losartan-potassium and Cerebral-Hemorrhage

Tissue plasminogen activator (tPA) administered within 4.5h of symptom onset restores cerebral blood flow (CBF) and promotes neurological recovery of stroke patients. However, the narrow therapeutic time window and the risk of intracerebral hemorrhage after tPA treatment pose major hurdles to its clinical usage. In light of the failures of neuroprotective therapies in clinical trials, emerging concepts suggest that neuroprotection alone without restoration of tissue perfusion and vascular integrity may not be adequate for treatment of acute stroke. Here we review evidence of the use of adjuvant pharmacological agents to extend the therapeutic window for tPA via targeting the neurovascular unit and the underlying mechanisms of the combination therapy in experimental stroke.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Boronic Acids; Bortezomib; Cerebral Hemorrhage; Drug Therapy, Combination; Erythropoietin; Fibrinolytic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Minocycline; Pyrazines; Stroke; Tissue Plasminogen Activator

Red blood cell (RBC) transfusions convey benefits but they also carry risks. Among NICU patients, some transfusion risks are well defined and their occurrence odds can be estimated and weighed against benefits. However other risks are poorly defined and it is not currently possible to estimate their occurrence adds or weigh these against benefits.. We reviewed publications in the past 15 years, listed in PubMed, dealing with risks and benefits of RBC transfusions to newborn infants.. Risks of RBC transfusion to adult patients decreased significantly with the advent of nucleic acid testing for viral pathogens. However, new or previously unknown risks of transfusions have been suggested for neonatal recipients. These include developmental delay, intraventricular hemorrhage, and necrotizing enterocolitis. These potential transfusion risks are all currently in the form of statistical associations, and cause-and-effect relationships have not been proven. Mean of reducing transfusions, tested during the past 15 years, include adopting transfusions guidelines, erythropoietic stimulating agents, delayed cord clamping, cord stripping, drawing all NICU admission blood tests from the placenta, and limiting phlebotomy losses for blood testing.. We advocate always attempt to weigh benefits and risks when ordering a transfusion for a neonatal patient. Certainly some such are life-saving or otherwise clearly beneficial. Perhaps others carry risks unbalanced by meager benefit. Efforts to improve NICU transfusion practice have been proposed and appear to be working to diminish costs and improve outcomes.

Topics: Adult; Anemia; Blood Transfusion, Autologous; Cerebral Hemorrhage; Developmental Disabilities; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Risk Assessment; Risk Factors; Umbilical Cord

Topics: Animals; Apoptosis; Brain Diseases; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Disorders; Erythropoietin; Humans; Ischemia; Neurons; Neuroprotective Agents; Stroke

The vascular events that happen during ischemic stroke worsen outcomes in patients by causing edema, hemorrhagic transformation, and general neurologic tissue compromise. In the past 2 decades, clinical trials in patients after ischemic stroke focused on neuroprotection, but these strategies have failed in providing actual benefit. Vascular protection represents a new field to be explored in acute ischemic stroke in order to develop new approaches to therapeutic intervention.. We identified tactics likely to provide vascular protection in patients with ischemic stroke. These tactics are based on knowledge of the molecular processes involved.. The pathologic processes due to vascular injury after an occlusion of a cerebral artery can be separated into acute (those occurring within hrs), subacute (hrs to days), and chronic (days to mo). Targets for intervention can be identified for all three stages. In the acute phase, superoxide is the predominant mediator, followed by inflammatory mediators and proteases in the subacute phase. In the chronic phase, proapoptotic gene products have been implicated. Many already-marketed therapeutic agents (statins, angiotensin modulators, erythropoietin, minocycline, and thiazolidinediones), with proven safety in patients, have been shown to have activity against some of the key targets of vascular protection.. Currently available pharmacologic agents are poised for clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiotensin-Converting Enzyme Inhibitors; Brain; Brain Edema; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Minocycline; Stroke; Thiazolidinediones; Thrombolytic Therapy

Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date.. To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH.. Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022.. Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life.. Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023).. Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores.. This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials.. ClinicalTrials.gov Identifier: NCT02076373.

