losartan-potassium and Cognition-Disorders

The purpose of this study is to systematically review the efficacy and safety of adjunctive erythropoietin (EPO) in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on randomized controlled trials (RCTs).. Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment.. Four RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria. Adjunctive EPO could improve schizophrenia-related cognitive performance. In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo. In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression.. This preliminary study found that adjunctive EPO appears to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major adverse effects observed. Further higher quality RCTs with larger samples are needed to confirm the findings.. CRD42017058094.

Topics: Bipolar Disorder; Cognition Disorders; Depressive Disorder, Major; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates.. To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs).. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources.. RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age.. Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment.. Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81),. Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.

Topics: Cognition Disorders; Developmental Disabilities; Erythropoietin; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Neuroprotection; Randomized Controlled Trials as Topic; Recombinant Proteins

Prematurity remains the major cause of neonatal morbidity and mortality, with 15 million preterm births occurring worldwide in 2010. Infants born less than 37 weeks gestation are at high risk of abnormal neurodevelopmental outcomes, given that the central nervous system is extremely sensitive to an abnormal intra- and extra-uterine environment. Children born preterm have multiple neurodevelopmental sequelae involving dynamic and complex cognitive deficits. Former preterm infants have difficulty with each domain of cognition, including executive function, language, learning and memory, complex attention, perceptual-motor function and social cognition when compared to children born at term. Although deficits are not always severe, even mild delays can be impactful, resulting in a spectrum of outcomes from difficulties in school to an inability to lead an independent adult life. Here, we review current literature on the cognitive outcomes of infants born preterm with a focus on how specific disruption in crucial neurodevelopmental pathways render these children vulnerable to dynamic deficits in cognition as they mature. Further, we highlight promising therapies and intervention strategies aimed at mitigating these deficits, including the use of erythropoietin. With an increasing number of preterm infants surviving, understanding developmental deficits will allow therapies to be developed and optimized, in order to ensure the best outcome for this vulnerable patient population.

Topics: Cognition; Cognition Disorders; Developmental Disabilities; Erythropoietin; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

Various studies highlight cognitive impairments in cancer patients. This paper proposes a review of longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce these cognitive impairments. Longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce cognitive impairments in adult cancer patients and published between 1993 and 2013 were identified, with the exception of studies that implied patients suffering from CNS tumor or metastasis. Pharmacological interventions (n = 11) suggested the positive impact of modafinil on memory and executive functions. Non-pharmacological interventions (n = 10) suggested the positive impact of cognitive revalidation and stimulation programs, psycho-education and meditation on several memory, attentional and executive objective as well as subjective functions. Non-pharmacological interventions show more significant cognitive benefits than pharmacological interventions. Some longitudinal controlled studies support the usefulness of interventions aiming to reduce cognitive impairments in cancer patients. Further studies should evaluate the effectiveness of programs combining technics aiming to reduce cognitive impairments and psychotherapeutic technics aiming to support patients' coping with illness.

Topics: Adult; Benzhydryl Compounds; Case-Control Studies; Central Nervous System Stimulants; Cognition; Cognition Disorders; Darbepoetin alfa; Donepezil; Erythropoietin; Estradiol; Executive Function; Female; Humans; Indans; Longitudinal Studies; Male; Meditation; Methylphenidate; Modafinil; Neoplasms; Piperidines

Recent advances in understanding the cellular and molecular basis of psychiatric illnesses have shed light on the important role played by trophic factors in modulating functional parameters associated with disease causality and drug action. Disease mechanisms are now thought to involve multiple cell types, including neurons and endothelial cells. These functionally distinct but interactively coupled cell types engage in cellular cross talk via shared and common signaling molecules. Dysregulation in their cellular signaling pathways influences brain function and alters behavioral performance. Multifunctional trophic factors such as VEGF and EPO that possess both neurotrophic and angiogenic actions are of particular interest due to their ability to rescue structural and plasticity deficits in neurons and vasculature. Obtaining insight into the behavioral, cellular and molecular actions of multi-functional trophic factors has the potential to open new and transformative therapeutic approaches.

Topics: Animals; Antidepressive Agents; Astrocytes; Behavior, Animal; Biomimetics; Cognition Disorders; Depression; Disease Models, Animal; Endothelial Cells; Erythropoietin; Humans; Neurons; Vascular Endothelial Growth Factors

This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms 'erythropoietin AND (psychotic disorders OR schizophrenia)'. Seventy-eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood-brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.

Topics: Blood-Brain Barrier; Cognition Disorders; Erythropoietin; Humans; Inflammation; Neurogenesis; Neuroprotective Agents; Oxidative Stress; Schizophrenia

Neurocognitive dysfunction is a common postoperative complication exacerbated by cardiopulmonary bypass triggering a systemic inflammatory response. This clinical column focuses on the up-regulation of endogenous erythropoietin related to neurological inflammation and the use of recombinant erythropoietin as a neuroprotective pharmacotherapeutic agent.

Topics: Cardiac Surgical Procedures; Cognition Disorders; Erythropoietin; Hematinics; Humans; Hypoxia; Inflammation; Recombinant Proteins

The Standards, Options and Recommendations on the use of erythropoietin in cancer patients are recalled. The recent literature is analysed and allows some further comments to the SOR. Medico-economic aspects, new schedules of administration, extra-hematologic virtues of erythropoietin and its impact on cancer outcomes are debated.

Topics: Adult; Anemia; Brain; Child; Cognition Disorders; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Heart; Hematinics; Humans; Medical Oncology; Practice Guidelines as Topic; Recombinant Proteins

Anemia is highly prevalent in patients with lung cancer, often occurring at baseline and frequently exacerbated as a result of treatment with platinum-based chemotherapy. Anemia has been shown to have a negative effect on quality of life in patients with lung cancer, and additional data indicate that decreases in hemoglobin in these patients are associated with impaired survival. Multiple clinical studies have demonstrated that treatment of anemia with erythropoietic agents in patients with lung cancer results in a significant increase in hemoglobin, decrease in transfusions, and improvement in quality of life. Ongoing research is evaluating whether erythropoietic therapy can reduce cognitive impairment associated with lung cancer, cytotoxic therapy, and anemia. Despite the known adverse effects of anemia and the established benefits of erythropoietic therapy in anemic patients with lung cancer, more than half of these patients do not receive any anemia treatment. The purpose of this review is to report results of the European Cancer Anaemia Survey that describe the prevalence of anemia in patients with lung cancer, to review the major studies evaluating the clinical outcomes of erythropoietic therapy in patients with lung cancer, to discuss the recent safety concerns regarding the use of erythropoietic agents in patients with cancer treated to high hemoglobin levels, and to describe various novel therapeutic applications of erythropoietic agents in lung cancer.

Topics: Anemia; Antineoplastic Agents; Cognition Disorders; Erythropoietin; Humans; Lung Neoplasms; Quality of Life; Survival Rate

Neuropsychiatric side effects are common with interferon-based therapy for chronic hepatitis C, and their prompt recognition and management is essential to effective patient care. Depression induced by interferon has been a significant cause of early treatment discontinuation in clinical trials. The need to monitor for and treat interferon-induced depression is well established, but whether to use antidepressants prophylactically remains controversial. Nonetheless, clinicians should maintain a low threshold for antidepressant therapy. Other significant neuropsychiatric side effects include anxiety, hypomania or mania, fatigue, and cognitive dysfunction. These can be additional sources of patient distress during interferon therapy and require appropriate intervention through patient education, psychotropic medications, support, and behavioral techniques.

