losartan-potassium and Nervous-System-Diseases

Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is a transmembrane receptor protein which is a part of the most prominent family of receptor tyrosine kinases (RTKs). It serves a crucial role in both physiological, biological, and functional states binding with their ligand like Ephrins. Its abundance in the majority of the body's systems has been reported. Moreover, it draws much attention in the CNS since it influences axonal and vascular guidance. Also, it has a widespread role at the pathological state of various CNS disorders. Reports suggest it obstructs axonal regeneration in various neurodegenerative diseases and neurological disorders. Although, neuro-regeneration is still an open challenge to the modern drug discovery community.  Hence, in this review, we will provide information about the role of EphA4 in neurological diseases by which it may emerge as a therapeutic target for CNS disease. We will also provide a glance at numerous signaling pathways that activate or inhibit the EphA4-associated biological processes contributing to the course of neurodegenerative diseases. Thus, this work might serve as a basis for futuristic studies that are related to the target-based drug discovery in the field of neuro-regeneration. Pathological and physiological events associated with EphA4 and Ephrin upregulation and interaction.

Topics: Carcinoma, Hepatocellular; Erythropoietin; Humans; Liver Neoplasms; Nervous System Diseases; Protein Binding

Topics: Acute Lung Injury; Adult; Anemia; Blood Preservation; Blood Specimen Collection; Brain Injuries; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Myocardial Ischemia; Nervous System Diseases; Sepsis; Shock; Stroke; Subarachnoid Hemorrhage

This review summarizes target populations of neonates for which erythropoietin (Epo) neuroprotective therapy might be of benefit, and the mechanisms by which Epo functions as a neuroprotective agent. Potential risks of Epo are reviewed. Finally, the progression of Epo neuroprotection from preclinical studies to translational studies is discussed.

Topics: Brain; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Nervous System Diseases; Neuroprotective Agents; Risk Factors

Topics: Animals; Central Nervous System; Erythropoietin; Humans; Nervous System Diseases; Neurons; Neuroprotective Agents; Receptors, Erythropoietin

Cytokine and growth factor--erythropoietin (EPO)--apart from it's hematopoietic function is now considered to be a cytoprotective agent in a variety of vascular diseases, nervous system disorders and metabolic impairments. Recent work has elucidated that erythropoietin controls a variety of signal transduction pathways involving Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription, Wnt proteins, forkhead transcription factors, caspases, and nuclear factor kappaB. Further investigations of cellular pathways controlled by erythropoietin can be the base for therapeutic applicability of this cytokine throughout the body.

Topics: Animals; Cytoprotection; Erythropoietin; Humans; Janus Kinase 2; Metabolic Diseases; Nervous System Diseases; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction; TYK2 Kinase; Vascular Diseases

Advances in the care of high-risk newborn babies have contributed to reduced mortality rates for premature and term births, but the surviving neonates often have increased neurological morbidity. Therapies aimed at reducing the neurological sequelae of birth asphyxia at term have brought hypothermia treatment into the realm of standard care. However, this therapy does not provide complete protection from neurological complications and a need to develop adjunctive therapies for improved neurological outcomes remains. In addition, the care of neurologically impaired neonates, regardless of their gestational age, clearly requires a focused approach to avoid further injury to the brain and to optimize the neurodevelopmental status of the newborn baby at discharge from hospital. This focused approach includes, but is not limited to, monitoring of the patient's brain with amplitude-integrated and continuous video EEG, prevention of infection, developmentally appropriate care, and family support. Provision of dedicated neurocritical care to newborn babies requires a collaborative effort between neonatologists and neurologists, training in neonatal neurology for nurses and future generations of care providers, and the recognition that common neonatal medical problems and intensive care have an effect on the developing brain.

Topics: Anesthetics, Inhalation; Anticonvulsants; Antioxidants; Asphyxia Neonatorum; Electroencephalography; Erythropoietin; Humans; Hypothermia, Induced; Infant, Newborn; Intensive Care, Neonatal; Monitoring, Physiologic; Nervous System Diseases; Neuroprotective Agents; Seizures; Xenon

Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.