Topics: Birth Weight; Brain Injuries; Cerebral Hemorrhage; Child, Preschool; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Male

Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury.. The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH.. This was a single-blinded prospective randomized controlled trial. Preterm infants ≤ 32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age.. A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality (p = 0.176) or incidence of neurological disability (p = 0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199-0.796; p = 0.009. In addition, the incidence of Mental Development Index scores of < 70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122-0.875; p = 0.026.. Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH.. The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690).

Topics: Cerebral Hemorrhage; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Neuroprotective Agents; Prospective Studies; Recombinant Proteins; Single-Blind Method; Treatment Outcome

Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome.. This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth.. The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count.. No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.

Topics: Apgar Score; Brain Diseases; Cerebral Hemorrhage; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Male; Maximum Tolerated Dose; Probability; Recombinant Proteins; Reference Values; Retinopathy of Prematurity; Risk Assessment; Survival Analysis; Treatment Outcome

Thrombopoietin (TPO) and its receptor (TPOR) are expressed in the central nervous system (CNS). Although TPO shares significant homology with various neurotrophins, recent data indicate a proapoptotic function of TPO in the CNS. In this study, TPO concentrations were analyzed in the cerebrospinal fluid (CSF) of neonates. Human neuroblastoma-derived SH-SY5Y cells were established to elucidate the effects of inflammation and hypoxia on neuronal Tpo expression. TPO was detectable in the CSF of 6 of 15 neonates with bacterial infection/sepsis (median 140, range 2-613 pg/mL), 5 of 9 neonates with posthemorrhagic hydrocephalus (median 31, range 1.4-469 pg/mL), 3 of 4 neonates with posthemorrhagic hydrocephalus plus bacterial infection/sepsis or meningitis (median 97, range 6-397 pg/mL), but not in controls ( n = 3). Neither the presence of detectable TPO nor its level in the CSF significantly correlated with any clinical or laboratory parameter. In SH-SY5Y cells, TPO and TPOR expression was detected by RT-PCR and Western blot analysis. In vitro, interleukin-6 (IL-6) did not significantly change Tpo gene expression. In contrast, Tpo mRNA expression significantly decreased under hypoxia, whereas erythropoietin (EPO) mRNA expression increased. In conclusion, our data provide evidence that in neuronal cells, TPO production is regulated by different mechanisms than in hepatocytes.

Topics: Cell Hypoxia; Cell Line, Tumor; Central Nervous System; Cerebral Hemorrhage; Erythropoietin; Female; Humans; Hydrocephalus; Infant, Newborn; Longitudinal Studies; Male; Meningitis, Bacterial; Neurons; Predictive Value of Tests; Sepsis; Thrombopoietin

Anemia in preterm infants is the pathophysiological process with greater and more rapid decline in hemoglobin compared to the physiological anemia in infants. There is a need for transfusions and administration of human recombinant erythropoietin.. To determine the frequency of anemia in premature infants at the Pediatric Clinic, University Clinical Center Sarajevo, as well as parameter values in the blood count of premature infants and to explore a relationship between blood transfusions with the advent of intraventricular hemorrhage (determine treatment outcome in preterm infants).. Research is retrospective study and it included the period of six months in year 2014. Research included 100 patients, gestational age < 37 weeks (premature infants). Data were collected by examining the medical records of patients at the Pediatric Clinic, UCCS.. The first group of patients were premature infants of gestational age ≤ 32 weeks (62/100) and the second group were premature infants of gestational age 33-37 weeks (38/100). Among the patients, 5% were boys and 46% girls. There was significant difference in birth weight and APGAR score among the groups. In the first group, there were 27.42% of deaths, while in the second group, there were only 10.53% of deaths. There was a significant difference in the length of treatment. There was a statistically significant difference in the need for transfusion among the groups. 18 patients in the first group required a transfusion, while in the second group only 3 patients.. Preterm infants of gestational age ≤ 32 weeks are likely candidates for blood transfusion during treatment. Preterm infants of gestational age ≤ 32 weeks have the risk of intracranial bleeding associated with the application of blood transfusion in the first week of life.