Topics: Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Antiviral Agents; Anxiety; Bipolar Disorder; Clinical Trials as Topic; Cognition Disorders; Comorbidity; Depression; Erythropoietin; Fatigue; Hepatitis C, Chronic; Humans; Interferons; Mental Disorders; Psychotropic Drugs; Recombinant Proteins; Risk Factors; Substance-Related Disorders

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant chemotherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for chemotherapy-related anemia. Treatment with epoetin alfa also improved health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In animal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.

Topics: Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cognition Disorders; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Quality of Life; Rats; Recombinant Proteins

Cancer-related anemia often develops from the infiltration of marrow by malignant cells, impaired hemoglobin (Hb) production related to chemotherapy or radiation therapy, iron deficiency, or low endogenous erythropoietin levels. Patients with cancer-related anemia may experience cognitive dysfunction including decreased mental alertness, poor concentration, and memory problems. Anemia-mediated cerebral hypoxia may cause symptoms such as headache, vertigo, tinnitus, and dizziness. These symptoms often are exacerbated in the elderly patient with cancer and related to underlying low Hb concentrations. Restoring Hb levels via the administration of iron supplements, blood transfusions, or, more recently, erythropoiesis-stimulating therapy (epoetin alfa) results in significant improvement of cognitive function. The use of epoetin alfa as a treatment option for patients with chemotherapy-associated anemia and an Hb concentration less than 10 g/dL has been recommended by the American Society of Clinical Oncology and the American Society of Hematology. Erythropoiesis-stimulating therapies are a promising treatment option for cancer-related anemia that may improve cognitive function and quality of life for patients with cancer.

Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Cognition Disorders; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Recombinant Proteins

Erythropoietin, in its standard role for the treatment of anemia, is often mechanistically regarded simply as increasing blood oxygen-carrying capacity and hence decreasing tumor hypoxia. In reality, erythropoietin (a member of the cytokine superfamily) is expressed in a multitude of tissues/cell types including erythroid and cancer cells, and the liver and central nervous system. Erythropoietin expression is induced by hypoxia-inducible factor-1, which itself is induced during hypoxia. Whereas it has no endogenous tyrosine kinase activity of its own, erythropoietin, via constitutively associated JAK2, can activate several signaling pathways including STAT5, RAS, and phosphoinositol 3-kinase. An increased understanding of these pathways is already opening up new clinical indications, particularly in terms of oncology and neurology. Current arrays/molecular endpoint studies in clinical trials should identify key components of the particular signaling pathways that will guide further use in the development of both better synergistic therapies as well as new molecular targets.

Topics: Anemia; Cognition Disorders; Erythropoietin; Humans; Neoplasms; Oligonucleotide Array Sequence Analysis; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Topics: Adaptation, Physiological; Anemia; Cardiovascular System; Cognition Disorders; Drug Costs; Epoetin Alfa; Erythropoietin; Exercise; Heart Failure; Hematocrit; Hemodynamics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Renal Dialysis; Risk; Thrombophilia; Treatment Outcome

Impaired cognitive function, a common morbidity associated with end-stage renal disease (ESRD), can hinder a patient's ability to work with the dialysis team and live well. A combination of adequate dialysis and correction of anemia with Epoetin alfa can mitigate the neurobehavioral syndrome associated with ESRD and lead to improved cognition. In the presence of suspected cognitive impairment, nursing management should emphasize techniques that provide individualized, innovative, and ongoing reinforcement of treatment goals and outcomes to improve patients' overall quality of life.

Topics: Anemia; Cognition Disorders; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Quality of Life; Renal Dialysis

The uremia of chronic renal failure (CRF) can alter brain electrophysiology and cognitive function, even in the well-dialyzed patient. The effect of uremia on brain function can be assessed by electrophysiologic techniques such as electroencephalogram (EEG), sensory-evoked potentials (EPs), and cognitive event-related potentials (ERPs), and through a series of neuropsychologic tests. Five tests have been used clinically to measure the speed and efficiency of cognitive functioning and include the following: Number Cancellation, Trailmaking Test, Symbol Digit Modalities Test, Rey Auditory Verbal Learning Test, and Controlled Oral Word Association Test. Test performance by patients with CRF is often below that of healthy controls. Auditory ERPs, a sensitive indicator of subtle changes in central nervous system (CNS) function in uremia, result in the generation of a P300 component wave that varies in amplitude and latency with patient variables such as attention and effort. Although dialysis tends to normalize P300 latencies, the waves remain somewhat prolonged in most patients. The anemia often observed in patients receiving chronic dialysis appears to aggravate uremic encephalopathy. This effect can be reversed when anemia is corrected following administration of recombinant human erythropoietin (epoetin). Improvement in P300 amplitudes, and, in some cases, decreases in P300 latencies correlated well with epoetin-induced increases in hematocrit levels. With the correction of anemia, that component of brain dysfunction not attributable to retention of uremic toxins can largely be reversed.

Topics: Anemia; Brain; Cognition Disorders; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

High-dose recombinant human erythropoietin (rhEpo) has been shown to improve cognitive performance in both healthy volunteers and in patients suffering from diseases affecting the brain. The aim of this study was to examine whether administration of low-dose and even micro-dose rhEpo improves cognitive performance in healthy volunteers.. We enrolled 25 healthy volunteers in a double-blind, randomised, placebo-controlled study to receive either low-dose rhEpo (n = 8, 60 IU/kg/week), micro-dose rhEpo (n = 9, 20 IU/kg/week), or saline (n = 8) for four weeks. Two cognitive performance-tests, the Raven Standard Progressive Matrices (Raven) and the Number Finder (NUFI), were performed during the first and last day of the study period. Semi-structured interviews were conducted weekly and were coded according to a scale.. Subjects receiving micro-dose rhEpo improved significantly measured by the Raven score (p = 0.04), and subjects receiving low-dose rhEpo treatment improved significantly measured by the NUFI score (p = 0.047), whereas no improvement was found in experienced cognitive performance in any of the groups. We found no significant difference in either Raven, NUFI or self-reported results between the groups.. In this small study, we found no significant effect of low-dose or micro-dose rhEpo on visual attention, cognitive performance in complex cognitive tasks or self-experienced cognitive performance compared with placebo.. The Aase and Ejnar Danielsen's Foundation. Danish Ministry of Science, Innovation and Higher Education.. ClinicalTrials.gov identifier: NCT03093506.

