placebo, the overall mortality of EPO-treated patients was significantly reduced (RR 0.68 [95% CI 0.50-0.93];. The results showed that the administration of EPO may reduce the risk of mortality without enhancing the occurrence of DVT in TBI patients. However, the effect of EPO on neurological outcome remains indistinct. Through subgroup analysis, we demonstrated that the dose of EPO may be a potential factor affecting the heterogeneity in neurological function and that the follow-up duration may influence the stability of the result.

Topics: Adult; Brain Injuries, Traumatic; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Prognosis; Publication Bias; Risk; Treatment Outcome; Venous Thrombosis; Young Adult

The purpose of this study was to evaluate the effects of erythropoietin (EPO) on mortality and neurological outcomes in patients with traumatic brain injury (TBI).. Electronic databases of studies published up to January 5, 2017 were searched to retrieve relevant investigations comparing the outcomes of EPO-treated patients and untreated patients following TBI. We calculated the relative risk (RR) of mortality, neurologic outcomes, and deep vein thrombosis (DVT) with corresponding 95% confidence interval (CI) using meta-analysis.. Six randomized controlled clinical trials met the eligibility criteria. In total, 1041 patients were included among the studies. EPO was found to significantly reduce the occurrence of mortality (RR 0.68 [95% CI 0.50-0.95]; P = 0.02), but did not significantly reduce poor functional outcome (RR 1.22 [95% CI 0.82-1.81]; P = 0.33). There were no significant differences in the occurrence of complications, such as DVT, between the treatment groups (RR -0.02 [95% CI -0.06-0.02]; P = 0.81).. Results of the present meta-analysis suggest that the use of EPO may prevent death following TBI without causing adverse events, such as deep vein thrombosis. However, the role of EPO in improving neurological outcome(s) remains unclear. Further well-designed, randomized controlled trials using modified protocols and involving specific patient populations are required to clarify this issue, and to verify the findings.

Topics: Age Factors; Brain Injuries, Traumatic; Chi-Square Distribution; Erythropoietin; Humans; Randomized Controlled Trials as Topic

Pediatric traumatic brain injury (TBI) remains a leading cause of childhood morbidity and mortality worldwide. Most efforts to reduce the chronic impact of pediatric TBI involve prevention and minimization of secondary injury. Currently, no treatments are used in routine clinical care during the acute and subacute phases to actively repair injury to the developing brain. The endogenous pluripotent cytokine erythropoietin (EPO) holds promise as an emerging neuroreparative agent in perinatal brain injury (PBI). EPO signaling in the central nervous system (CNS) is essential for multiple stages of neurodevelopment, including the genesis, survival and differentiation of multiple lineages of neural cells. Postnatally, EPO signaling decreases markedly as the CNS matures. Importantly, high-dose, extended EPO regimens have shown efficacy in preclinical controlled cortical impact (CCI) models of infant TBI at two different, early ages by independent research groups. Specifically, extended high-dose EPO treatment after infantile CCI prevents long-term cognitive deficits in adult rats. Because of the striking differences in the molecular and cellular responses to both injury and recovery in the developing and mature CNS, and the excellent safety profile of EPO in infants and children, extended courses of EPO are currently in Phase III trials for neonates with PBI. Extended, high-dose EPO may also warrant testing for infants and young children with TBI.

Topics: Animals; Brain Injuries, Traumatic; Child, Preschool; Erythropoietin; Humans; Infant; Infant, Newborn; Neuroprotective Agents

OBJECTIVE Erythropoietin (EPO) exerts a neuroprotective effect in animal models of traumatic brain injury (TBI). However, its effectiveness in human patients with TBI is unclear. In this study, the authors conducted the first meta-analysis to assess the effectiveness and safety of EPO in patients with TBI. METHODS In December 2015, a systematic search was performed of PubMed, Web of Science, MEDLINE, Embase, the Cochrane Library databases, and Google Scholar. Only English-language publications of randomized controlled trials (RCTs) using EPO in patients with TBI were selected for analysis. The assessed outcomes included mortality, favorable neurological outcome, hospital stay, and associated adverse effects. Continuous variables were presented as mean difference (MD) with a 95% confidence interval (CI). Dichotomous variables were presented as risk ratio (RR) or risk difference (RD) with a 95% CI. Statistical heterogeneity was examined using both I

Topics: Brain Injuries, Traumatic; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