Topics: Anemia, Neonatal; Blood Transfusion; Cerebral Hemorrhage; Erythropoietin; Female; Gestational Age; Hemoglobins; Hospitals, University; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Retrospective Studies; Severity of Illness Index; Treatment Outcome

To evaluate the incidence, onset, duration, characteristics and importance of late-onset neutropenia (defined as absolute neutrophil count<1500 μl(-1) at 3 weeks of age or later) in a group of very low birth weight (VLBW) infants.. Routine complete blood cell counts (CBCs) obtained from VLBW infants over a period of 7 years were gathered retrospectively, including those of newborns with weekly CBCs taken over a duration of at least 3 weeks. Data were obtained from between January 2003 and December 2009.. CBCs of 399 newborns were included. Values were obtained from birth to 36 weeks of postnatal age. Late-onset neutropenia was observed in 259 cases (65%). Neutropenic infants had a mean of 0.5 weeks lower gestational age. Late-onset neutropenia was more frequent in children with intraventricular hemorrhage but not in patients who received erythropoietin. The median age of neutropenia onset was 7 weeks in extremely low birth weight infants and 6 weeks in VLBW infants. The fifth percentile of neutrophils between weeks 3 and 4 was 1280 μl(-1) and between weeks 13 and 15 was 500 μl(-1). The average duration was 2 weeks with normalized values after 18 weeks.. A neutrophil count <1500 μl(-1) after the third week of life is frequently observed in VLBW infants and should not be used as a lower reference limit. The fifth percentile varies according to postnatal age from around 1300 μl(-1) in week 4 of life, decreasing to a nadir of 500 μl(-1) between 3 and 4 months of age. Values normalize in the first year of life.

Topics: Age of Onset; Cerebral Hemorrhage; Erythropoietin; Female; Humans; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Leukocyte Count; Male; Neutropenia; Retrospective Studies

Erythropoietin (EPO) has been shown to be neuroprotective in various models of neuronal injury. The aim of the present study was to investigate the beneficial effect of recombinant human EPO (rhEPO) following intracerebral hemorrhage (ICH) and the underlying molecular and cellular mechanisms. ICH was induced using autologous blood injection in adult rats. rhEPO (5000 IU/kg) or vehicle was administered to rats with ICH 2 h following surgery and every 24 h for 1 or 3 days. To study the involvement of the PI3K signaling pathway in the rhEPO‑mediated effect, the PI3K inhibitor wortmannin (15 µg/kg), was intravenously administered to rats with ICH 90 min prior to rhEPO treatment. Brain edema was measured 3 days following ICH and behavioral outcomes were measured at 1, 7, 14, 21 and 28 days following ICH using the modified neurological severity score (mNSS) and the corner turn test. Proinflammatory cytokines, including tumor necrosis factor (TNF)‑α, interleukin (IL)-1β and IL-6, in the ipsilateral striatum were analyzed using an enzyme-linked immunosorbent assay 24 h following ICH. Neuronal apoptosis in the perihematomal area was determined by NeuN and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) double-staining. The results showed that rhEPO treatment reversed ICH, increased brain water content, upregulated proinflammatory cytokines, neuronal loss and apoptosis in the perihematomal area and rescued behavioral deficits in injured rats. Inhibiting the PI3K pathway with wortmannin abolished the rhEPO‑mediated neuroprotective effects. Moreover, western blot analysis showed that rhEPO induced the upregulation of Akt phosphorylation and downregulation of glycogen synthase kinase (GSK)‑3β phosphorylation, which were reversed by pretreatment with wortmannin, indicating the involvement of PI3K signaling in rhEPO-mediated anti-apoptotic and anti-inflammatory effects following ICH. In conclusion, these results suggested that rhEPO may exert its beneficial effects in ICH through the activation of the PI3K signaling pathway.