Topics: Adult; Cognition; Cognition Disorders; Double-Blind Method; Erythropoietin; Female; Healthy Volunteers; Humans; Male; Recombinant Proteins; Young Adult

Numerous animal studies and clinical trials have demonstrated that erythropoietin (EPO) has therapeutic effects in ischemic and degenerative diseases. However, few clinical trials have investigated the effect of EPO in Parkinson's disease (PD) patients. This study was an exploratory pilot study to investigate the effects of recombinant human EPO (rhEPO) on motor and non-motor symptoms (NMS) in PD patients.. A total of 26 PD patients at the Hanyang University Hospital were enrolled in the study. The participants were randomly assigned to rhEPO and placebo groups. The rhEPO group was infused intravenously (40,000 IU each) twice a week for 5 weeks. Clinical improvement was estimated using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), the NMS Scale (NMSS) and the 39-Item Parkinson's Disease Questionnaire (PDQ-39). [(18)F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) photon emission tomography (PET) scanning was performed on each participant at baseline and again after 12 months.. The rhEPO administration significantly improved the NMSS and PDQ-39 scores at 12 months. The UPDRS-III, which reflects motor function, did not change significantly after the rhEPO treatment. With the NMSS, the domains of cardiovascular autonomic function, sleep/fatigue, mood/cognition and attention/memory showed significant changes. None of the participants experienced any serious adverse effects.. We found that rhEPO had beneficial effects on NMS but not on motor function. Dopaminergic refractory NMS, such as cardiovascular autonomic dysfunction and cognition, showed improvement after the administration of rhEPO. Our results suggest that rhEPO might be a good candidate for the treatment of NMS in PD patients.

Topics: Aged; Aged, 80 and over; Brain; Cognition Disorders; Erythropoietin; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Single-Blind Method; Sleep Wake Disorders; Surveys and Questionnaires; Time Factors; Tomography, X-Ray Computed; Tropanes; Vascular Diseases

Available drug treatments for bipolar disorder fail to reverse patients' cognitive deficits. Erythropoietin has neurotrophic actions and aids neurocognitive function. The aim of the study was to investigate the potential of erythropoietin to treat cognitive dysfunction in bipolar disorder.. Patients with an ICD-10 diagnosis of bipolar disorder in remission were randomized, with stratification by age and gender, to receive 8 weekly erythropoietin (40,000 IU) or saline (sodium chloride [NaCl], 0.9%) infusions in a double-blind, parallel-group design. The first patient was randomized in September 2009 and last assessment was completed in October 2012. Patients were assessed at baseline and at weeks 9 and 14. The primary outcome was change in verbal memory indexed by the total words recalled across Rey Auditory Verbal Learning Test learning trials (I-V) from baseline to week 9; secondary outcomes were sustained attention and facial expression recognition; and tertiary outcomes were attention, executive function, subjective cognitive function, and mood. Analysis was by intention to treat, using repeated-measures analysis of covariance adjusted for stratification variables and mood. The statistical threshold for which results were considered significant was P ≤ .05 (2-tailed).. 44 patients were randomized; given 1 dropout after baseline, results were analyzed for 43 patients (erythropoietin: n = 23; saline: n = 20). There was no significant improvement of verbal memory in erythropoietin versus saline groups (P = .10). However, erythropoietin enhanced sustained attention (P = .001), recognition of happy faces (P = .03), and speed of complex information processing across learning, attention, and executive function (P = .01). These effects occurred in absence of changes in simple reaction times or mood (P values ≥ .16) and were maintained after red blood cell normalization.. This is the first trial investigating erythropoietin to treat cognitive dysfunction in bipolar disorder. The findings highlight erythropoietin as a candidate treatment for deficits in attention and executive function in bipolar disorder.. ClinicalTrials.gov identifier: NCT00916552.

Topics: Adolescent; Adult; Aged; Attention; Bipolar Disorder; Cognition Disorders; Double-Blind Method; Erythropoietin; Executive Function; Female; Humans; Learning; Male; Mental Recall; Middle Aged; Reaction Time; Recognition, Psychology; Recombinant Proteins; Young Adult

Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial.. We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score.. Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome.. This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy.

Topics: Brain; Child, Preschool; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Treatment Outcome

Neurocognitive dysfunction complicates coronary artery bypass surgery. Erythropoietin may be neuroprotective. We sought to determine whether human recombinant erythropoietin would reduce the incidence of neurocognitive dysfunction after surgery.. We randomly assigned 32 elective first-time coronary artery bypass graft patients to receive placebo or 375 U/kg, 750 U/kg, or 1500 U/kg of recombinant human erythropoietin divided in 3 daily doses, starting the day before surgery. Primary outcomes were feasibility and safety, and secondary outcomes were neurocognitive dysfunction at discharge and 2 months.. All subjects were male, mean age 60 years (range 46 to 73). No significant differences were found in pump time, cross-clamp time, or hospital length of stay. Mortality and pure red cell aplasia were not observed. One patient in the 375 U/kg group had ST changes compatible with myocardial injury immediately postoperative, but no other thrombotic complications were observed. Neurocognitive dysfunction occurred in 21/32 (66%) of patients at discharge and 5/32 (16%) at 2 months. Neurocognitive dysfunction at discharge by group was: placebo 6/8 (75%), 375 U/kg 4/8 (50%), 750 U/kg 6/8 (75%), and 1500 U/kg 5/8 (63%). Neurocognitive dysfunction at 2 months by group was: placebo 3/8 (38%), 375 U/kg 1/8 (13%), 750 U/kg 1/8 (13%), and 1500 U/kg 0/8 (0%). Neurocognitive dysfunction at 2 months for erythropoietin at any dose was 2/24 (8.3%) versus 3/8 (38%) for placebo (P=0.085).. This study demonstrates feasibility and safety for the use of human recombinant erythropoietin as a neuroprotectant in coronary artery bypass graft surgery. A trend in the reduction of neurocognitive dysfunction at 2 months was associated with erythropoietin use. A multicenter randomized controlled trial is warranted.

Topics: Aged; Cognition Disorders; Coronary Artery Bypass; Double-Blind Method; Erythropoietin; Feasibility Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neuroprotective Agents; Postoperative Complications; Recombinant Proteins

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

Topics: Adult; Chronic Disease; Cognition; Cognition Disorders; Erythropoietin; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Growth Factors; Neuronal Plasticity; Placebo Effect; Recombinant Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Treatment Outcome

It is believed widely that chemotherapy-induced cognitive impairment occurs in a subgroup of patients with breast cancer. However, recent reports have provided no evidence that chemotherapy affects cognition. In this study, the authors questioned whether cognitive compromise in patients with breast cancer is attributable to chemotherapy. In addition, the effects of therapy-induced menopause and of the erythropoiesis-stimulating factor darbepoetin alpha on cognitive performance were assessed.. A battery of neuropsychological tests was used to assess cognitive performance in 101 patients with breast cancer before neoadjuvant chemotherapy (T1) and toward the end of neoadjuvant chemotherapy (T2) with combined epirubicin, paclitaxel, and cyclophosphamide with concomitant darbepoetin alpha. Repeated-measures multiple analyses of variance and a reliable-change approach were used for statistical analyses.. At T1, the group means ranged below the test norms in 5 of 12 cognitive tests. At T2, multiple analyses of variance (MANOVA) indicated a significant overall improvement in the test results (P<.001). After correcting for practice effects, cognitive decline predominated in 27% of patients, whereas improvement predominated in 28% of patients. Cognitive performance was not related significantly to self-reported cognitive problems, anxiety and depression, menopause, or darbepoetin alpha administration.. Even before chemotherapy, a subgroup of patients with breast cancer showed cognitive compromise that was unrelated to anxiety or depression. During chemotherapy, cognitive function remained stable in most patients, improved in a subgroup, and deteriorated in another subgroup. The deterioration may have been caused by side effects of chemotherapy, but it also may have been related to currently unidentified factors that cause prechemotherapy cognitive compromise. Therapy-induced menopause and darbepoetin alpha did not appear to influence cognition.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cognition; Cognition Disorders; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Longitudinal Studies; Menopause; Middle Aged; Neoadjuvant Therapy; Neuropsychological Tests; Prospective Studies

The neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategies have largely failed. However, successful neuroprotection and/or neuroregeneration in MS have not been demonstrated yet. Encouraged by the multifaceted neuroprotective effects of recombinant human erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were (i) evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and (ii) collecting first evidence of potential efficacy on clinical outcome parameters. Eight MS patients, five randomly assigned to high-dose (48,000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale (EDSS), and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.