Topics: Animals; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Nervous System Diseases

Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule not affecting hematocrit. It is a potentially important pharmacological agent that may be applied to the treatment of several diseases affecting central and peripheral system neurons.. Carbamylated erythropoietin is a prime candidate for development because of its potent cell survival and function enhancing effects. This article reviews the preclinical development profile of CEPO in animal models to determine whether further clinical development is justified.. The review spans a detailed analysis of patents and scientific publications related to CEPO in animal models.. Use of CEPO in treating diseases such as stroke and traumatic brain and spinal cord injuries is important because these conditions affect millions of patients every year. Extensive preclinical studies support further clinical studies of CEPO for acute ischemic stroke. However, further studies are required for testing CEPO in patients with many other indications.

Topics: Animals; Brain Injuries; Clinical Trials as Topic; Diabetic Neuropathies; Disease Models, Animal; Erythropoietin; Humans; Motor Neuron Disease; Nervous System Diseases; Spinal Cord Injuries; Stroke; Treatment Outcome

Erythropoietin (EPO) was first identified as a hematopoietic cytokine that stimulates proliferation and differentiation of erythroid progenitor cells and was approved by the Food and Drug Administration as a treatment for chronic renal disease patients with anemia. In neural tissues, EPO is working via EPO receptors and induces non-hematopoietic effects. Recent studies have demonstrated that EPO exerts therapeutic potentials on neurological disorders such as ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and Parkinson's disease. EPO treatment has been shown to reduce the ischemic infarct and hemorrhage volume, decrease neuronal death including apoptosis, and improve survival rates in animal models. The mechanism of EPO action in neurological disorders involves neuroprotection and promotion of neurogenesis and angiogenesis. Clinical trials of EPO treatments in neurological diseases have accumulated positive results. In stroke patients, EPO treatment may reduce infarct volume and improve functional outcomes. EPO administration has proven safe in animal studies and adult human patients, although safety and efficacy data in neonates and infants are incomplete and long-term multi-center patient evaluations are necessary. Available information suggests that EPO is a promising therapeutic drug for the treatment of neurological diseases.

Topics: Animals; Erythropoietin; Gene Expression; Humans; Nervous System Diseases; Neuroprotective Agents; Receptors, Erythropoietin

Many hematopoietic growth factors are produced locally in the brain. Among these, erythropoietin (Epo), has a dominant role for neuroprotection, neurogenesis, and acting as a neurotrophic factor in the central nervous system. These functions make erythropoietin a good candidate for treating diseases associated with neuronal cell death.

Topics: Animals; Brain; Brain Chemistry; Erythropoietin; Humans; Nervous System Diseases; Nervous System Physiological Phenomena; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

Topics: Animals; Erythropoietin; Humans; Nervous System Diseases

Two hematopoietic cytokines are currently gaining increasing attention within neurological research. Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have long been known for their ability to induce the proliferation of certain populations of hematopoietic lineage cells. However, it has recently been found that EPO, G-CSF, and their respective receptors are also expressed in the human central nervous system (CNS) and may be an important part of the brain's endogenous system of protection. Both hematopoietic cytokines have been shown to have neuroprotective potential in a variety of animal disease models both in vitro and in vivo, through the inhibition of apoptosis, induction of angiogenesis, exertion of anti-inflammatory and neurotrophic effects, as well as by the enhancement of neurogenesis. EPO and G-CSF have been extensively studied in the context of hematological disorders and have recently been successfully applied in the first clinical trials in stroke patients. Intravenous high-dose EPO therapy was associated with an improvement in the clinical outcome and preclinical studies with intravenous high-dose G-CSF therapy have clearly shown that it has considerable neuroprotective potential in the acute, as well as in the chronic phase of stroke. In this review, the current knowledge of the neuroprotective mechanisms of EPO and G-CSF is summarized with regard to in vitro and in vivo data. Focus is placed on the role of EPO in neurological disease models with an emphasis on its influence on functional outcome. New experimental results are assessed in detail and correlated with the findings of recent clinical studies.