To determine the diagnostic and prognostic value of glial fibrillary acidic protein (GFAP) and S100B after traumatic brain injury (TBI) in an Erythropoietin (EPO) clinical trial and examine whether EPO therapy reduces biomarker concentrations.. Forty-four patients with moderate-to-severe TBI were enrolled to a sub-study of the EPO-TBI trial. Patients were randomized to either Epoetin alfa 40,000 IU or 1 ml sodium chloride 0.9 as subcutaneous injection within 24 h of TBI.. GFAP and S100B were measured in serum by ELISA from D0 (within 24 h of injury, prior to EPO/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse vs. focal TBI, 6-month outcome scores (GOS-E) and EPO or placebo treatments. At D0 GFAP was significantly higher than S100B (951 pg/mL vs. 476 pg/mL, p = 0.018). ROC analysis of S100B at 1D post-injury distinguished favorable vs. unfavorable outcomes (area under the curve = 0.73; p = 0.01). EPO did not reduce concentration of either biomarker.. Elevated serum concentrations of GFAP and S100B after TBI reflect a robust, acute glial response to injury. Consistent with lack of improved outcome in TBI patients treated with EPO and prior findings on neuronal and axonal markers, glial biomarker concentrations and acute profiles were not affected by EPO.

Topics: Adult; Australia; Biomarkers; Brain Injuries, Traumatic; Erythropoietin; Female; Glial Fibrillary Acidic Protein; Humans; Male; Middle Aged; Prognosis; S100 Calcium Binding Protein beta Subunit

Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS.. The authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI.. Two hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94-42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)-6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20-1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01-1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24-2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18-19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06-1.40, p = 0.006).. Admission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.

Topics: Adolescent; Adult; Aged; Biomarkers; Brain Injuries, Traumatic; Cytokines; Erythropoietin; Female; Glasgow Outcome Scale; Humans; Male; Middle Aged; Multiple Organ Failure; Probability; Young Adult

Long-term neurological response to treatment after a severe traumatic brain injury (sTBI) is a dynamic process. Failure to capture individual heterogeneity in recovery may impact findings from single endpoint sTBI randomized controlled trials (RCT). The present study re-examined the efficacy of erythropoietin (Epo) and transfusion thresholds through longitudinal modeling of sTBI recovery as measured by the Disability Rating Scale (DRS). This study complements the report of primary outcomes in the Epo sTBI RCT, which failed to detect significant effects of acute treatment at 6 months post-injury.. We implemented mixed effects models to characterize the recovery time-course and to examine treatment efficacy as a function of time post-injury and injury severity.. The inter-quartile range (25th-75th percentile) of DRS scores was 20-28 at week1; 8-24 at week 4; and 3-17 at 6 months. TBI severity group was found to significantly interact with Epo randomization group on mean DRS recovery curves. No significant differences in DRS recovery were found in transfusion threshold groups.. This study demonstrated the value of taking a comprehensive view of recovery from sTBI in the Epo RCT as a temporally dynamic process that is shaped by both treatment and injury severity, and highlights the importance of the timing of primary outcome measurement. Effects of Epo treatment varied as a function of injury severity and time. Future studies are warranted to understand the possible moderating influence of injury severity on treatment effects pertaining to sTBI recovery. (JINS, 2019, 25, 293-301).

Topics: Adult; Brain Injuries, Traumatic; Erythropoietin; Humans; Longitudinal Studies; Outcome Assessment, Health Care; Severity of Illness Index

The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034;

Topics: Adult; Brain Injuries, Traumatic; Cost-Benefit Analysis; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Patient Acceptance of Health Care; Quality-Adjusted Life Years; Treatment Outcome; Young Adult