Topics: Adult; Aged; Cognition Disorders; Disability Evaluation; Dose-Response Relationship, Drug; Erythropoietin; Evoked Potentials, Motor; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Neuroprotective Agents; Neuropsychological Tests; Psychomotor Performance; Recombinant Proteins; Treatment Outcome; Walking

Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants.. Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes.. Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL.. Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome.

Topics: Blood Transfusion; Child Development; Cognition Disorders; Developmental Disabilities; Erythropoietin; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Infant, Very Low Birth Weight; Male; Predictive Value of Tests; Psychomotor Disorders

Impaired cognition, fatigue, and diminished quality of life (QOL) are commonly associated with breast cancer chemotherapy. This randomized, double-blind, placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood, and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy. Patients were randomized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks. Cognitive function was assessed by Executive Interview (EXIT25) and Clock Drawing Tasks; mood by Profile of Mood States; anemia-related symptoms, including fatigue, by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale; and QOL by Linear Analog Scale Assessment. Ninety-four patients were evaluable for efficacy and safety. Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 +/- 3.3; the mean change was 0.3 +/- 2.4 in the placebo group (a negative change indicates improved executive function). There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment. Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy. Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo. Epoetin alfa therapy was well tolerated. These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy.

Topics: Adult; Affect; Aged; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Double-Blind Method; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Injections, Subcutaneous; Middle Aged; Neoadjuvant Therapy; Placebos; Quality of Life; Recombinant Proteins; Treatment Outcome

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Intravenous recombinant human erythropoietin (Eprex Cilag) was used in 28 hemodialyzed children, treated in 3 French paediatric centers, from November 1989 to November 1990. Transfusion dependency disappeared in all cases: the number of transfusions decreased from 7.3 unit/patient/year to 0.6 unit/pt/year. The mean haemoglobin concentration for the whole group increased from 6.6 +/- 0.8 g/dl, to 9.2 +/- 1.2 at 6 months and 9.7 +/- 0.7 g/dl at 1 year. Twenty-two out of 28 children reached the target haemoglobin value of 9.6 g/dl (6 mmol/dL) within a mean time of 16.5 weeks. Poor responses were due to either a premature withdrawal of treatment because of renal transplantation, or too low a dosage for the age. The study showed indeed that the dose requirement was significantly dependent on physical development: the mean dosage required to maintain haemoglobin concentration at the target value was 300 U/kg/week in children weighing less than 20 kg, 222 U/kg/week in 20-30 kg children, and 135 U/kg/week in those weighing more than 30 kg (p = 0.02). The only complication was an increase in blood pressure, observed in 43% of cases. The increase of anti-hypertensive medication was always successful in controlling blood pressure, and hospitalization was required in only one case. The improvement in general condition was obvious, and in several cases, the cognitive abilities seemed to improve. The growth deficit remained unchanged.

Topics: Adolescent; Anemia; Appetite; Blood Transfusion; Body Weight; Child; Child, Preschool; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Female; France; Growth Disorders; Hemoglobins; Humans; Hypertension; Immunologic Factors; Infant; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Treatment Outcome

There are conflicting reports concerning the association of motor disabilities with increased risk of mental disorders. This investigation will provide a good understanding about defining the possible association between tremor and risk of anxiety and cognitive alterations. Beside, a secondary objective of the current study was to determine the effect of erythropoietin (EPO) on harmaline-induced motor and cognitive impairments. Male Wistar rats were used for the present study. The animal model of Esential tremor (ET) was established by the intraperitoneal injection of harmaline. EPO (5000 U/kg, i.p.) administered to the animals 1 h prior to harmaline injection. Exploratory, balance, anxiety related behaviors and cognitive function were assessed using footprint, open field, wire grip, rotarod and shuttle box tests. Findings demonstrated EPO ameliorated tremor scores that was induced by harmaline. Harmaline impaired cognitive functions of the treated rats, whereas EPO showed a promising effect against the cognitive impairments induced by harmaline. EPO can be offered as a potential neuroprotective agent in the treatment of patients with ET that manifest locomotor and cognitive impairments; however, further studies are needed to clarify the exact mechanisms.

Topics: Animals; Anxiety; Biomechanical Phenomena; Cognition Disorders; Erythropoietin; Essential Tremor; Exploratory Behavior; Gait; Harmaline; Male; Neuroprotective Agents; Postural Balance; Rats, Wistar

There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.

Topics: Administration, Oral; Animals; Behavior, Animal; Brain; Brain Injuries; Cognition Disorders; Erythropoietin; Glycine; Hypoxia-Inducible Factor 1, alpha Subunit; Infarction, Middle Cerebral Artery; Male; Motor Activity; Organ Specificity; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Quinolones; Rats, Sprague-Dawley; RNA, Messenger; Sensation; Stroke; Vascular Endothelial Growth Factor A

Topics: Brain; Cognition; Cognition Disorders; Erythropoietin; Genetic Testing; Humans; Infant, Newborn; Infant, Premature; Magnetic Resonance Imaging; Male; Randomized Controlled Trials as Topic

Sepsis-associated encephalopathy (SAE) is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology underlying SAE is poorly understood and the pharmacologic treatment is lacking. The purpose of the present study was to investigate the effects of erythropoietin (EPO) on cognitive impairments in an animal model of SAE induced by peripheral administration of lipopolysaccharide (LPS). Mice were randomly divided into the sham + vehicle, sham + EPO, LPS + vehicle, and LPS + EPO groups. EPO was administrated 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed on days 6 and 7 with open field and fear conditioning tests, respectively. The survival rate was estimated by the Kaplan-Meier method. The levels of proinflammatory responses, oxidative stress, and apoptosis-related markers were measured in the hippocampus at the indicated time points. The synaptic morphometry changes in the CA1 region were observed with transmission electron microscopy. Our results showed that LPS administration resulted in high mortality rate and cognitive impairments, which were accompanied by increased expressions of interleukin-1β, malondialdehyde, cleaved caspase-3, and abnormal synaptic morphometry changes in the hippocampus. Notably, EPO treatment reversed the cognitive impairments and rescued the brain pathology induced by LPS administration. In conclusion, our data suggested that treatment with EPO reduced the mortality rate and ameliorated cognitive impairments in an animal model of SAE.

