[ARTICLE] Erythropoietin Attenuates the Brain Edema Response after Experimental Traumatic Brain Injury – Full Text

ABSTRACT

Erythropoietin (EPO) has neuroprotective effects in multiple central nervous system (CNS) injury models; however EPO’s effects on traumatic brain edema are elusive. To explore EPO as an intervention in traumatic brain edema, male Sprague–Dawley (SD) rats were subjected to blunt, controlled traumatic brain injury (TBI). Animals were randomized to EPO 5000 IU/kg or saline (control group) intraperitoneally within 30 min after trauma and once daily for 4 consecutive days. Brain MRI, immunohistofluorescence, immunohistochemistry, and quantitative protein analysis were performed at days 1 and 4 post- trauma. EPO significantly prevented the loss of the tight junction protein zona occludens 1 (ZO-1) observed in control animals after trauma. The decrease of ZO-1 in the control group was associated with an immunoglobulin (Ig)G increase in the perilesional parenchyma, indicating blood–brain barrier (BBB) dysfunction and increased permeability. EPO treatment attenuated decrease in apparent diffusion coefficient (ADC) after trauma, suggesting a reduction of cytotoxic edema, and reduced the IgG leakage, indicating that EPO contributed to preserve BBB integrity and attenuated vasogenic edema. Animals treated with EPO demonstrated conserved levels of aquaporin 4 (AQP4) protein expression in the perilesional area, whereas control animals showed a reduction of AQP4. We show that post TBI administration of EPO decreases early cytotoxic brain edema and preserves structural and functional properties of the BBB, leading to attenuation of the vasogenic edema response. The data support that the mechanisms involve preservation of the tight junction protein ZO-1 and the water channel AQP4, and indicate that treatment with EPO may have beneficial effects on the brain edema response following TBI.

Introduction

Traumatic brain injury (TBI) is a major cause of early death and neurological disability throughout the world and remains a major public health problem.^1,2 Injury mechanisms in brain trauma include several cascades of events such as release of excitotoxic molecules, metabolic challenges, inflammation, and apoptosis, accompanied by breakdown of the blood–brain barrier (BBB) and cell swelling, which can finally lead to cell death. Despite several recent clinical studies based on promising experimental evidenc targeting injury mechanisms, there are currently no available pharmacological treatments that convincingly counteract secondary injuries and/or improve long-term functional recovery after human TBI.^3–9

Erythropoietin (EPO) is a glycoprotein cytokine that has been investigated in TBI research. EPO is produced mainly in the kidney, but also locally in brain cells under hypoxic conditions.^10,11 EPO receptors have been found throughout the brain in various cell types such as neurons, astrocytes, and endothelial cells.^12–14 In the literature, there is a substantial body of evidence in support of non-hematopoietic, neuroprotective effects of EPO^11,15 in models of central nervous system (CNS) injury such as ischemia, trauma, intracranial hemorrhages, and diffuse axonal injuries. The proposed mechanisms include decreased inflammatory response,^16–18 decrease of oxidative stress and anti-apoptotic effects.^16,19,20

The effects of EPO treatment in clinical CNS lesions/injuries have varied. A recent randomized, prospective, placebo-controlled clinical trial in ischemic stroke showed that EPO significantly improved long-term neurological outcome.²¹Following moderate or severe TBI, results on EPO treatment have been conflicting. One study found decreased mortality and improved neurological outcome,²² whereas the recent study by Nichol and colleagues did not find that EPO resulted in significant improvement of functional outcome when assessed 6 months after TBI.²³

The clinical course that follows severe TBI is characterized by brain edema development and an associated increase in intracranial pressure contributing to most of the early deaths following trauma. Using a TBI model we have previously shown that the dynamic course of edema development include co-existing vasogenic and cytotoxic brain edema.²⁴The aim of the present study was to investigate whether EPO treatment can modulate the dynamic brain edema response following experimental focal brain injury. […]

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FIG. 2.  (A) High magnification confocal immunofluorescence image of zona occludens 1 (ZO-1) (red), the glial cell marker glial fibrillary acidic protein (GFAP) (green), and the nucleus marker DAPI (blue) from brain area with blood vessels (longitudinal view of blood vessel to the left), to illustrate the specificity and localization of the antibody binding. (B) Monochromatic presentation of GFAP immunofluorescence. (C) Monochromatic presentation of ZO-1 immunofluorescence. (D) Summary data on ZO-1 immunofluorescence in the traumatized, ipsilateral, hemisphere normalized against the contralateral side at days 1 and 4 after trauma in control and erythropoietin (EPO)-treated animals. ZO-1 was significantly reduced after trauma in the control group. EPO prevented the loss of ZO-1 at both time points after trauma. Values presented as mean ± SD. DAPI, 4′,6-diamidino-2-phenylindole; #p < 0.05, ##p < 0.01 compared with naïve animals; **p < 0.01, ***p < 0.001 between groups.

[Abstract] Therapeutic effect of erythropoietin in patients with traumatic brain injury – CNS

Abstract

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(2) and chi-square tests. RESULTS Of the 346 studies identified in the search, 5 RCTs involving 915 patients met the inclusion criteria. The overall results demonstrated that EPO significantly reduced mortality (RR 0.69, 95% CI 0.49-0.96, p = 0.03) and shortened the hospitalization time (MD -7.59, 95% CI -9.71 to -5.46, p < 0.0001) for patients with TBI. Pooled results of favorable outcome (RR 1.00, 95% CI 0.88-1.15, p = 0.97) and deep vein thrombosis (DVT; RD 0.00, 95% CI -0.05 to 0.05, p = 1.00) did not show a significant difference.

CONCLUSIONS The authors suggested that EPO is beneficial for patients with TBI in terms of reducing mortality and shortening hospitalization time without increasing the risk of DVT. However, its effect on improving favorable neurological outcomes did not reach statistical significance. Therefore, more well-designed RCTs are necessary to ascertain the optimum dosage and time window of EPO treatment for patients with TBI.

Source: Traumatic Brain Injury Resource Guide – Research Reports – Therapeutic effect of erythropoietin in patients with traumatic brain injury