OBJECTIVE Posttraumatic hydrocephalus (PTH) affects 11.9%-36% of patients undergoing decompressive craniectomy (DC) and is an important cause of morbidity after traumatic brain injury (TBI). Early diagnosis and treatment of PTH can prevent further neurological compromise in patients who are recovering from TBI. There is limited data on predictors of shunting for PTH after DC for TBI. METHODS Prospectively collected data from the erythropoietin severe TBI randomized controlled trial were studied. Demographic, clinical, and imaging data were analyzed for enrolled patients who underwent a DC. All head CT scans during admission were reviewed and assessed for PTH by the Gudeman criteria or the modified Frontal Horn Index ≥ 33%. The presence of subdural hygromas was categorized as unilateral/bilateral hemispheric or interhemispheric. Using L1-regularized logistic regression to select variables, a multiple logistic regression model was created with ventriculoperitoneal shunting as the binary outcome. Statistical significance was set at p < 0.05. RESULTS A total of 60 patients who underwent DC were studied. Fifteen patients (25%) underwent placement of a ventriculoperitoneal shunt for PTH. The majority of patients underwent unilateral decompressive hemicraniectomy (n = 46, 77%). Seven patients (12%) underwent bifrontal DC. Unilateral and bilateral hemispheric hygromas were noted in 31 (52%) and 7 (11%) patients, respectively. Interhemispheric hygromas were observed in 19 patients (32%). The mean duration from injury to first CT scan showing hemispheric subdural hygroma and interhemispheric hygroma was 7.9 ± 6.5 days and 14.9 ± 11.7 days, respectively. The median duration from injury to shunt placement was 43.7 days. Multivariate analysis showed that the presence of interhemispheric hygroma (OR 63.6, p = 0.001) and younger age (OR 0.78, p = 0.009) were significantly associated with the need for a shunt after DC. CONCLUSIONS The presence of interhemispheric subdural hygromas and younger age were associated with shunt-dependent hydrocephalus after DC in patients with severe TBI.

Topics: Adult; Age Factors; Blood Transfusion; Brain Injuries, Traumatic; Cerebrospinal Fluid Shunts; Decompressive Craniectomy; Erythropoietin; Female; Humans; Hydrocephalus; Male; Postoperative Complications

To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups.. Single-center, prospective observational study.. A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia.. Forty-four patients with moderate-to-severe traumatic brain injury.. Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury.. Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain.. Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

Topics: Adult; Australia; Biomarkers; Brain Injuries, Traumatic; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoietin; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Neurofilament Proteins; Prospective Studies; Ubiquitin Thiolesterase

This study aimed to explore the efficacy and safety of recombinant human erythropoietin (RHE) for the treatment of severe traumatic brain injury (STBI).. One hundred and twenty eligible patients with STBI were randomly divided into an intervention group or a control group equally. Patients in the intervention group received RHE. The participants in the control group received 0.9% saline. The outcome measurements included the Glasgow Outcome Scale (GOS) scores, mortality, and any adverse events.. At the end of 10-week follow-up after treatment, RHE neither showed greater efficacy in GOS scores (1-2, P = .43; 3-4, P = .25; 5-6, P = .58; 7-8, P = .23), nor the lower mortality in the intervention group than those in the control group (P = .47). In addition, both groups had similar safety profile.. This study found that RHE did not improve the neurological outcomes in patients with STBI.

Topics: Adult; Brain Injuries, Traumatic; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins

We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI).. Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain.. We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury.. There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33-1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12-0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66-3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings.. This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

Topics: Adult; Brain Injuries, Traumatic; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Humans; Male; Prospective Studies; Treatment Outcome

Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone.. A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality.. Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007).. In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies.. Therapeutic study, level III.

Topics: Abbreviated Injury Scale; Adult; Brain Injuries, Traumatic; Erythropoietin; Female; Humans; Injury Severity Score; Male; Middle Aged; Multiple Trauma; Treatment Outcome

To investigate the short-term effect of recombinant human erythropoietin (EPO) on patients with severe traumatic brain injury.. One hundred and fifty-nine patients with severe traumatic brain injury were randomly divided into EPO (n=79) and control group (n=80). EPO group was treated with subcutaneous injection of EPO (100 units/kg) on day 1, 3, 6, 9 and 12 following the brain injury. Glasgow outcome scores (GOS) were used to evaluate the outcomes three months after the treatment. Serum neuron specific enolase (NSE) and S-100β protein were measured within the first three months after treatment.. In the end, 146 patients (75 of the EPO group and 71 of the control group) completed the trial. Three months after the treatment, Good recovery was found in 33.3% of the EPO and 12.6% of the control group patients (p<0.05). Serum NSE and S-100β protein were decreased gradually in both groups after treatment, but their levels in the EPO group were lower than that of control group (p<0.05). There was no statistically significant difference in blood pressure, hemoglobin levels, pneumonia, sepsis or thromboembolic events between the two groups three months after the treatment (p>0.05).. Treatment with five doses of recombinant human erythropoietin is associated with an improved functional recovery in patients with severe traumatic brain injury. This treatment does not seem to increase the risk of thromboembolic events or severe infections.