Topics: Animals; Apoptosis; Cognition Disorders; Erythropoietin; Injections, Intraperitoneal; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Treatment Outcome

Topics: Bipolar Disorder; Cognition Disorders; Erythropoietin; Female; Humans; Male

Topics: Bipolar Disorder; Cognition Disorders; Erythropoietin; Female; Humans; Male

Pneumococcal meningitis is characterized by a severe inflammatory reaction in the subarachnoid and ventricular space of the brain, disruption of the blood-brain barrier, hearing loss, and neurologic sequelae in as many as 27% of surviving patients. Several experimental studies have shown that erythropoietin (EPO) and its receptor are expressed in the central nervous system and have neuroprotective properties through the inhibition of apoptosis, as well as anti-inflammatory, antioxidant, angiogenic, and neurotrophic effects. In the current study, we demonstrated the effect of erythropoietin (EPO) on lipid peroxidation, protein carbonylation, superoxide dismutase (SOD), catalase (CAT), myeloperoxidase (MPO), and behavioral parameters in rats with pneumococcal meningitis. EPO decreased lipid peroxidation and protein carbonylation, and it prevented protein degradation in the hippocampus and frontal cortex. MPO activity was decreased, and both SOD and CAT activity were increased in the first 6 hours after pneumococcal meningitis induction. Novel object recognition memory was impaired in the meningitis group; however, adjuvant treatment with EPO prevented memory impairment during both the short- and long-term retention tests. The meningitis group showed no difference in motor and exploratory activity between training and test sessions in the open-field task, which indicates that habituation memory was impaired; however, adjuvant treatment with EPO prevented habituation memory impairment. Although there are some limitations with respect to the animal model of pneumococcal meningitis, this study suggests that adjuvant treatment with EPO contributed to decreased oxidative stress and prevented cognitive impairment.

Topics: Animals; Behavior, Animal; Catalase; Cognition Disorders; Erythropoietin; Lipid Peroxidation; Meningitis, Pneumococcal; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase

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 is a hematopoietic cytokine factor with various biological effects and its receptors are expressed in the central nervous system, which helps in normal brain development and exerts neuroprotection in different models of brain injury. The present study was designed to evaluate the neuroprotective role of erythropoietin in Aroclor 1254 induced oxidative stress in mice. Neurotoxicity was induced by Aroclor 1254 (10 mg/kg bw/day). Erythropoietin was administered simultaneously with Aroclor 1254 for 14 days in co-treatment groups and administered before induction of neurotoxicity for 7 days in case of pretreatment groups. To assess the behavioural parameters in observation with learning and memory, open field and Y-maze were employed. Acetylcholinesterase, glutamate, antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) were estimated in brain tissue and corticosterone in plasma to evaluate the intensity of oxidative signalling in brain. Triglycerides and total cholesterol were estimated in plasma. Both doses of erythropoietin (500 and 1000 IU/kg) pretreatment and co-treatment, (i) significantly increased the habituation memory and percentage alteration which are indicative of the cognitive improvement, (ii) attenuated the Aroclor 1254 induced rise in acetylcholinesterase activity, corticosterone, triglycerides and total cholesterol, (iii) increased the glutamate and antioxidant enzyme levels. These results indicate that erythropoietin protects against Aroclor 1254 induced neurotoxicity and improves the cognitive function and that this cytokine could be a promising therapeutic agent for stress induced neurodegeneration.

Topics: Animals; Antioxidants; Behavior, Animal; Brain; Chlorodiphenyl (54% Chlorine); Cholesterol; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Glutamic Acid; Male; Maze Learning; Memory; Mice; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidative Stress; Triglycerides

Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia and has been proposed as a potent therapeutic target for cerebral ischemia. However, research on the expression and effects of HIF-1α in subarachnoid hemorrhage (SAH) is limited. The aim of the present study was to investigate the expression of HIF-1α in the hippocampus and its possible protective effect against hippocampal apoptosis and cognitive dysfunction in a rat model of SAH. Seventy-two Sprague-Dawley (SD) rats were randomly divided into the sham group, the SAH+vehicle group, and the SAH+YC-1 group. Immunohistochemical staining and western blotting analyses revealed that the expression of HIF-1α and its downstream effectors, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporter 1 (GLUT1), increased in the hippocampus 48h after the induction of SAH. YC-1 blocked this upregulation. The number of active caspase-3-positive cells and the expression of active caspase-3 in the hippocampus significantly increased in the YC-1 group relative to the vehicle group. A cell death assay further revealed that DNA fragmentation was significantly increased at 48h in the YC-1 group compared with the vehicle group. In Morris water maze (MWM) tests, the YC-1 group showed increased escape latency times and distances as well as reduced time spent and distance traveled in the target quadrant. These results indicate that hippocampal apoptosis increased and cognitive function deteriorated when HIF-1α was inhibited, suggesting that HIF-1α has a neuroprotective effect in SAH and may represent an effective therapeutic target.

Topics: Animals; Apoptosis; Blood Pressure; Caspase 3; Cognition Disorders; Disease Models, Animal; DNA Fragmentation; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Excitatory Amino Acid Transporter 2; Hippocampus; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Male; Maze Learning; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Reaction Time; Subarachnoid Hemorrhage; Vascular Endothelial Growth Factor A

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cognition Disorders; Deoxyguanosine; Depression; Erythropoietin; Growth Hormone-Releasing Hormone; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Learning Disabilities; Lipid Peroxidation; Male; Maze Learning; Mice; Mice, Inbred C57BL; Oxidative Stress; Receptor, IGF Type 1; Sermorelin; Signal Transduction; Sleep

To evaluate long-term outcomes of 60 extremely low birth weight (ELBW) infants treated with or without three injections of high-dose erythropoietin (Epo).. A retrospective analysis of anthropometric and neurodevelopmental outcome data comparing 30 ELBW infants enrolled in a phase I/II study examining the pharmacokinetics of high-dose Epo (500, 1000 and 2500 U/kg × 3 doses) administered to 30 concurrent controls.. Birth characteristics and growth from 4 to 36 months were similar for untreated and Epo-treated patients. Multiple linear regression analysis of neurodevelopmental follow-up scores from 17/25 Epo-treated and 18/26 control infants identified that Epo correlated with improvement of cognitive (R=0.22, P=0.044) and motor (R=0.15, P=0.026) scores. No negative long-term effects of Epo treatment were evident.. Retrospective analysis of the only available long-term follow-up data from ELBW infants given high-dose Epo treatment suggests that Epo treatment is safe and correlates with modest improvement of neurodevelopmental outcomes.