Topics: Animals; Apoptosis; Brain; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; In Vitro Techniques; Inflammation; Models, Neurological; Neovascularization, Physiologic; Nervous System Diseases; Neurology; Neuroprotective Agents; Parkinson Disease; Research Design; Signal Transduction; Stroke

The discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPO expression in the brain is induced by hypoxia. Practically all brain cells are capable of production and release of EPO and expression of its receptor. EPO exerts multifaceted protective effects on brain cells. It protects neuronal cells from noxious stimuli such as hypoxia, excess glutamate, serum deprivation or kainic acid exposure in vitro by targeting a variety of mechanisms and involves neuronal, glial and endothelial cell functions. In rodent models of ischemic stroke, EPO reduces infarct volume and improves functional outcome, but beneficial effects have also been observed in animal models of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. EPO has a convenient therapeutic window upon ischemic stroke and favorable pharmacokinetics. Results from first therapeutic trials in humans are promising, but will need to be validated in larger trials. The safety profile and effectiveness of EPO in a wide variety of neurologic disease models make EPO a candidate compound for a potential first-line therapeutic for neurologic emergencies.

Topics: Animals; Brain Chemistry; Brain Diseases; Erythropoietin; Humans; Mental Disorders; Nervous System Diseases; Neuroprotective Agents; Recombinant Proteins

This article is a selective extension of a review on recombinant human erythropoietin (rHu-EPO) as an anti-anaemic drug, published in this journal in 2000. It summarises the recent advances in understanding the molecular mechanisms by which the hypoxia-inducible transcription factor 1 (HIF-1) regulates O(2)-dependent genes, including the EPO gene in brain. With respect to brain integrity, EPO exerts positive effects in two different ways. First, rHu-EPO raises the blood haemoglobin concentration and, hence, the O(2) capacity of the blood in anaemic patients. The restored O(2) supply ameliorates attention difficulties and psychomotor slowing, improves memory capacities and normalises neuroendocrine functions. Second, EPO can act as a neurotrophic and neuroprotective factor directly in brain. EPO and its receptor are expressed in the cerebral cortex, cerebellum, hippocampus, pituitary gland and spinal cord. In vitro EPO protects against glutamate-induced cell death in a dose-dependent way. In animal models it reduces volumes of brain ischaemia, protects the cortex from hypoxic damage and leads to survival of neurons and synapses. One can expect that in the near future rHu-EPO will be used therapeutically in cerebral ischaemia, brain trauma, inflammatory diseases, and neural degenerative disorders. A first clinical trial has shown the neuroprotective effectiveness of the drug in cerebral ischaemia.

Topics: Animals; Brain; Erythropoietin; Humans; Nervous System Diseases; Recombinant Proteins

Erythropoietin (Epo) is a hematopoietic growth factor and cytokine which stimulates erythropoiesis. In recent years, Epo has been shown to have important nonhematopoietic functions in the nervous system. Nonerythropoietic actions of Epo include a critical role in the development, maintenance, protection and repair of the nervous system. A wide variety of experimental studies have shown that Epo and its receptor are expressed in the nervous system and Epo exerts remarkable neuroprotection in cell culture and animal models of nervous system disorders. In this review, we summarize the current knowledge on the neurotrophic and neuroprotective properties of Epo, the mechanisms by which Epo produces neuroprotection and the signal transduction systems regulated by Epo in the nervous system.

Topics: Animals; Erythropoietin; Humans; Nervous System Diseases; Nervous System Physiological Phenomena; Receptors, Erythropoietin

Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine. Emerging evidence now exists supporting a physiologic role for EPO within the nervous system. EPO is expressed in the developing central nervous system and is capable of regulating the production of neuronal progenitor cells. There are numerous preclinical studies demonstrating a neuroprotective potential for EPO in a variety of disorders of both the central and peripheral nervous systems. A small pilot study in patients with acute ischemic stroke has recently been completed and the results are encouraging. Its mechanism of action is multifactorial but probably related to its ability to act as an antiapoptotic agent. Its widespread use clinically for the treatment of anemias has given us the experience and knowledge of its safety and pharmacokinetics. EPO is thus an ideal compound to study for the potential treatment of a variety of neurologic disorders.

