Erythropoietin and neuroprotection: a therapeutic perspective

Abstract

Recombinant erythropoietin (EPO) is used to correct for anaemia caused by chronic renal failure or cancer therapy. Improvement of the quality of life of anaemic patients treated with EPO was recently demonstrated and preliminary clinical results suggest an improvement of cognitive functions in patients receiving EPO. High expression of EPO and its receptor in the brain during embryonic development has led to the investigation of not only the neurotrophic role of EPO but also its neuroprotective properties. The neuroprotective effects of EPO have various complementary actions including antagonism of the effects of glutamate, increased expression of antioxidant enzymes, changes in production of neurotransmitters and induction of neuroglobin. Convincing experimental results suggest a blood-brain transport of EPO whereas clinical pharmacokinetic data do not as yet support this. The neuroprotective effects of EPO and its therapeutic promise need to be underlined.

Plasticity and remodeling of brain

“…EPO passes the blood brain barrier [80][81][82][83]. The EPO receptor is present on parenchymal cells [80,84,85], and EPO is required for the normal brain development [86,87]. EPO systemically administered to adult male rats one day after stroke significantly improves neurological outcome after middle cerebral artery occlusion [38], and has been shown to significantly improve recovery after spinal cord injury [80], traumatic brain injury [39] and EAE [48,88].…”

Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system

“…CNS-derived EPO is vital for the development of neuronal networks (Milano and Collomp, 2005). Previous studies have shown that in the absence of EPO or the EPO receptor, increased neuronal apoptosis was detected in mice just before the mice died from severe anemia in utero (Yu et al, 2001;Yu et al, 2002).…”

“…For example, children with congenital heart disease could have systemic hypoxia, while patients with intracranial diseases may have regional cerebral hypoxia. Considering the pivotal role of EPO in neuroprotection (Milano and Collomp, 2005), midazolam may affect the clinical course of such patients by suppressing EPO production in the brain. However, the present study only investigated brainderived EPO in a systemic hypoxia model.…”

Erythropoietin: when liability becomes asset in neurovascular repair

“…With this broad expression of both Epo and EpoR, a pleiotrophic role for Epo is anticipated. Whereas Epo is best known for its role in hematopoiesis as a factor that leads to the proliferation and differentiation of erythroid precursors, it is also involved in diverse nonhematopoietic biological functions (10,17,18). These pleiotrophic effects of Epo include: (a) neuroprotection by decreasing neuronal apoptosis and inflammation in acute brain injury models, by protecting the mouse retina against light-induced degeneration (19) and by reducing retinal ganglion cell loss following axotomy (20); (b) cytoprotection by inhibiting apoptosis and promoting angiogenesis to improve cardiac function in cardiac ischemia models of heart failure (21, 22); and (c) modulation of tissue remodeling by regulating cell maturation and division, preventing intimal hyperplasia (23), and reducing pulmonary vascular remodeling (24) in a hypoxic rat model of pulmonary hypertension without affecting hemodynamics or right ventricular hypertrophy.…”