Erythropoietin in Brain Development and Beyond

Alnaeeli, Mawadda; Wang, Lili; Piknová, Barbora; Rogers, Heidi; Li, Xiaoxia; Noguchi, Constance Tom

doi:10.1155/2012/953264

Cited by 47 publications

(49 citation statements)

References 203 publications

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“…Systemic Epo production is induced by transcription factors- hypoxia inducible factor (HIF) -1 and HIF-2 through tightly regulated pathways (39-42). HIF molecules are heterodimeric basic-helix-loop-helix per-aryl hydrocarbon receptor nuclear transporter-Sim (PAS) consisting of common constitutively expressed beta subunits and inducible alpha subunits (43, 44).…”

Section: Mechanism Of Action Of Epo and Epormentioning

confidence: 99%

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Rangarajan¹,

Juul²

2014

Pediatric Neurology

108

106

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BACKGROUND In the last two decades, there has been considerable evolution in the understanding role of erythropoietin (Epo) in neuroprotection. Epo has both paracrine and autocrine functions in the brain. Epo binding results in neurogenesis, oligodendrogenesis, and angiogenesis. Epo and its receptor are upregulated by exposure to hypoxia and proinflammatory cytokines following brain injury. While Epo aids in recovery of locally injured neuronal cells, it provides negative feedback to glial cells in the penumbra, thereby limiting extension of injury. This forms the rationale for use of recombinant Epo and Epo mimetics in neonatal and adult injury models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage and neonatal hypoxic-ischemia. METHOD Review of published literature (Pubmed, Medline and Google scholar) RESULTS Preclinical neuroprotective data are reviewed and the rationale for proceeding to clinical trials is discussed. Results from Phase I/II trials are presented, as are updates on ongoing and upcoming clinical trials of Epo neuroprotection in neonatal populations. CONCLUSIONS The scientific rationale and preclinical data for Epo neuroprotection are promising. Phase II and III clinical trials are currently in process to determine the safety and efficacy of neuroprotective dosing of Epo for extreme prematurity and hypoxic ischemic encephalopathy in neonates.

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Section: Mechanism Of Action Of Epo and Epormentioning

confidence: 99%

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Rangarajan¹,

Juul²

2014

Pediatric Neurology

108

106

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“…EPO has been shown to act directly on neural cells in culture and offers protection in animal models of injury [273]. In a rat model of hypoxia-ischemia by transient uterine artery occlusion, neonatal administration of recombinant EPO was shown to improve the survival of oligodendrocytes and GABAergic neurons, restore myelin production and motor performance in adult rats [185].…”

Section: The Prodromal High-risk Phenotype and Onset Of Schizophreniamentioning

confidence: 99%

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

2013

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Schizophrenia is a chronic and debilitating mental illness characterized by a broad range of abnormal behaviors, including delusions and hallucinations, impaired cognitive function, as well as mood disturbances and social withdrawal. Due to the heterogeneous nature of the disease, the causes of schizophrenia are very complex; its etiology is believed to involve multiple brain regions and the connections between them, and includes alterations in both gray and white matter regions. The onset of symptoms varies with age and severity, and there is some debate over a degenerative or developmental etiology. Longitudinal magnetic resonance imaging studies have detected progressive gray matter loss in the first years of disease, suggesting neurodegeneration; but there is also increasing recognition of a temporal association between clinical complications at birth and disease onset that supports a neurodevelopmental origin. Presently, neuronal abnormalities in schizophrenia are better understood than alterations in myelin-producing cells of the brain, the oligodendrocytes, which are the predominant constituents of white matter structures. Proper white matter development and its structural integrity critically impacts brain connectivity, which affects sensorimotor coordination and cognitive ability. Evidence of defective white matter growth and compromised white matter integrity has been found in individuals at high risk of psychosis, and decreased numbers of mature oligodendrocytes are detected in schizophrenia patients. Inflammatory markers, including proinflammatory cytokines and chemokines, are also associated with psychosis. A relationship between risk of psychosis, white matter defects and prenatal inflammation is being established. Animal models of perinatal brain injury are successful in producing white matter damage in the brain, typified by hypomyelination and/or dysmyelination, impaired motor coordination and prepulse inhibition of the acoustic startle reflex, recapitulating structural and functional characteristics observed in schizophrenia. In addition, elevated expression of inflammation-related genes in brain tissue and increased production of cytokines by blood cells from patients with schizophrenia indicate immunological dysfunction and abnormal inflammatory responses, which are also important underlying features in experimental models. Microglia, resident immune defenders of the central nervous system, play important roles in the development and protection of neural cells, but can contribute to injury under pathological conditions. This article discusses oligodendroglial changes in schizophrenia and focuses on microglial activity in the context of the disease, in neonatal brain injury and in various experimental models of white matter damage. These include disorders associated with premature birth, and animal models of perinatal bacterial and viral infection, oxygen deprivation (hypoxia) and excess (hyperoxia), and elevated systemic proinflammatory cytokine levels. We briefly review the effects of treatme...

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“…EPO-R may also be hypoxia sensitive (Giatromanolaki et al, 2009; Lam et al, 2009; Shein et al, 2005; Theus et al, 2008), though there are conflicting literature reports (Alnaeeli et al, 2012; Digicaylioglu et al, 1995). Since these molecules are all are up-regulated by 3xwAIH (10 wks) in phrenic motor neurons (Satriotomo et al, 2012; Dale, Satriotomo and Mitchell, unpublished observations), we hypothesized that 3xwAIH would enhance pMF induced by spinal VEGF and/or EPO receptor activation.…”

Section: Introductionmentioning

confidence: 99%

Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermittent hypoxia

Dale

Mitchell

2013

Respiratory Physiology & Neurobiology

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Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) exert neurotrophic and neuroprotective effects in the CNS. We recently demonstrated that VEGF, EPO and their receptors (VEGF-R2, EPO-R) are expressed in phrenic motor neurons, and that cervical spinal VEGF-R2 and EPO-R activation elicit long-lasting phrenic motor facilitation (pMF). Since VEGF, VEGF-R, EPO, and EPO-R are hypoxia-regulated genes, and repetitive exposure to acute intermittent hypoxia (rAIH) up-regulates these molecules in phrenic motor neurons, we tested the hypothesis that 4 weeks of rAIH (10 episodes per day, 3 days per week) enhances VEGF- or EPO- induced pMF. We confirm that cervical spinal VEGF and EPO injections elicit pMF. However, neither VEGF- nor EPO-induced pMF was affected by rAIH pre-conditioning (4 wks). Although our data confirm that spinal VEGF and EPO may play an important role in respiratory plasticity, we provide no evidence that rAIH amplifies their impact. Further experiments with more robust protocols are warranted.

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Erythropoietin in Brain Development and Beyond

Cited by 47 publications

References 203 publications

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermittent hypoxia

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