Topics: Adult; Brain Injuries, Traumatic; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Phosphopyruvate Hydratase; Recombinant Proteins; Recovery of Function; S100 Calcium Binding Protein beta Subunit

Topics: Brain Injuries, Traumatic; Erythropoietin; Humans

Erythropoietin (EPO) has neuroprotective effects in central nervous system injury models. In clinical trials EPO has shown beneficial effects in traumatic brain injury (TBI) as well as in ischemic stroke. We have previously shown that EPO has short-term effects on astrocyte glutamatergic signaling in vitro and that administration of EPO after experimental TBI decreases early cytotoxic brain edema and preserves structural and functional properties of the blood-brain barrier. These effects have been attributed to preserved or restored astrocyte function. Here we explored the effects of EPO on astrocytes undergoing oxygen-glucose-deprivation, an in vitro model of ischemia. Measurements of glutamate uptake, intracellular pH, intrinsic NADH fluorescence, Na,K-ATPase activity, and lactate release were performed. We found that EPO within minutes caused a Na,K-ATPase-dependent increase in glutamate uptake, restored intracellular acidification caused by glutamate and increased lactate release. The effects on intracellular pH were dependent on the sodium/hydrogen exchanger NHE. In neuron-astrocyte co-cultures, EPO increased NADH production both in astrocytes and neurons, however the increase was greater in astrocytes. We suggest that EPO preserves astrocyte function under ischemic conditions and thus may contribute to neuroprotection in ischemic stroke and brain ischemia secondary to TBI.

Topics: Astrocytes; Brain Injuries, Traumatic; Erythropoietin; Glutamic Acid; Humans; Ischemia; Ischemic Stroke; Models, Theoretical; NAD; Sodium-Potassium-Exchanging ATPase

Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown.. We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010-2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5-8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI.. Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47-1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI [Formula: see text] 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2-22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome.. EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI.

Topics: Brain Injuries, Traumatic; Erythropoietin; Humans; Multiple Trauma; Survival Analysis; Treatment Outcome

Traumatic brain injury (TBI) can result in axonal loss and demyelination, leading to persistent damage in the white matter. Demyelinated axons are vulnerable to pathologies related to an abnormal myelin structure that expose neurons to further damage. Oligodendrocyte progenitor cells (OPCs) mediate remyelination after recruitment to the injury site. Often this process is inefficient due to inadequate OPC proliferation. To date, no effective treatments are currently available to stimulate OPC proliferation in TBI. Recombinant human erythropoietin (rhEPO) is a pleiotropic neuroprotective cytokine, and its receptor is present in all stages of oligodendroglial lineage cell differentiation. Therefore, we hypothesized that rhEPO administration would enhance remyelination after TBI through the modulation of OPC response. Utilizing a murine model of controlled cortical impact and a primary OPC culture in vitro model, we characterized the impact of rhEPO on remyelination and proliferation of oligodendrocyte lineage cells. Myelin black gold II staining of the peri-contusional corpus callosum revealed an increase in myelinated area in association with an increase in BrdU-positive oligodendrocytes in injured mice treated with rhEPO. Furthermore, morphological analysis of OPCs showed a decrease in process length in rhEPO-treated animals. RhEPO treatment increased OPC proliferation after in vitro CSPG exposure. Erythropoietin receptor (EPOr) gene knockdown using siRNA prevented rhEPO-induced OPC proliferation, demonstrating that the rhEPO effect on OPC response is EPOr activation dependent. Together, our findings demonstrate that rhEPO administration may promote myelination by increasing oligodendrocyte lineage cell proliferation after TBI.

Topics: Animals; Brain Injuries, Traumatic; Cell Differentiation; Cell Proliferation; Erythropoietin; Humans; Hypoxia; Mice; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Recombinant Proteins

Therapeutic interventions targeting secondary insults, such as delayed hypoxemia, provide a unique opportunity for treatment in severe traumatic brain injury (TBI). Erythropoietin (EPO) is a hypoxia-responsive cytokine with important roles in neurodevelopment, neuroprotection and neuromodulation. We hypothesized that recombinant human erythropoietin (rhEPO) administration would mitigate injury in a combined injury model of TBI and delayed hypoxemia. Utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we characterized how ongoing rhEPO administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We employed novel object recognition (NOR) and fear conditioning to assess long-term memory. At 1-month post-injury, we observed a significant increase in cued-fear memory response in the rhEPO-injured mice compared with vehicle-injured mice. This was associated with neuroprotection and neurogenesis in the hippocampus and mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. Early rhEPO treatment after injury reduced neurodegeneration and increased excitatory synaptic density in the hippocampus and amygdala at 6 months post-injury. However at 6 months post-injury (4 months after discontinuation of rhEPO), we did not observe changes in behavioral assessments nor MAPK/CREB pathway activation. In summary, these data demonstrate that ongoing rhEPO treatment initiated at a clinically feasible time point improves neurological, cognitive, and histological outcomes after TBI in the setting of secondary hypoxemic insults.

