epoetin-alfa and Brain-Diseases

In its hormonal role, erythropoietin is produced by the kidney in response to hypoxic stress and signals the bone marrow to increase the number of circulating erythrocytes. It has become clear in recentyears, however, that erythropoietin and its receptor are members of a cytokine superfamily that mediates diverse functions in nonhematopoietic tissues. Nonhormonal erythropoietin actions include a critical role in the development, maintenance, protection, and repair of the central nervous system (CNS). Our group has found serendipitously that recombinant human erythropoietin administered into the systemic circulation is not strictly excluded from the brain. Human recombinant erythropoietin appears within the cerebrospinal fluid in neuroprotective concentrations, probably by translocation initiated by binding to the erythropoietin receptor on the luminal surface of the endothelium. This observation suggested that recombinant human erythropoietin could be therapeutic for CNS diseases, a possibility further supported by positive findings in a model of ischemic stroke. Recombinant human erythropoietin administered systemically either in advance of, or up to 3 hours after, a cerebral arterial occlusion in rats prevents apoptosis of neurons within the ischemic penumbra and reduces infarction volume by 75%. Erythropoietin also dramatically reduces postinfarct inflammation in this model. Other brain and spinal cord injuries such as mechanical trauma, experimental autoimmune encephalitis or subarachnoid hemorrhage also respond favorably to erythropoietin administered within a similar window of time. In addition to ameliorating neuronal injury, erythropoietic therapy also directly modulates neuronal excitability and acts as a trophic factor for neurons in vivo and in vitro. Erythropoietin may therefore provide benefit in epileptic or degenerative neurologic diseases. Given the outstanding safety record for recombinant human erythropoietin after more than a decade in widespread clinical use, the results of multiple preclinical investigations suggest that this cytokine or its derivatives may be useful for treatment of a variety of nervous system diseases.

Topics: Brain; Brain Diseases; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Humans; Neuroprotective Agents; Recombinant Proteins

Erythropoietin is the primary physiological regulator of erythropoiesis, and it exerts its effect by binding to cell surface receptors. It has recently been shown that both erythropoietin and its receptor are found in the human cerebral cortex, and that, in vitro, the cytokine is synthesized by astrocytes and neurons, has neuroprotective activity, and is up-regulated following hypoxic stimuli. In animal models, exogenous recombinant human erythropoietin has been reported to be beneficial in treating experimental global and focal cerebral ischemia and reducing nervous system inflammation. These findings suggest that exogenous administration of erythropoietic agents (darbepoetin alfa [Aranesp], epoetin alfa [Epogen, Procrit], and epoetin beta [NeoRecormon]) may be a potential therapeutic tool for central nervous system injury. However, transport of protein therapeutics to the brain's extracellular environment via systemic blood supply generally does not occur due to the negligible permeability of the brain capillary endothelial wall. Therefore, in order to pharmacologically exploit and fully realize the therapeutic benefits of exogenous erythropoietic agents in CNS dysfunction, mechanisms of action and the potential impact of biodistribution barriers need to be elucidated.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Diseases; Clinical Trials as Topic; Darbepoetin alfa; Disease Models, Animal; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Neuroprotective Agents; Receptors, Erythropoietin; Recombinant Proteins

Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies.. To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age.. A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age.. Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.. The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome.. At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89).. In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes.. clinicaltrials.gov Identifier: NCT00413946.

Topics: Brain; Brain Diseases; Double-Blind Method; Epoetin Alfa; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Magnetic Resonance Imaging; Neuroprotective Agents; Recombinant Proteins; Retinopathy of Prematurity