Growth Hormone and Neuronal Hemoglobin in the Brain-Roles in Neuroprotection and Neurodegenerative Diseases

Abstract

In recent years, evidence for hemoglobin (Hb) synthesis in both animal and human brains has been accumulating. While circulating Hb originating from cerebral hemorrhage or other conditions is toxic, there is also substantial production of neuronal Hb, which is influenced by conditions such as ischemia and regulated by growth hormone (GH), insulin-like growth factor-I (IGF-I), and other growth factors. In this review, we discuss the possible functions of circulating and brain Hb, mainly the neuronal form, with respect to the neuroprotective activities of GH and IGF-I against ischemia and neurodegenerative diseases. The molecular pathways that link Hb to the GH/IGF-I system are also reviewed, although the limited number of reports on this topic suggests a need for further studies. In summary, GH and/or IGF-I appear to be significant determinants of systemic and local brain Hb concentrations through mediating responses to oxygen and metabolic demand, as part of the neuroprotective effects exerted by GH and IGF-I. The nature and quantity of the latter deserve further exploration in specific experiments.

Keywords: anemia; erythropoietin; growth hormone; hemoglobin; insulin-like growth factor I; ischemia; neurodegenerative diseases; stroke.

Figure 1

Model of crosstalk between neuronal hemoglobin (nHb), growth hormone (GH), and insulin-like growth factor 1 (IGF-I), and the known relations to brain diseases. With respect to interactions with neuronal Hb (nHb), the green arrows are beneficial, and the red arrows are detrimental pathways. Please, observe that circulating or free HbA has other effects not included in this figure. In general, GH and IGF-I levels within the normal ranges are optimal for the metabolism of oxygen and iron and for the mitochondria, which is beneficial for the brain. With age or for other reasons (e.g., genes, environment), the levels of GH and IGF-I decline, and the metabolism deteriorates leading to lower levels of nHb. This has adverse effects on degenerative brain diseases (AD, PD, MS), although in some aspects nHb may also respond in a manner that slows the disease progression. References for the depicted relationships are given in the main text.

Figure 2

GH and/or IGF-I act as significant determinants of Hb concentrations by adapting adequate levels of Hb to the oxygen demand. STAT5, which is a key transcription factor of GH, is sufficient to allow erythropoiesis and myelopoiesis in vitro and in vivo. The PI3K/AKT/mTOR pathways lie downstream of the IGF-I-receptor. AKT phosphorylation of GATA-1 and its partner FOG-1 coordinates erythroid proliferation and differentiation. HIF-1 induced by IGF-I regulates the supply of oxygen to the cell by creating a balance between oxygen demand and oxygen supply. nHb, Neuronal hemoglobin; GH, growth hormone; IGF-I, insulin-like growth factor 1; STAT5, signal transducer and activator of transcription 5; PI3K/AKT/mTOR, phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin; GATA-1, globin transcription factor 1; HIF-1, hypoxia inducible factor 1; FOG-1, friend-of-GATA1. References for the depicted relationships are given in main text.