Topics: Animals; Brain; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Nervous System Diseases; Neuroprotective Agents; Recombinant Proteins

To provide an overview of the current knowledge on neuroprotective properties of Erythropoietin (Epo), mechanisms by which Epo produces neuroprotection, and signaling pathways regulated by Epo in the nervous system.. The Medline database was searched for articles on the neuroprotective properties of Epo. Experimental and clinical studies were systematically reviewed.. In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, Epo and the Epo receptor (EpoR) have recently been shown to exist and function in the nervous system. The Epo/EpoR system plays a critical role in neurodevelopment and neuroprotection. Epo ameliorates or prevents neuronal injury by neuroprotective, anti-apoptotic, anti-inflammatory, anti-oxidant, angiogenic, neurogenic and neurotrophic effects in cell culture and animal models of neurological diseases. The clinical effectiveness of recombinant human Epo in ischemic stroke in human patients has also been reported recently.. Recent studies suggest that Epo is a potential novel neurotherapeutic agent and further clinical studies are warranted.

Topics: Animals; Erythropoietin; Humans; Nervous System Diseases; Neuroprotective Agents; Signal Transduction

In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, erythropoietin and the erythropoietin receptor have recently been shown to modulate cellular signal transduction pathways that extend beyond the erythropoietic function of erythropoietin. In particular, erythropoietin has been linked to the prevention of programmed cell death in neuronal systems. Although this work is intriguing, the underlying molecular mechanisms that serve to mediate neuroprotection by erythropoietin are not well understood. Further analysis illustrates that erythropoietin modulates two distinct components of programmed cell death that involve the degradation of DNA and the externalization of cellular membrane phosphatidylserine residues. Initiation of the cascades that modulate protection by erythropoietin and its receptor may begin with the activation of the Janus tyrosine kinase 2 protein. Subsequent downstream mechanisms appear to lead to the activation of multiple signal transduction pathways that include transcription factor STAT5 (signal transducers and activators of transcription), Bcl-2, protein kinase B, cysteine proteases, mitogen-activated protein kinases, protein-tyrosine phosphatases, and nuclear factor-kappaB. New knowledge of the cellular pathways regulated by erythropoietin in neuronal environments will potentially solidify the development and initiation of therapeutic strategies against nervous system disorders.

Topics: Animals; Apoptosis; Brain; Cysteine Endopeptidases; Erythropoietin; Gene Expression; Humans; Models, Animal; Nervous System Diseases; Neurons; Protein Kinases; Receptors, Erythropoietin; Signal Transduction

Preclinical studies suggest that growth factors in the early days after stroke improve final outcome. A prior study found three doses of human choriogonadotropin alfa followed by three doses of erythropoietin to be safe after stroke in humans. A proof of concept trial (REGENESIS) was initiated but placed on regulatory hold during review of an erythropoietin neuroprotective trial. Due to financial constraints, the trial was largely moved to India, using lower erythropoietin doses, as the REGENESIS-LED trial.. Entry criteria included National Institutes of Health Stroke Scale 8-20, supratentorial ischemic stroke, and 24-48 h poststroke at start of therapy. Patients were randomized to three QOD doses of subcutaneous human choriogonadotropin alfa followed by three QD doses of intravenous erythropoietin (three escalating dose cohorts, 4000-20,000 IU/dose) vs. placebo. Primary outcomes were safety and neurological recovery.. The study was halted early by the sponsor after 96 enrollees. There was no significant difference across treatment groups in the proportion of patients experiencing death, serious adverse events, or any adverse event. There was no significant difference in National Institutes of Health Stroke Scale score change from baseline to Day 90 between placebo and active treatment, whether active cohorts were analyzed together or separately, and no exploratory secondary measure of neurological recovery showed a significant difference between groups.. Administration of human choriogonadotropin alfa followed by erythropoietin is safe after a new ischemic stroke. At the doses studied, placebo and active groups did not differ significantly in neurological recovery. Study limitations, such as the use of multiple assessors, differences in rehabilitation care, and being underpowered to show efficacy, are discussed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain Ischemia; Chorionic Gonadotropin; Cohort Studies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; International Cooperation; Magnetic Resonance Imaging; Male; Middle Aged; Nervous System Diseases; Outcome Assessment, Health Care; Recombinant Proteins; Severity of Illness Index; Stroke; Time Factors; Tomography Scanners, X-Ray Computed; Treatment Outcome; Young Adult