Topics: Brain Diseases; Cognition Disorders; Developmental Disabilities; Erythropoietin; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Pregnancy; Pregnancy Outcome; Retrospective Studies

Carbamylated erythropoietin (CEPO) is attracting widespread interest because of its neuroprotective effects without influencing erythropoiesis. Here we show that CEPO, unlike EPO, does not stimulate erythropoiesis. Both CEPO and EPO inhibit the death/apoptosis of neurons in the hypoxic model of primary neurons and induce neuron proliferation and differentiation in hypoxic mice. Hypoxic mice show apparent memory deficits at 3 and 30 days after hypoxia. The administration of CEPO/EPO significantly improves cognitive and behavioral defects after hypoxic insults. Further investigation shows that CEPO/EPO induces neuron proliferation and differentiation and promotes the generation of choline acetyltransferase (ChAT)(+) neurons in hypoxic mice. Phosphorylated AKT was colabeled with ChAT(+) neurons and coexpressed in bromodeoxyuridine-positive cells, suggesting that the PI3K/AKT pathway may play a pivotal role in CEPO/EPO-cholinergic neuron generation. These results reveal that CEPO/EPO ameliorates hypoxia-induced cognitive and behavioral defects possibly through the generation of ChAT-positive neurons.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Choline O-Acetyltransferase; Cognition Disorders; Erythropoietin; Flow Cytometry; Hypoxia; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents

Septic encephalopathy is characterized by changes in mental status and an increase in neuronal apoptosis. Accumulating evidence has shown that recombinant human erythropoietin (rhEPO) protects brain against ischemia and hypoxia injury. However, whether rhEPO exerts neuroprotective effects on septic encephalopathy remains unclear. We designed the current study to evaluate possible neuroprotection of rhEPO in a model of sepsis.. For this in vitro study, we determined hippocampal neuronal apoptosis by lactate dehydrogenase release, cell counting kit-8 assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining after treatment with lipopolysaccharide. We transfected the signal transducer and activator of transcription 3 (STAT3) short hairpin RNA at 14 d in vitro for 48 h. For the in vivo study, we performed cecal ligation and peroration surgery. We detected the expression of phospho-Janus-activated kinase 2 (JAK2), total JAK2, phospho-STAT3, total STAT3, Bax and Bcl-XL by Western blot, and examined behavior using the Morris water maze.. Treatment with rhEPO reduces apoptosis and increases cell viability in lipopolysaccharide-treated neuronal cultures. In cecal ligation and peroration rats, rhEPO attenuated the inhibition of phospho-JAK2 and phospho-STAT3. In addition, rhEPO enhanced the expression of Bcl-XL, but depressed Bax, which was abolished by additional administration of inhibitor of JAK2/STAT3 signaling 2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide,2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide or (E)-3(6-bromopyridin-2-yl)-2-cyano-N-([S0-1-phenylethyl]acrylamide)in vivo, and was ameliorated by STAT3 short hairpin RNA transfection in vitro. Alternatively, we confirmed the neuronal protective effect of rhEPO by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelingstaining. For the Morris water maze study, rhEPO improved learning and memory disorders without an alternation in locomotor activity.. These results indicated that rhEPO improves brain dysfunction by reducing neuronal apoptosis, and JAK2/STAT3 signaling is likely to be involved. Application of rhEPO may serve as a potential therapy for the treatment of septic encephalopathy.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Brain Diseases; Cecum; Cell Survival; Cognition Disorders; Disease Models, Animal; Endotoxemia; Erythropoietin; Humans; Janus Kinase 2; Learning Disabilities; Ligation; Lipopolysaccharides; Male; Memory Disorders; Neurons; Rats; Rats, Sprague-Dawley; Recombinant Proteins; STAT3 Transcription Factor

Topics: Animals; Cognition Disorders; Erythropoietin; Female; Hematinics; Male; Microtubule-Associated Proteins; Nitric Oxide Synthase

Sepsis is characterized by systemic biochemical alterations including the central nervous system in the early times and cognitive impairment at later times after sepsis induction in the animal model. Recent studies have shown that, besides its hematological activity, erythropoietin (EPO) has cytoprotective effects on various cells and tissues. In order to corroborate elucidating the effects of alternative drugs for sepsis treatment, we evaluated the effects of both acute and chronic EPO treatment on oxidative stress and energetic metabolism in the hippocampus, and cognitive impairment, respectively, after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or sham operation. In the acute treatment, EPO was administered once immediately after CLP induction. The rats were then killed after 6 and 24 h, and the hippocampus was removed for analysis of oxidative stress and energetic metabolism, respectively. Regarding the chronic treatment, EPO was administered once daily until the 4th day after induction. Aversive memory was tested on the 10th day after surgery. It was observed that the acute use of EPO (a single dose) alters the oxidative parameters and energetic metabolism. Chronic use (4 days) reversed cognitive impairment in the sepsis animal model. Mortality rates were attenuated only during chronic treatment.

Topics: Analysis of Variance; Animals; Avoidance Learning; Citrate (si)-Synthase; Cognition Disorders; Creatine Kinase; Disease Models, Animal; Electron Transport; Electron Transport Chain Complex Proteins; Energy Metabolism; Erythropoietin; Inhibition, Psychological; Ligation; Male; Oxidative Stress; Rats; Rats, Wistar; Sepsis; Statistics, Nonparametric; Time Factors

In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction.. IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates.. The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Analysis of Variance; Animals; Cells, Cultured; Cerebral Cortex; Cognition Disorders; Deoxyguanosine; Disease Models, Animal; Embryo, Mammalian; Erythropoietin; Escape Reaction; Gene Expression Regulation; Humans; Hypoxia; Injections, Intraperitoneal; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Memory; Mice; Mice, Inbred C57BL; NADPH Oxidases; Neurons; Phosphopyruvate Hydratase; Sleep Apnea Syndromes; Swimming; Time Factors

To investigate the effects of carbamylated erythropoietin, a modified erythropoietin lacking erythropoietic activity, on brain edema and functional recovery in a model of diffuse traumatic brain injury.. Adult male Wistar rats.. Neurosciences and physiology laboratories.. Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution (traumatic brain injury-saline) or carbamylated erythropoietin (50 μg/kg; traumatic brain injury-carbamylated erythropoietin). A third group received no traumatic brain injury insult (sham-operated).. Three series of experiments were conducted to investigate: 1) the effect of carbamylated erythropoietin on brain edema before and 1 hr after traumatic brain injury using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 10 rats per group), and the phosphorylation level of brain extracellular-regulated kinase-1/-2 was also determined to indicate the presence of an activated cell signaling pathway; 2) the time course of brain edema using magnetic resonance imaging between 4 and 6 hrs postinjury and the gravimetric technique at 6 hrs (n = 10 rats per group); and 3) motor and cognitive function over 10 days post traumatic brain injury, testing acute somatomotor reflexes, adhesive paper removal, and two-way active avoidance (n = 8 rats per group). Compared to traumatic brain injury-saline rats, rats receiving traumatic brain injury-carbamylated erythropoietin showed a significant reduction in brain edema formation at 1 hr that was sustained until 6 hrs when results were comparable with sham-operated rats. This antiedematous effect of carbamylated erythropoietin was possibly mediated through an early inhibition of extracellular-regulated kinase-1/-2 phosphorylation. Compared to traumatic brain injury-saline rats, traumatic brain injury-carbamylated erythropoietin rats showed improved functional recovery of the acute somatomotor reflexes post traumatic brain injury, took less time to remove adhesive from the forelimbs, and showed higher percentages of correct avoidance responses.. Our findings indicate that early posttraumatic administration of carbamylated erythropoietin reduces brain edema development until at least 6 hrs postinjury and improves neurologic recovery. Carbamylated erythropoietin can thus be considered as a potential agent in the treatment of traumatic brain injury-induced diffuse edema.