Topics: Animals; Brain Injuries, Traumatic; Cyclic AMP Response Element-Binding Protein; Erythropoietin; Fear; Humans; Hypoxia; Mice; Mitogen-Activated Protein Kinases; Neuroprotection; Recombinant Proteins

Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown.. A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use.. Twenty-nine university-affiliated teaching hospitals in seven countries.. A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline.. None.. We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death.. In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Topics: Acute Kidney Injury; Brain Injuries, Traumatic; Diuretics, Osmotic; Erythropoietin; Female; Fluid Therapy; Humans; Intracranial Pressure; Male; Mannitol; Saline Solution, Hypertonic; Treatment Outcome

Traumatic brain injury (TBI) is a serious health problem with few available treatment options. Rh-erythropoietin (rh-EPO) is a potential therapeutic drug for TBI, but it cannot cross the blood-brain barrier (BBB) directly. In this regard, a novel strategy to deliver rh-EPO for enhanced TBI treatment is via the development of Tween 80 modified albumin nanoparticles using electrostatic spray technology.. The rh-EPO loaded Tween 80 modified albumin nanoparticles (rh-EPO-Tw-ABNPs) were prepared by electrostatic spray technology, while the process parameters were optimized via a single factor design. Investigation of physicochemical properties, bioactivity and stability of rh-EPO-Tw-ABNPs was carried out. The in vitro release and biocompatibility with nerve cells were also analyzed. The in vivo brain targeting efficiency, brain edema relieving effect and the expression of aquaporin 4 (AQP4) and glial fibrillary acidic protein (GFAP) in the brain were evaluated in TBI model rats.. The particle size of optimal rh-EPO-Tw-ABNPs was about 438 ± 45 nm, with a zeta potential of -25.42 ± 0.8 mv. The average drug loading ratio of rh-EPO-Tw-ABNPs was 21.3± 3.7 IU/mg with a relative bioactivity of 91.6 ± 4.1%. The in vitro release of rh-EPO from the nanoparticles was rather slow, while neither the blank Tw-ABNPs nor rh-EPO-Tw-ABNPs exhibited toxicity on the microglia cells. Furthermore, in vivo experiments indicated that the rh-EPO-Tw-ABNPs could enhance the distribution of EPO in the brain and relieve brain edema more effectively. Moreover, compared with an rh-EPO injection, the rh-EPO-Tw-ABNPs could increase the AQP4 level but reduced GFAP expression in the brain with more efficiency.. The rh-EPO-Tw-ABNPs could enhance the transport of rh-EPO into the brain with superior therapeutic effect for TBI.

Topics: Albumins; Animals; Aquaporin 4; Brain; Brain Edema; Brain Injuries, Traumatic; Drug Liberation; Erythropoietin; Glial Fibrillary Acidic Protein; Humans; Male; Nanoparticles; Neurons; Particle Size; Rats, Sprague-Dawley; Recombinant Proteins; Rheology; Static Electricity

In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus.. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury.. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury.. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury.

Topics: Animals; Animals, Newborn; Brain Injuries, Traumatic; Brain-Derived Neurotrophic Factor; Cognition; Erythropoietin; Hippocampus; Male; Maze Learning; Models, Animal; Neurons; Rats; Rats, Sprague-Dawley

Traumatic brain injury (TBI) can be complicated by TBI-triggered acute lung injury (ALI), in which inflammation plays a central role. It has been reported that an Erythropoietin-derived peptide (pHBSP) was able to ameliorate TBI; however, its function in TBI-caused ALI has not been reported yet.. In this study, we studied the effect of pHBSP on TBI-caused ALI by using a weight-drop induced TBI model. At 8 h and 24 h post-TBI, pulmonary edema (PE) and bronchoalveolar lavage fluid (BALF) proteins were measured, and haematoxylin and eosin (H&E) staining of lung sections was carried out. At 24 h following TBI, the lungs were harvested for immunofluorescence staining and qRT-PCR analysis.. At 8 h and 24 h post-TBI, pHBSP treatment significantly decreased wet/dry ratios, decreased total BALF protein, and attenuated the histological signs of pulmonary injury. At 24 h post-TBI, pHBSP treatment decreased the accumulation of CD68+ macrophages in the lung and reduced the mRNA levels of TNF-α, IL-6, IL-1β and iNOS in the lung.. We identified the protective role that pHBSP played in TBI-caused ALI, suggesting that pHBSP is a potent candidate for systemic therapy in TBI patients.