Neonates undergoing complex congenital heart surgery have a significant incidence of neurologic problems. Erythropoietin has antiapoptotic, antiexcitatory, and anti-inflammatory properties to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full-term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety and indicate efficacy.. Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin or placebo. Neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development III was performed at age 12 months.. Fifty-nine patients received the study drug. Safety profile, including magnetic resonance imaging brain injury, clinical events, and death, was not different between groups. Three patients in each group died. Forty-two patients (22 in the erythropoietin group and 20 in the placebo group; 79% of survivors) returned for 12-month follow-up. In the group receiving erythropoietin, mean Cognitive Scale scores were 101.1 ± 13.6, Language Scale scores were 88.5 ± 12.8, and Motor Scale scores were 89.9 ± 12.3. In the group receiving placebo, Cognitive Scale scores were 106.3 ± 10.8 (P = .19), Language Scores were 92.4 ± 12.4 (P = .33), and Motor Scale scores were 92.6 ± 14.1 (P = .51).. Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups; however, this pilot study was not powered to definitively address this outcome. Lessons learned suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population.

Topics: Cardiac Surgical Procedures; Erythropoietin; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Nervous System Diseases; Neuroprotective Agents; Prospective Studies; Single-Blind Method

Erythropoietin has been reported to possess neuroprotective properties in animal studies. No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight (ELBW) infants treated with recombinant human erythropoietin (rEpo) and evaluated it at school age.. Of 200 ELBW infants treated from 1993 to 1998, 171 (86%) survived, and 148 (87%) were followed up to the age of 10 to 13 years. The neurodevelopmental and school outcome of the ELBW infants receiving rEpo treatment for stimulation of erythropoiesis in the first weeks of life (n = 89) was compared to that of untreated children (n = 57). To test for a neuroprotective effect of erythropoietin therapy, analyses of variance (ANOVAs) were conducted with erythropoietin treatment and intraventricular hemorrhage (IVH) as independent variables and Hamburg-Wechsler Intelligence Test for Children-III (HAWIK-III) intelligence quotient (IQ) scores as dependent variables.. The rEpo group scored significantly better than untreated children in the overall developmental assessment (55% vs 39% normally developed, p < 0.05) as well as in the psychological examination (mean composite HAWIK-III IQ score, 90.8 vs 81.3, p < 0.005). The results of ANOVAs show that these differences were ascribable to children with IVH. Whereas those children with IVH treated with rEpo scored significantly better than untreated children (52% vs 6% normally developed, composite HAWIK-III IQ score, 90.3 vs 67.0), treated and untreated children without IVH did not differ in their outcome. The treatment and control groups were comparable in perinatal parameters relevant to prognosis.. The results of our observational study confirm the hypothesis of a neuroprotective effect of rEpo in ELBW infants with IVH. This offers a promising preventative therapeutic option for the treatment of these high-risk infants.

Topics: Adolescent; Age Factors; Analysis of Variance; Chi-Square Distribution; Child; Developmental Disabilities; Erythropoietin; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Intelligence Tests; Longitudinal Studies; Male; Nervous System Diseases; Neuropsychological Tests; Recombinant Proteins; Treatment Outcome; Ultrasonography

Experimental study with rats.. To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI).. Brazil.. Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor-evoked potential test in 42 days. The spinal cord was histologically evaluated.. There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference.. This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI.

