Article

Brain Protection by Erythropoietin: A Manifold Task

Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Physiology (Impact Factor: 5.65). 11/2008; 23(5):263-74. DOI: 10.1152/physiol.00016.2008
Source: PubMed

ABSTRACT 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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    • "Interestingly, Epo exposure in PC12 cells, a cell line considered as a reliable model for the study of carotid body glomus cells, increases their intracellular Ca 2+ concentration, induces membrane depolarization , and increases cell survival, dopamine release and tyrosine hydroxylase activity (reviewed in (Jelkmann 2007 ; Rabie and Marti 2008 "
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    ABSTRACT: During hypoxic or hypoxemic conditions, tissue oxygenation and arterial O(2) carrying capacity are upregulated by two complementary systems, namely the neural respiratory network (central and peripheral) that leads to increased minute ventilation thereby increasing tissue oxygenation, and erythropoietin (Epo) release by the kidney that activates erythropoiesis in bone marrow to augment arterial blood O(2) carrying capacity. Despite the fact that both neural respiratory control and Epo-mediated elevation of red blood cells are responsible for keeping arterial O(2) content optimal, no interaction between these systems has been described so far. Here we review data obtained in our laboratory demonstrating that ventilatory and erythropoietic systems are tightly connected. We found Epo is the key factor mediating this relationship through modulation of the chemoreflex pathway. Moreover, we showed that this interaction occurs in a sex-dependent manner.
    Advances in Experimental Medicine and Biology 01/2012; 758:55-62. DOI:10.1007/978-94-007-4584-1_8 · 2.01 Impact Factor
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    • "The progress in peptide mimetics technologies offers intriguing future possibilities for the treatment or prevention of central nervous system (CNS) diseases (Molina-Holgado et al., 2008; Skaper, 2008). Erythropoietin (EPO) is a classic example of a complex protein that is of interest for CNS diseases based on its neuroprotective, neurotrophic, and antiinflammatory potential (Rabie & Marti, 2008; Velly et al., 2010). However, its application is limited by its bone marrow–stimulating properties, which can result in an increase in blood viscosity and blood pressure (Velly et al., 2010). "
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    ABSTRACT: The selection of a minimal active sequence of erythropoietin allowed the design of peptide mimetics that exert beneficial effects in the central nervous system but lack an erythropoietic effect. Erythropoietin has been suggested as a promising therapeutic and prophylactic for epilepsies based on its neuroprotective, neuroregenerative, and antiinflammatory potency. Therefore, it is of particular interest to evaluate whether the nonerythropoietic erythropoietin-derived peptide pHBSP can affect epileptogenesis. In a post-status epilepticus model in rats, we determined the effects of pHBSP and of recombinant human erythropoietin with short-term administration following status epilepticus. Both pHBSP and erythropoietin further enhanced the status epilepticus-associated increase in hippocampal cell proliferation. Thereby, pHBSP seemed to promote neuronal differentiation and survival resulting in a significant increase in neurogenesis. Neither pHBSP nor erythropoietin affected the number of animals exhibiting spontaneous recurrent seizures as well as the seizure frequency in the chronic phase. In the Morris water maze, pHBSP attenuated cognitive deficits in epileptic animals. In conclusion, the helix B-derived erythropoietin peptide pHBSP can modulate the cellular and cognitive consequences of a status epilepticus. The impact of pHBSP on spatial learning might indicate that the peptide allows beneficial effects on epileptogenesis-associated cognitive deficits. However, it needs to be considered that learning deficits were not abolished by pHBSP and that the effects were not observed consistently until the end of the study. Therefore, adjustment of timing, duration, and dose of peptide administration might be necessary to further evaluate the efficacy of pHBSP.
    Epilepsia 11/2011; 52(12):2333-43. DOI:10.1111/j.1528-1167.2011.03302.x · 4.58 Impact Factor
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    • "During the last two decades, animal and human studies have revealed that Epo has protective functions against hypoxic, ischemic, and traumatic brain injuries, as well as delayed degenerative diseases such as Alzheimer's, Parkinson's, epilepsy, and multiple sclerosis (reviewed in [17]). Interestingly, most reports on non-erythropoietic Epo functions point towards a protective effect of this cytokine against various types of injuries. "
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    ABSTRACT: In addition to its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions against acute and delayed degenerative diseases of the brain. Moreover, we have recently demonstrated that endogenously synthesized Epo and soluble Epo receptor (a negative regulator of Epo binding to the Epo receptor) in the central nervous system play a crucial role in facilitating the ventilatory response and acclimatization to hypoxia. Here we hypothesized that cerebral Epo in the brainstem is implicated in the process that allows cardiorespiratory acclimatization to high altitude hypoxia during the postnatal period. Thus, we evaluated the postnatal ontogeny of cerebral Epo concentration of Sprague-Dawley rats living and reproducing at high altitude for longer than 19 years (3600 m in La Paz, Bolivia). Our results show that postnatal Epo concentration in high-altitude rats is higher in the brainstem than in the forebrain. Moreover, although Epo concentration in the forebrain of high-altitude rats is similar to sea-level controls, Epo level in the brainstem is surprisingly 2-fold higher in high-altitude rats than in sea-level controls. These findings strongly suggest that brainstem Epo plays an important role in tolerance to high altitude hypoxia after birth. From a clinical perspective, a better understanding of the role of Epo in the postnatal development of cardiorespiratory responses in neonates exposed to acute or chronic hypoxia might be useful.
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