Topics: Acute Lung Injury; Animals; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Erythropoietin; Lung; Macrophages; Male; Nitric Oxide Synthase Type II; Peptides; Rats; Rats, Inbred Lew; Time Factors

Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 μg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham-operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post-injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI-saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p < 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed.

Topics: Animals; Brain Injuries, Traumatic; Erythropoietin; Humans; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neuroprotective Agents; Rats; Rats, Wistar

Experimental studies targeting traumatic brain injury (TBI) have reported that erythropoietin (EPO) is an endogenous neuroprotectant in multiple models. In addition to its neuroprotective effects, it has also been shown to enhance reparative processes including angiogenesis and neurogenesis. Based on compelling pre-clinical data, EPO was tested by the Operation Brain Trauma Therapy (OBTT) consortium to evaluate therapeutic potential in multiple TBI models along with biomarker assessments. Based on the pre-clinical TBI literature, two doses of EPO (5000 and 10,000 IU/kg) were tested given at 15 min after moderate fluid percussion brain injury (FPI), controlled cortical impact (CCI), or penetrating ballistic-like brain injury (PBBI) with subsequent behavioral, histopathological, and biomarker outcome assessments. There was a significant benefit on beam walk with the 5000 IU dose in CCI, but no benefit on any other motor task across models in OBTT. Also, no benefit of EPO treatment across the three TBI models was noted using the Morris water maze to assess cognitive deficits. Lesion volume analysis showed no treatment effects after either FPI or CCI; however, with the 5000 IU/kg dose of EPO, a paradoxical increase in lesion volume and percent hemispheric tissue loss was seen after PBBI. Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No treatment effects were seen on biomarker levels after FPI, whereas treatment at either dose exacerbated the increase in GFAP at 24 h in PBBI but attenuated 24-4 h delta UCH-L1 levels at high dose in CCI. Our data indicate a surprising lack of efficacy of EPO across three established TBI models in terms of behavioral, histopathological, and biomarker assessments. Although we cannot rule out the possibility that other doses or more prolonged treatment could show different effects, the lack of efficacy of EPO reduced enthusiasm for its further investigation in OBTT.

Topics: Animals; Biomarkers; Brain Injuries, Traumatic; Disease Models, Animal; Erythropoietin; Glial Fibrillary Acidic Protein; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recovery of Function; Ubiquitin Thiolesterase

There is currently no effective medical treatment for traumatic brain injury (TBI). Beyond the immediate physical damage caused by the initial impact, additional damage evolves due to the inflammatory response that follows brain injury. Here we show that therapy with JM4, a low molecular weight 19-amino acid nonhematopoietic erythropoietin (EPO) peptidyl fragment, containing amino acids 28-46 derived from the first loop of EPO, markedly reduces acute brain injury. Mice underwent controlled cortical injury and received either whole molecule EPO, JM4, or sham-treatment with phosphate-buffered saline. Animals treated with JM4 peptide exhibited a large decrease in number of dead neural cells and a marked reduction in lesion size at both 3 and 8 days postinjury. Therapy with JM4 also led to improved functional recovery and we observed a treatment window for JM4 peptide that remained open for at least 9 h postinjury. The full-length EPO molecule was divided into a series of 6 contiguous peptide segments; the JM4-containing segment and the adjoining downstream region contained the bulk of the death attenuating effects seen with intact EPO molecule following TBI. These findings indicate that the JM4 molecule substantially blocks cell death and brain injury following acute brain trauma and, as such, presents an excellent opportunity to explore the therapeutic potential of a small-peptide EPO derivative in the medical treatment of TBI.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Injuries, Traumatic; Cell Death; Erythropoietin; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Peptide Fragments