Topics: Animals; Disease Models, Animal; Erythropoietin; Evoked Potentials, Motor; Follow-Up Studies; Immunosuppressive Agents; Locomotion; Nervous System Diseases; Rats; Rats, Wistar; Recovery of Function; Spinal Cord Injuries; Statistics, Nonparametric; Tacrolimus; Time Factors

Recent data on newborn animals exposed to anesthetics have raised safety concerns regarding anesthesia practices in young children. Indeed, studies on rodents have demonstrated a widespread increase in brain apoptosis shortly after exposure to sevoflurane, followed by long-term neurologic impairment. In this context, we aimed to evaluate the protective effect of rh-EPO, a potent neuroprotective agent, in rat pups exposed to sevoflurane.. At postnatal day 7, 75 rat pups were allocated into three groups: SEVO + EPO (n = 27) exposed to sevoflurane 2 vol% (0.5 MAC) for 6 h in an air/O2 mixture (60/40) + 5000 UI.kg(-1) rh-EPO IP; SEVO (n = 27) exposed to sevoflurane + vehicle IP; and CONTROL (n = 21) exposed to the mixture without sevoflurane + vehicle IP. Three days after anesthesia (D10), apoptosis was quantified on brain extract with TUNEL method and caspase 3. NGF and BDNF expression was determined by Western blotting. Rats reaching adulthood were evaluated in terms of exploration capacities (object exploration duration) together with spatial and object learning (water maze and novel object test).. Sevoflurane exposure impaired normal behavior in adult rats by reducing the exploratory capacities during the novel object test and impaired both spatial and object learning capacities in adult rats (water maze, ratio time to find platform 3rd trial/1st trial: 1.1 ± 0.2 vs 0.4 ± 0.1; n = 9, SEVO vs CONTROL; P = 0.01). Rh-EPO reduced sevoflurane-induced behavior and learning abnormalities in adult rats (water maze, ratio time to find platform 3rd trial/1st trial: 0.3 ± 0.1 vs 1.1 ± 0.2; n = 9, SEVO + EPO vs SEVO; P = 0.01). Three days after anesthesia, rh-EPO prevented sevoflurane-induced brain apoptosis (5 ± 3 vs 35 ± 6 apoptotic cells·mm(-2) ; n = 6, SEVO + EPO vs SEVO; P = 0.01) and elevation of caspase three level and significantly increased the brain expression of BDNF and NGF (n = 6, SEVO + EPO vs SEVO; P = 0.01).. Six hours of sevoflurane anesthesia in newborn rats induces significant long-term cognitive impairment. A single administration of rh-EPO immediately after postnatal exposure to sevoflurane reduces both early activation of apoptotic phenomenon and late onset of neurologic disorders.

Topics: Anesthetics, Inhalation; Animals; Animals, Newborn; Apoptosis; Blood Gas Analysis; Brain; Cognition Disorders; Epoetin Alfa; Erythropoietin; Maze Learning; Memory; Methyl Ethers; Nervous System Diseases; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Recombinant Proteins; Sevoflurane

Erythropoietin (EPO) has been demonstrated to possess significant neuroprotective effects in stroke. We determined if the nano-drug form of human recombinant EPO (PLGA-EPO nanoparticles [PLGA-EPO-NP]) can enhance neuroprotection at lower dosages versus human recombinant EPO (r-EPO).. Established neonatal rat model of unilateral ischemic stroke was used to compare r-EPO, PLGA-EPO-NP and phosphate-buffered saline, given by daily intraperitoneal injections, followed by infarction volume and Rotarod Performance Test assessment.. PLGA-EPO-NP significantly reduced infarction volumes 72 hours after injury compared with the same concentrations of r-EPO. Functional deficits were significantly reduced by 300 U/kg PLGA-EPO-NP versus controls, with deficit attenuation apparent at significantly lower dosages of PLGA-EPO-NP versus r-EPO.. PLGA-EPO-NP is neuroprotective and beneficial against deficits after brain ischemia, at significantly reduced dosages versus r-EPO.

