Brain Protection by Erythropoietin: A Manifold Task

Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Physiology (Impact Factor: 4.86). 11/2008; 23(5):263-74. DOI: 10.1152/physiol.00016.2008
Source: PubMed


Many hematopoietic growth factors are produced locally in the brain. Among these, erythropoietin (Epo), has a dominant role for neuroprotection, neurogenesis, and acting as a neurotrophic factor in the central nervous system. These functions make erythropoietin a good candidate for treating diseases associated with neuronal cell death.

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    • "A potential candidate in this respect is erythropoietin (Epo) that by inhibiting apoptosis of erythroid progenitor cells increases the number of circulating red blood cells (Jelkmann, 1992). Apart from this classical function, Epo has also similar biological effects in many nonhematopoietic tissues including the central and peripheral nervous system (Gassmann et al., 2003; Grimm et al., 2002; Marti et al., 2000; Rabie and Marti, 2008; Toth et al., 2008; Vitellaro- Zuccarello et al., 2007). Thus, the question arose as to a putative protective effect of Epo in the inner ear. "
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    ABSTRACT: So far, typical causes of presbycusis such as degeneration of hair cells and/or primary auditory (spiral ganglion) neurons cannot be treated. Because erythropoietin's (Epo) neuroprotective potential has been shown previously, we determined hearing thresholds of juvenile and aged mice overexpressing Epo in neuronal tissues. Behavioral audiometry revealed in contrast to 5 months of age, that 11-month-old Epo-transgenic mice had up to 35 dB lower hearing thresholds between 1.4 and 32 kHz, and at the highest frequencies (50-80 kHz), thresholds could be obtained in aged Epo-transgenic only but not anymore in old C57BL6 control mice. Click-evoked auditory brainstem response showed similar results. Numbers of spiral ganglion neurons in aged C57BL6 but not Epo-transgenic mice were dramatically reduced mainly in the basal turn, the location of high frequencies. In addition, there was a tendency to better preservation of inner and outer hair cells in Epo-transgenic mice. Hence, Epo's known neuroprotective action effectively suppresses the loss of spiral ganglion cells and probably also hair cells and, thus, development of presbycusis in mice.
    Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.08.015 · 5.01 Impact Factor
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    • "Epo, on the other hand, is mainly expressed by glial cells and neurons [39]. Contrary to VEGF, Epo is not only neuroprotective [6], [7] but also stabilizes BBB function, e.g. by VEGF antagonism [40] and conservation of TJ integrity [11], [12]. Thus, it can be anticipated that VEGF and Epo synergistically increase neuronal survival upon ischemic insult, while Epo in addition counteracts VEGF-induced hyperpermeability. "
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    ABSTRACT: Ischemic stroke results in disruption of the blood-brain barrier (BBB), edema formation and neuronal cell loss. Some neuroprotective factors such as vascular endothelial growth factor (VEGF) favor edema formation, while others such as erythropoietin (Epo) can mitigate it. Both factors are controlled by hypoxia inducible transcription factors (HIF) and the activity of prolyl hydroxylase domain proteins (PHD). We hypothesize that activation of the adaptive hypoxic response by inhibition of PHD results in neuroprotection and prevention of vascular leakage. Mice, subjected to cerebral ischemia, were pre- or post-treated with the novel PHD inhibitor FG-4497. Inhibition of PHD activity resulted in HIF-1α stabilization, increased expression of VEGF and Epo, improved outcome from ischemic stroke and reduced edema formation by maintaining BBB integrity. Additional in vitro studies using brain endothelial cells and primary astrocytes confirmed that FG-4497 induces the HIF signaling pathway, leading to increased VEGF and Epo expression. In an in vitro ischemia model, using combined oxygen and glucose deprivation, FG-4497 promoted the survival of neurons. Furthermore, FG-4497 prevented the ischemia-induced rearrangement and gap formation of the tight junction proteins zonula occludens 1 and occludin, both in cultured endothelial cells and in infarcted brain tissue in vivo. These results indicate that FG-4497 has the potential to prevent cerebral ischemic damage by neuroprotection and prevention of vascular leakage.
    PLoS ONE 01/2014; 9(1):e84767. DOI:10.1371/journal.pone.0084767 · 3.23 Impact Factor
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    • "EpoR did not co-localise with astrocytes, or damaged axons. While EPO expression is restricted to neurons and astrocytes only, EpoR is expressed on the cell membrane of neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells [82]. Previous reports have documented heightened expression of astrocytic EpoR under hypoxic conditions both in vitro and in vivo[65,78,83], and thus, we hypothesised increased numbers of astrocytes expressing the EpoR after TAI + Hx, and even more so in TAI + Hx + EPO rats, as EPO is thought to act in a paracrine manner in the brain [83]; however, this was not corroborated. "
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    ABSTRACT: Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia. Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30 minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000 IU/kg) or saline at 1 and 24 hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests; 2) axonal pathology (NF-200); 3) callosal degradation (hematoxylin and eosin stain); 3) dendritic loss (MAP2); 4) expression and localisation of the EPO receptor (EpoR); 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta. EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI + Hx). A single dose of EPO at 1 hour reduced axonal damage in the white matter of TAI + Hx rats at 1 day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI + Hx rats; however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1 day after TAI + Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2 hours after TAI + Hx, concomitant to a decrease in CD68 positive cells at 7 and 14 days. When administered EPO, TAI + Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.
    Journal of Neuroinflammation 12/2013; 10(1):156. DOI:10.1186/1742-2094-10-156 · 5.41 Impact Factor
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