Topics: Animals; Brain; Brain Edema; Brain Injuries; Cognition Disorders; Erythropoietin; Magnetic Resonance Imaging; Male; Psychomotor Disorders; Rats; Rats, Wistar; Reflex; Time Factors

Sleep disordered breathing (SDB), which is characterized by intermittent hypoxia (IH) during sleep, causes substantial cardiovascular and neurocognitive complications and has become a growing public health problem. SDB is associated with suppression of growth hormone (GH) secretion, the latter being integrally involved in the growth, development, and function of the CNS. Since GH treatment is able to attenuate neurocognitive deficits in a hypoxic-ischemic stroke model, GH, GH receptor (GHR) mRNA expression, and GH protein expression were assessed in rat hippocampus after exposures to chronic sustained hypoxia (CH, 10% O(2)) or IH (10% O(2) alternating with 21% O(2) every 90 s). In addition, the effect of GH treatment (50 μg/kg daily s.c. injection) on erythropoietin (EPO), vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and GLUT-1 mRNA expression and neurobehavioral function was assessed. CH significantly increased GH mRNA and protein expression, as well as insulin-like growth factor-1 (IGF-1). In contrast, IH only induced a moderate increase in GH mRNA and a slight elevation in GH protein at day 1, but no increases in IGF-1. CH, but not IH, up-regulated GHR mRNA in the hippocampus. IH induced marked neurocognitive deficits compared with CH or room air (RA). Furthermore, exogenous GH administration increased hippocampal mRNA expression of IGF-1, EPO, and VEGF, and not only reduced IH-induced hippocampal injury, but also attenuated IH-induced cognitive deficits. Thus, exogenous GH may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from SDB-associated neuronal loss and associated neurocognitive dysfunction.

Topics: Animals; Caspase 3; Cognition Disorders; Disease Models, Animal; Erythropoietin; Glucose Transporter Type 1; Growth Hormone; Heme Oxygenase-1; Hippocampus; Humans; Hypoxia; Insulin-Like Growth Factor I; Male; Maze Learning; Rats; Rats, Sprague-Dawley; Receptors, Somatotropin; Vascular Endothelial Growth Factor A

The selection of a minimal active sequence of erythropoietin allowed the design of peptide mimetics that exert beneficial effects in the central nervous system but lack an erythropoietic effect. Erythropoietin has been suggested as a promising therapeutic and prophylactic for epilepsies based on its neuroprotective, neuroregenerative, and antiinflammatory potency. Therefore, it is of particular interest to evaluate whether the nonerythropoietic erythropoietin-derived peptide pHBSP can affect epileptogenesis.. In a post-status epilepticus model in rats, we determined the effects of pHBSP and of recombinant human erythropoietin with short-term administration following status epilepticus.. Both pHBSP and erythropoietin further enhanced the status epilepticus-associated increase in hippocampal cell proliferation. Thereby, pHBSP seemed to promote neuronal differentiation and survival resulting in a significant increase in neurogenesis. Neither pHBSP nor erythropoietin affected the number of animals exhibiting spontaneous recurrent seizures as well as the seizure frequency in the chronic phase. In the Morris water maze, pHBSP attenuated cognitive deficits in epileptic animals.. In conclusion, the helix B-derived erythropoietin peptide pHBSP can modulate the cellular and cognitive consequences of a status epilepticus. The impact of pHBSP on spatial learning might indicate that the peptide allows beneficial effects on epileptogenesis-associated cognitive deficits. However, it needs to be considered that learning deficits were not abolished by pHBSP and that the effects were not observed consistently until the end of the study. Therefore, adjustment of timing, duration, and dose of peptide administration might be necessary to further evaluate the efficacy of pHBSP.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Bromodeoxyuridine; Cell Proliferation; Cognition Disorders; Disease Models, Animal; Electric Stimulation; Erythropoietin; Exploratory Behavior; Female; Humans; Maze Learning; Microglia; Neurogenesis; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Serine Endopeptidases; Status Epilepticus

STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.

Topics: Animals; Behavior, Animal; Cognition Disorders; Darbepoetin alfa; Discrimination Learning; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Erythropoietin; Female; Hematinics; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Microtubule-Associated Proteins; NADPH Dehydrogenase; Neuropsychological Tests; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Prosencephalon; Recognition, Psychology

Cognitive dysfunction is a potential side effect of chemotherapy, and erythropoietin might be protective. A previously reported study compared quality-of-life in women undergoing chemotherapy for breast cancer who were randomized to receive epoetin-alpha or standard care. Here, we report a non-randomized sub-study in which cognitive function of participants was evaluated at 12-30 months after chemotherapy.. The primary endpoint was the proportion of women with moderate-severe cognitive impairment, as measured by the High Sensitivity Cognitive Screen (HSCS). Subjects also completed the Revised Hopkins Verbal Learning Test (HVLT-R), the Functional Assessment of Cancer Therapy--Fatigue (FACT-F) and FACT-G self-report questionnaires for fatigue and quality-of-life, and the Hospital Anxiety and Depression Scale.. Of 278 patients receiving adjuvant treatment in the primary study, 87 participated in the sub-study: 45 had received epoetin-alpha and 42 standard care. Groups were well matched for age and type of chemotherapy. Eight patients (9%) had moderate-severe cognitive dysfunction by the HSCS: six of them in the epoietin-alpha group (not significant). There were no significant differences in the HVLT-R, or in fatigue, but patients who had received epoetin-alpha reported better quality-of-life.. This study failed to demonstrate a protective effect of epoetin-alpha against the development of delayed cognitive dysfunction after chemotherapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Case-Control Studies; Cognition Disorders; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Matched-Pair Analysis; Middle Aged; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Selective neuronal loss is closely associated with cognitive impairments that occur following status epilepticus (SE). Our previous study suggested that erythropoietin (Epo) pre-treatment suppressed hippocampal neuronal death in rats after 1 h of SE convulsions. However, the underlying protective mechanism remained unclear. In the present study, we investigated the anti-apoptotic mechanism of Epo pre-treatment in the hippocampus using Li-pilocarpine-induced SE in rats. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to detect apoptosis and the Morris water maze was employed to assess spatial learning ability and to analyze the protective effects of Epo. Levels of Bcl-2 family (Bid, Bcl-2 and Bax) markers were examined via Western blot and immunofluorescence. We found that Epo pre-treatment prevented SE-induced cognitive impairments. The protection and cognitive effects were associated with higher levels of Bcl-2 and lower levels of Bax. The present results suggest that systemic Epo pre-treatment can confer neuroprotection following SE, and may provide novel insights into pathogenesis and treatment following SE injury.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Cognition Disorders; Disease Models, Animal; Erythropoietin; Hippocampus; In Situ Nick-End Labeling; Male; Maze Learning; Muscarinic Agonists; Neuroprotective Agents; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus

We hypothesized that higher cumulative doses of recombinant erythropoietin (rEPO) for extremely preterm infants during the first 6 postnatal weeks would improve developmental outcomes, as evidenced in evaluations with the Bayley Scales of Infant Development-II Revised.. This was a retrospective cohort study with a data set for a group (N = 366) of infants of <1500 g and < or =30 weeks of gestation that was created initially to examine the association between rEPO treatment and retinopathy of prematurity. Infants who underwent developmental follow-up evaluations at corrected age of >12 months were included. The associations between rEPO doses and higher Bayley Scales of Infant Development Psychomotor Developmental Index and Mental Developmental Index (MDI) scores were estimated in multivariate linear regression analyses.. Eighty-two infants underwent developmental evaluations after 12 months. The median age of evaluation was 25 months. The median 6-week cumulative rEPO dose was 3750 U/kg. In multivariate analyses, Psychomotor Developmental Index (PDI) scores were associated with transfusions, female gender, birth weight, and 5-minute Apgar scores (R(2) = 0.39). MDI scores were associated with 6-week rEPO dose, female gender, prenatal steroid treatment for > or =48 hours, and breast milk feedings (R(2) = 0.40).. These findings identify a dose-response relationship between rEPO treatment and improved MDI scores. They are consistent with findings of adult studies and animal brain injury models and await confirmation.

Topics: Child Development; Child, Preschool; Cognition Disorders; Cohort Studies; Developmental Disabilities; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Linear Models; Male; Multivariate Analysis; Predictive Value of Tests; Pregnancy; Probability; Psychomotor Disorders; Recombinant Proteins; Retrospective Studies; Risk Assessment; Statistics, Nonparametric; Time Factors; Treatment Outcome

The primary aim of this study was to assess whether epoetin alpha (Ea) would improve cognitive performance in a group of anaemic cancer patients receiving chemotherapy. The secondary aim was to confirm the positive impact of Ea on haematological parameters, and quality of life (QOL). Fifty patients with solid tumours and haemoglobin (Hb) <11.0 g/dL received Ea 40,000 units once weekly for 12 weeks and were administered the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire prior to Ea therapy and at study completion. No clinically significant alterations were observed on cognitive function during Ea treatment. Changes in cognitive function were unrelated to Hb change and there were no significant differences in cognitive performance between Ea responders and non-responders. The analyses revealed clinically significant improvements in Hb levels, physical and role function, and clinically meaningful reductions in fatigue. Hb changes were significantly associated with the magnitude of improvement in QOL parameters. The lack of a clinical benefit in cognition observed in this study during Ea treatment may redirect the focus of research from enhancing to maintaining cognitive function, since stability in cognitive performance through time may be as well clinically important.

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Agents; Chemotherapy, Adjuvant; Cognition Disorders; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Recombinant Proteins; Treatment Outcome; Young Adult

Our aim is to study the effect of improvement in anemia on event-related potentials (ERPs; P300) as markers of cognitive dysfunction in predialysis and dialysis patients of chronic kidney disease (CKD). Thirty anemic patients of CKD (hemoglobin [Hb] < 9 g%), 15 in the predialysis group (Group A), and 15 patients on biweekly hemodialysis (Group B) were recruited for the study. Patients of uremic encephalopathy, dyselectrolytemia, and those with hearing problems were excluded. Both groups were given recombinant human erythropoietin (rhuEPO) 100 IU/kg biweekly for 6 weeks by the subcutaneous route. No intervention was performed in the third control group (Group C), which consisted of 30 normal healthy volunteers. The improvement in Hb was assessed every 2 weeks, and the amplitude and latency of the P300 component of the ERPs were studied before initiating treatment and after 6 weeks of rhuEPO administration. There was a significant increase in Hb in both the study groups without any significant alteration in kidney functions. A significant reduction in P300 latency was noted in both the study groups after intervention. Similarly, the amplitude of P300 also increased in both study groups, but attained statistical significance for the dialysis group only. No significant changes were observed in the control group. Administration of EPO in patients of anemia with CKD resulted in a significant improvement in the electrophysiological markers of cognitive function in the form of increased amplitudes and decreased latencies of P300 in both predialysis and dialysis patients.

Topics: Anemia; Chronic Disease; Cognition Disorders; Erythropoietin; Event-Related Potentials, P300; Hemoglobins; Humans; Kidney Diseases; Reaction Time; Recombinant Proteins

Erythropoietin has recently been studied for its role in the central nervous system (CNS). It has been shown to exert neuroprotective effects in different models of brain injury. We studied whether neuroprotective effects assessed from the reduction of neuronal loss after transient brain ischemia are associated to the preservation of learning ability. Recombinant human erythropoietin (0.5-25 U) was injected in the lateral cerebral ventricle of gerbils that are subjected to temporary (3 min) bilateral carotid occlusion. Post-ischemic histological evaluation of CA1 area neuronal loss and passive avoidance test were performed. Treatment with recombinant human erythropoietin significantly reduced delayed neuronal death in the CA1 area of the hippocampus and prevented cognition impairment in the passive avoidance test. These data indicate that recombinant human erythropoietin neuroprotective effects in brain ischemia are associated with the preservation of learning function.

Topics: Animals; Avoidance Learning; Behavior, Animal; Brain Ischemia; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Gerbillinae; Humans; Male; Neurons; Recombinant Proteins

Impaired cognitive function associated with end-stage renal disease (ESRD) can adversely affect a patient's quality of life and is only partially reversed by dialysis. Correction of anemia with Epoetin alfa improves cognitive function and other factors that affect quality of life. Thus, nephrology nurses can improve their patients' quality of life by ensuring adequate dosing of Epoetin alfa so that anemia is corrected and cognitive function benefits are achieved. In addition, a knowledge of how cognitive function is evaluated helps nurses analyze research studies related to this area.

Topics: Adult; Anemia; Cognition Disorders; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Neuropsychological Tests; Nursing Assessment; Quality of Life

To evaluate the effects of recombinant human erythropoietin (rHuEPO) on brain function, 15 chronic hemodialysis patients were studied by event-related P300, stimulus-related evoked potentials, and trailmaking before (hematocrit 22.7%) and after rHuEPO (hematocrit 30.6%). P300 peak latency elicited by a tone discrimination paradigm improved (391 before vs. 366 ms after; Cz = vertex; P less than 0.01) confirming beneficial effects on cerebral cognitive processing. P300 amplitude (13.6 vs. 15.8 microV; P = 0.06) and trailmaking tended to improve (55 vs. 43 s). P300 measures were influenced by low hemoglobin levels before rHuEPO (P less than 0.01), suggesting that severe anemia may contribute to uremic brain dysfunction. Furthermore, decrease of stimulus-related auditory brainstem I-V interpeak latency (4.28 before vs. 4.17 ms after; P less than 0.05) and increase of somatosensory N20/P25 amplitude (4.8 vs. 7.0 microV; P less than 0.05) pointed to improvement of sensory pathways by mechanisms unrelated to cognition. Brain dysfunction in chronic hemodialysis patients may, beside other factors, in part be caused by severe anemia and can be improved by rHuEPO treatment.

Topics: Anemia; Cognition Disorders; Erythropoietin; Evoked Potentials; Evoked Potentials, Somatosensory; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Trail Making Test