Topics: Animals; Animals, Newborn; Behavior, Animal; Brain Ischemia; Cerebral Infarction; Erythropoietin; Excipients; Female; Hypoxia, Brain; Injections, Intraperitoneal; Lactic Acid; Male; Nanoparticles; Nervous System Diseases; Neuroprotective Agents; Organ Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Postural Balance; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rotarod Performance Test

Erythropoietin (EPO) has demonstrated neuroprotective effects against traumatic brain injury (TBI), but the underlying mechanisms remain unclear. The signaling pathway of an antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), has been shown in our previous studies to play an important role in protecting mice from TBI-induced secondary brain injury. The present study explored the effect of recombinant human erythropoietin (rhEPO) on cerebral activation of the Nrf2 signaling pathway and secondary brain injury in mice after TBI. Adult male ICR mice were randomly divided into three groups: (1) Sham group; (2) TBI group; and (3) TBI+rhEPO group (n = 12 per group). Closed head injury was performed using Hall's weight-dropping method. rhEPO was administered at a dose of 5,000 IU/kg at 30 min after TBI. Brain samples were extracted at 24 hr after the trauma. The treatment with rhEPO markedly up-regulated the mRNA expression and activities of Nrf2 and its downstream cytoprotective enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1). Administration of rhEPO also significantly ameliorated the secondary brain injury, as shown by decreased severity of neurological deficit, brain edema, and cortical apoptosis. In summary, post-TBI rhEPO administration induces Nrf2-mediated cytoprotective responses in the injured brain, and this may be a mechanism whereby rhEPO improves the outcome following TBI.

Topics: Animals; Apoptosis; Brain Edema; Brain Injuries; Cerebral Cortex; DNA; Erythropoietin; Hand Strength; Humans; In Situ Nick-End Labeling; Male; Mice; NAD(P)H Dehydrogenase (Quinone); Nervous System Diseases; NF-E2-Related Factor 2; Protein Binding; Recombinant Proteins; RNA, Messenger; Signal Transduction

Erythropoietin (EPO) exhibits diverse cellular functions, including neurotrophic, anti-oxidant, anti-apoptotic, and anti-inflammatory effects in non-hematopoietic tissues. This study evaluated whether bone marrow mesenchymal stromal cells (MSCs) transduced with the EPO gene (EPO-MSCs) promoted neural cell survival and improved neurological deficits caused by ischemic stroke. EPO-MSCs stably produced high levels of EPO (10IU/ml) without any alteration of their mesenchymal phenotype. Both EPO transduction and treatment with 10 international units (IU) of recombinant human EPO (rhEPO) provided protection from H(2)O(2)-induced oxidative injury in human bone marrow mesenchymal stromal cells and in SH-SY5Y cells. EPO-MSCs were more protected than were MSCs treated with 10IU rhEPO (10U-MSCs). We also found that the expression of the neurotrophic factors BDNF, PD-ECGF, HGF, SDF-1alpha, and TGF-1beta increased in EPO-MSCs, while only BDNF and TGF-1beta increased in 10U-MSCs. Implantation of EPO-MSCs in an animal model of ischemic stroke significantly improved neurological function and decreased infarct volumes without affecting hematocrit level. An evaluation of the brain tissue 21days after implantation showed that EPO and phosphorylated Akt (a downstream mediator of EPO) increased only in brains implanted with EPO-MSCs. Transduction of the EPO gene into MSCs induced secretion of EPO and various trophic factors that may provide excellent neuroprotective effects in both in vitro and in vivo models of ischemic stroke.

Topics: Animals; Antigens, CD; Brain Infarction; Caspase 3; Cell Death; Cell Line; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Flow Cytometry; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hydrogen Peroxide; Infarction, Middle Cerebral Artery; Lentivirus; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Nerve Growth Factors; Nervous System Diseases; Rats; Statistics, Nonparametric; Tetrazolium Salts; Thiazoles; Transduction, Genetic

