The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin

Xenocostas, Anargyros; Cheung, Wing K.; Farrell, Francis X.; Zakszewski, Cindy; Kelley, Marian; Lutynski, Andrzej; Crump, Michael; Lipton, Jeffrey H.; Kiss, Thomas; Lau, Catherine Y.; Messner, Hans A.

doi:10.1007/s00228-005-0896-7

Cited by 98 publications

(63 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In patients given high doses of EPO intravenously, EPO increase in the cerebrospinal fluid was detected as early as 3 h after administration, followed first order kinetics, and depended on permeability of the blood-brain barrier, providing evidence that EPO transport proceeds via a first order transmembrane or non-receptor-mediated mechanism [55]. After single injection of a high level of EPO, cerebrospinal fluid of EPO reached levels up to 40 mIU/ml with a halflife similar to serum (26 h to 36 h).…”

Section: Intravenous Epo Administration In Patients and Non-human Primentioning

confidence: 96%

Role of erythropoietin in the brain

Noguchi

Asavaritikrai

Teng

et al. 2007

Critical Reviews in Oncology/Hematology

207

159

View full text Add to dashboard Cite

Multi-tissue erythropoietin receptor (EPO-R) expression provides for erythropoietin (EPO) activity beyond its known regulation of red blood cell production. This review highlights the role of EPO and EPO-R in brain development and neuroprotection. EPO-R brain expression includes neural progenitor cells (NPC), neurons, glial cells and endothelial cells. EPO is produced in brain in a hypoxia sensitive manner, stimulates NPC proliferation and differentiation, and neuron survival, and contributes to ischemic preconditioning. Mice lacking EPO or EPO-R exhibit increased neural cell apoptosis during development before embryonic death due to severe anemia. EPO administration provides neural protection in animal models of brain ischemia and trauma, reducing the extent of injury and damage. EPO stimulation of endothelial cells contributes to neuroprotection and is of particular importance since only low levels of EPO appear to cross the blood-brain barrier when administered at high dose intravenously. The therapeutic potential of EPO for brain ischemia/trauma and neurodegenerative diseases has shown promise in early clinical trial and awaits further validation.

show abstract

Section: Intravenous Epo Administration In Patients and Non-human Primentioning

confidence: 96%

Role of erythropoietin in the brain

Noguchi

Asavaritikrai

Teng

et al. 2007

Critical Reviews in Oncology/Hematology

207

159

View full text Add to dashboard Cite

show abstract

“…The molecular basis for this observation has not been established, but might be related to increased translation or stabilization of frataxin protein. In earlier studies, rhu-EPO was shown to cross the blood-brain barrier in a human pharmacokinetics study (Xenocostas et al, 2005) and in an animal model for brain injury (Brines et al, 2000). Clinical trials with rhuEPO are currently in progress.…”

Section: Discovery Of Molecules That Increase Frataxin Mrna or Proteinmentioning

confidence: 99%

Small molecules affecting transcription in Friedreich ataxia

Gottesfeld

2007

Pharmacology & Therapeutics

View full text Add to dashboard Cite

This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

show abstract

“…In contrast, EPO administered 30 min before water loading was not effective (data not shown). This is likely due to the substantial delay of several hours in the transport of peripherally-administered EPO into the brain (5,16).…”

Section: Epo Protects Against Neurological Symptoms Caused By Brain Ementioning

confidence: 99%

Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

Gunnarson

Song

Kowalewski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.aquaporin 4 ͉ brain edema ͉ glutamate E rythropoietin, the major haemopoietic growth factor, has in recent years emerged as one of the most efficient neuroprotective agents (1-3). It is well documented from both experimental and clinical studies that erythropoietin (EPO) attenuates the degree of brain damage after stroke (4-6). Stroke is associated with a massive release of glutamate and experimental studies have indicated that EPO also protects from glutamatetriggered neurotoxicity (7). EPO acts by preventing the destruction of viable tissue surrounding the site of an injury, that is, the penumbra that develops during the first 24-48 h after a brain insult (1). Cell swelling is one of the characteristic features of the penumbra (8, 9).Mounting evidence suggests that water uptake in astrocytes via the water channel aquaporin 4 (AQP4) is an important factor contributing to post-ischemic cell swelling (10, 11). Immunohistochemical studies have indicated a colocalization between EPO receptors and AQP4 in the brain (12, 13), particularly in glial cells at the interface between the brain parenchyma and the periphery. This raises the question whether EPO may modulate astrocyte water permeability and whether this effect may attenuate astrocyte water uptake after a brain insult. We have in a recent study demonstrated that glutamate increases astrocyte water permeability via activation of AQP4 (14). In the present study we have tested the possibility that EPO may counteract the effect of glutamate on astrocyte water permeability.To document the tissue protective role of EPO in brain edema, we first tested whether EPO reduces symptoms in a mouse model of water intoxication known to depend upon glial AQP4 (11). Observing a robust eff...

show abstract

The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin

Cited by 98 publications

References 23 publications

Role of erythropoietin in the brain

Role of erythropoietin in the brain

Small molecules affecting transcription in Friedreich ataxia

Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

Contact Info

Product

Resources

About