To investigate the healing effects of erythropoietin (EPO) and stem cells (SCs) in traumatic brain injury (TBI).. Twenty-nine Wistar albino rats were used and separated into the following groups: control (C), EPO, SC, and SC+EPO. Group C received a TBI only, with no treatment. In the EPO group, 1000 U/kg EPO was given intraperitoneally at 30 minutes after TBI. In SC group, immediately after formation of TBI, 3 × 10,000 CD34(+) stem cells were injected into the affected area. In the SC+EPO group, half an hour after TBI and the injection of stem cells, 1000 U/kg EPO was injected. Before and after injury, trauma coordination performance was measured by the rotarod and inclined plane tests.. Seven weeks after trauma, rat brains were examined by radiology and histology. Rotarod performance test did not change remarkably, even after the injury. Compared with group C, the SC+EPO group was found to have significant differences in the inclined plane test results.. Separately given, SCs and EPO have a positive effect on TBI, and our findings suggest that their coadministration is even more powerful.

Topics: Animals; Antigens, CD34; Brain; Brain Injuries, Traumatic; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Disease Models, Animal; Erythropoietin; Female; Humans; Injections, Intraperitoneal; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Rats, Wistar; Rotarod Performance Test; Treatment Outcome

OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1-4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13-28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst-like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13-16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EP

Topics: Age Factors; Animals; Animals, Newborn; Biomarkers; Brain Injuries, Traumatic; Calpain; Cerebral Cortex; Cytokines; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Gait Disorders, Neurologic; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Image Processing, Computer-Assisted; K Cl- Cotransporters; Male; Rats; Receptors, Erythropoietin; Statistics, Nonparametric; Symporters; Time Factors

The goal of this study was to investigate the protective effect of recombinant human EPO(rhEPO) on cerebral microvascular endothelial cells and the mechanisms by which rhEPO interacts with TJs proteins, claudin-5, Occludin and ZO-1 during the early period following traumatic brain injury.. Rats (n = 81) were randomly divided into sham-operated group, TBI group and rhEPO+TBI group. Traumatic brain injury was induced by the Marmarou method.. Rats were killed at 3, 24, 72 and 168 hours after TBI. The integrity of the blood-brain barrier was investigated by using a spectrophotometer to assess extravasation of Evans blue dye. The expression of Claudin-5, Occludin and ZO-1 were determined by immunohistochemistry and real-time fluorescence quantitative PCR.. From 3 hours to 3 days, rats in the TBI group demonstrated a remarkable increase in Evans blue content in the brain, relative to rats in the sham-operated group (p < 0.05). The expression of Claudin-5 and Occludin was significantly lower than those in the sham-operated group (p < 0.05). In contrast, rats in the TBI+rhEPO group demonstrated a significant decrease in brain levels.. It was found that administration of rhEPO protected cerebral microvascular endothelial cells and reduced permeability of BBB and the mechanisms may be due to increasing the expression of TJs proteins.

Topics: Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; Claudin-5; Disease Models, Animal; Drug Administration Schedule; Endothelial Cells; Erythropoietin; Gene Expression Regulation; Occludin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tight Junctions; Time Factors; Zonula Occludens-1 Protein

Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million people in the USA. A couple of regenerative pathways including activation of hypoxia-inducible transcription factor 1 alpha (HIF-1α) are initiated to reduce cellular damage following TBI; however endogenous activation of these pathways is not enough to provide neuroprotection after TBI. Thus we aimed to see whether sustained activation of HIF-1α can provide neuroprotection and neurorepair following TBI. We found that chronic treatment with dimethyloxaloylglycine (DMOG) markedly increases the expression level of HIF-1α and mRNA levels of its downstream proteins such as Vascular endothelial growth factor (VEGF), Phosphoinositide-dependent kinase-1 and 4 (PDK1, PDK4) and Erythropoietin (EPO). Treatment of DMOG activates a major cell survival protein kinase Akt and reduces both cell death and lesion volume following TBI. Moreover, administration of DMOG augments cluster of differentiation 31 (CD31) staining in pericontusional cortex after TBI, which suggests that DMOG stimulates angiogenesis after TBI. Treatment with DMOG also improves both memory and motor functions after TBI. Taken together our results suggest that sustained activation of HIF-1α provides significant neuroprotection following TBI.

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Amino Acids, Dicarboxylic; Angiogenesis Inducing Agents; Animals; Brain Injuries, Traumatic; Cell Death; Disease Models, Animal; Erythropoietin; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Nootropic Agents; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; RNA, Messenger; Vascular Endothelial Growth Factor A