Cerebral malaria (CM) in children is associated with a high mortality and long-term neurocognitive sequelae. Both erythropoietin (Epo) and vascular endothelial growth factor (VEGF) have been shown to be neuroprotective. We hypothesized that high plasma and cerebrospinal fluid (CSF) levels of these cytokines would prevent neurological sequelae in children with CM. We measured Epo, VEGF, and tumor necrosis factor in paired samples of plasma and CSF of Kenyan children admitted with CM. Logistic regression models were used to identify risk and protective factors associated with the development of neurological sequelae. Children with CM (n = 124) were categorized into three groups: 76 without sequelae, 32 with sequelae, and 16 who died. Conditional logistic regression analysis matching the 32 patients with CM and neurological sequelae to 64 patients with CM without sequelae stratified for hemoglobin level estimated that plasma Epo (>200 units/liter) was associated with >80% reduction in the risk of developing neurological sequelae [adjusted odds ratio (OR) 0.18; 95% C.I. 0.05-0.93; P = 0.041]. Admission with profound coma (adjusted OR 5.47; 95% C.I. 1.45-20.67; P = 0.012) and convulsions after admission (adjusted OR 16.35; 95% C.I. 2.94-90.79; P = 0.001) were also independently associated with neurological sequelae. High levels of Epo were associated with reduced risk of neurological sequelae in children with CM. The age-dependent Epo response to anemia and the age-dependent protective effect may influence the clinical epidemiology of CM. These data support further study of Epo as an adjuvant therapy in CM.

Topics: Africa; Child, Preschool; Erythropoietin; Female; Humans; Malaria, Cerebral; Male; Nervous System Diseases

We aimed to establish age-related reference values for Erythropoietin (EPO) in cerebrospinal fluid (CSF) and to evaluate concentrations in neurological diseases. CSF and serum EPO was measured in controls with tension-type headache (CTTH), in patients with ALS, dementia and depression using ELISA technique. Stability experiments showed CSF EPO to be stable for two and a half months and over two thaw/freeze cycles. A positive correlation of CSF EPO with age was found (P<0.01). We found a CSF/serum EPO concentration ratio of 0.126, pointing towards an intrathecal synthesis of EPO. The ALS group showed significantly lowered CSF EPO compared to age-matched CTTH (P<0.012), whereas the dementia and depression group showed no significant differences compared to CTTH.The establishment of age-related reference values in a large cohort of controls will improve the interpretation of future CSF EPO evaluations in neurological diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Depression; Erythropoietin; Humans; Middle Aged; Nervous System Diseases; Reference Values; Tension-Type Headache

Despite effective antibiotic treatment, neuronal injury is frequent among children and adults with bacterial meningitis resulting in a high rate of death and neurologic sequelae. The hematopoietic cytokine erythropoietin (EPO) provides neuroprotection in models of acute and chronic neurologic diseases. We studied whether recombinant EPO (rEPO) reduces neuronal damage in a rabbit model of Escherichia coli meningitis. Inflammation within the central nervous system (CNS) was monitored by measurement of bacterial load, pleocytosis, protein, and lactate in the cerebrospinal fluid (CSF). Neuronal damage was measured by quantification of the density of apoptotic neurons in the hippocampal dentate gyrus and the concentration of the global neuronal destruction marker neuron-specific enolase (NSE) in CSF. To increase clinical relevance, rEPO was applied as adjunctive therapy from the beginning of antibiotic therapy 12 h after infection. EPO treatment applied as an intravenous injection at a dose of 1000 IU/kg body weight resulted in plasma concentrations of 6993 +/- 1406 mIU/mL, CSF concentrations of 1291 +/- 568 mIU/mL, and a CSF-to-plasma ratio of 0.18 +/- 0.07 (mean +/- SD) 6 h after injection. Under these treatment conditions, no anti-inflammatory or neuroprotective effect of EPO was observed. "

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apoptosis; Dentate Gyrus; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Injections, Intravenous; Meningitis, Escherichia coli; Nervous System Diseases; Neurons; Neuroprotective Agents; Phosphopyruvate Hydratase; Rabbits; Recombinant Proteins; Severity of Illness Index; Time Factors

Topics: Animals; Clinical Trials as Topic; Drug Design; Erythropoietin; Humans; Ligands; Mental Disorders; Nervous System Diseases; Neuroprotective Agents; Receptors, Erythropoietin; Recombinant Proteins; Stroke

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

Topics: Animals; Apoptosis; Binding Sites; Cells, Cultured; Diabetic Neuropathies; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Ligands; Mice; Mice, Inbred C3H; Mutagenesis; Nervous System Diseases; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Spinal Cord Compression; Stroke; Structure-Activity Relationship