Immunohistochemical Localization of Erythropoietin and Its Receptor in the Developing Human Brain

Abstract

We have previously shown erythropoietin (Epo) and its receptor (Epo-R) to be present in the fetal human central nervous system (CNS), and Epo to be present in the spinal fluid of normal preterm and term infants. To investigate the cellular specificities and developmental patterns of expression of these polypeptides in the human brain-areas that have not been well researched-we designed the following study. Human brains ranging in maturity from 5 weeks post-conception to adult were preserved at the time of elective abortion, surgical removal (tubal pregnancy, or removal for temporal lobe epilepsy), or autopsy. Immunohistochemistry was used to localize Epo and Epo-R reactivity in brains of different stages of development. Astrocytes, neurons, and microglia were identified in sequential tissue sections by specific antibodies. At 5 to 6 weeks post-conception, both Epo and Epo-R localized to cells in the periventricular germinal zone. At 10 weeks post-conception, Epo immunoreactivity was present throughout the cortical wall, with the most intense immunoreactivity present in the ventricular and subventricular zones. Epo-R, in contrast, was localized primarily to the subventricular zone, with little staining evident in the ventricular zone. In late fetal brains, Epo-R reactivity was most prominent in astrocytic cells, although modest reactivity was observed in certain neuron populations. In contrast, Epo staining localized primarily to neurons in fetal brains, although a subpopulation of astrocytes was also immunoreactive. In postnatal brains, both astrocyte and neuron populations were immunoreactive with antibodies to Epo-R and Epo. From these results it is clear that Epo and its receptor are present in the developing human brain as early as 5 weeks post-conception, and each protein shows a specific distribution that changes with development. We speculate that Epo is important in neurodevelopment, and that it also plays a role in brain homeostasis later in life, functioning in an autocrine or paracrine manner.

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…In contrast to its antiapoptotic effect, EPO has not shown any activity in preventing necrosis in either the nervous system (Sinor and Greenberg 35 and Mennini et al, unpublished) or the heart. 12 The EPO/EPOR is highly prominent during fetal development, 36 with the very high levels of expression found in many tissues diminishing rapidly after birth to the generally low levels found in the adult. Gene knockout experiments 37 have suggested the importance of this system in development, as the embryos of EPOR À/À animals have abnormal brain development characterized by decreased neuronal progenitor cells as well as grossly decreased neuronal densities associated with massive neuronal apoptosis.…”

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

“…Despite its extensive glycosylation and large size, EPO has been shown in multiple experimental species and in man to cross the blood brain barrier (BBB) when administered peripherally (Ehrenreich et al, 2004). During brain development, the expression of both EPO and EPOR changes drastically (Buemi et al, 2005;Genc et al, 2004a,b;Juul et al, 1999). Lately, Ruscher et al (2002) hypothesized that EPO has paracrine functions in cerebral ischemia.…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…ЭПО оказывает влияние на разнообразные рецепторопосредованные и клеточ-ные специфические реакции, которые полезны после гипоксии-ишемии. ЭПО приписывают противовоспали-тельный, антиэксайтотоксический, антиоксидантный и антиапоптотический эффекты, а также содействие ней-ро-и ангиогенезу [86][87][88]. ЭПО экспрессируется в голов-ном мозге человека и животных, особенно в астроцитах и микроглии, на ранних стадиях жизни и поэтому необ-ходим для развития мозга, но постепенно снижается после рождения [89].…”