Topics: Animals; Apoptosis; Behavior, Animal; Blotting, Western; Brain Injuries; Cells, Cultured; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Fluorescent Antibody Technique; Male; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Stroke

Human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles and administered intraperitoneally in a dose of 0.05 mg/kg exhibited a neuroprotective effect in experimental intracerebral posttraumatic hematomas (hemorrhagic stroke) and reduced animal mortality. Human recombinant erythropoietin, native and adsorbed on lactic and glycolic acid copolymer-based nanoparticles, exhibited no antistroke effect on this model. Analysis of reverse transcription PCR products showed that human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles more than 2-fold increased the expression of BDNF and NGF neurotrophins in the rat brain frontal cortex and hippocampus.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Cerebral Hemorrhage; Cyanoacrylates; Drug Delivery Systems; Enbucrilate; Erythropoietin; Hematoma; Hippocampus; Humans; Male; Nanoparticles; Nerve Growth Factor; Neuroprotective Agents; Rats; Rats, Wistar; Recombinant Proteins; Stroke

Stroke affects infants at a rate of 26/100,000 live births each year. Of these strokes, approximately 6.7 are hemorrhagic strokes. Erythropoietin (EPO) is an anti-apoptotic and neuroprotective hormone. In adult rodents, EPO attenuates inflammatory factor expression and blood-brain barrier damage after intracerebral hemorrhage (ICH). However, the effect of EPO in neonatal ICH stroke remains unexplored. This investigation aimed to elucidate the underpinnings of inflammation after ICH in postnatal day 7 (P7) rats and the effect of human recombinant EPO (hrEPO) treatment on ICH-induced inflammation. The P7 rat pups were pretreated with hrEPO (5,000 U/kg i.p.) or saline vehicle 4 h prior to the induction of ICH by blood injection into the right cerebral cortex and basal ganglia. Supplemental half doses of hrEPO treatment or saline injections were subsequently given 16 h after ICH induction. Real-time PCR done 24 h after ICH showed reductions in interleukin1-β (IL1-β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) mRNA expression in the basal ganglia of the hrEPO-treated rats compared to saline-treated rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining indicated fewer dying cells in the hrEPO-treated brain. Our data suggest that hrEPO has an anti-inflammatory action in neonates after ICH. The suppression of inflammatory cascades likely contributes to hrEPO's neuroprotective effect, which may be explored as a therapeutic treatment for ICH.

Topics: Analysis of Variance; Animals; Animals, Newborn; Cell Death; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; In Situ Nick-End Labeling; Inflammation; Rats; Rats, Wistar; RNA, Messenger

The neuroprotective activity of recombinant human erythropoietin (r-HuEpo) sorbed on poly(butyl)cyanoacrilate nanoparticles (EPO-PBCA) and on polylactic-co-glycolic acid nanoparticles (EPO-PLGA) has been studied on Wistar rats with intracerebral post-traumatic hematoma (model of hemorrhagic stroke) (IPH-HS) in comparison to native r-HuEpo. It is established that EPO-PBCA produced a protective effect in rats after IPH-HS that was manifested by a decrease in the number of animals with neurological disorders such as circus movement, paresis, and paralysis of hind limbs; the drug also improved coordination (rotating rod test), reduced the number of lost animals, and decreased the loss weight among survived rats. In addition, EPO-PBCA optimized the research behavior of rats with IPH-HS in the open field test and prevented amnesia of passive avoidance reflex (PAR), which was caused by the IPH-HS. These effects were manifested during a two-week observation period. EPO-PLGA has a similar but much less pronounced effect on the major disorders caused by IPH-HS. The efficiency of native r-HuEpo as a neuropotective agent was insignificant and only manifested by decrease in the number of lost animals with IPH-HS.

Topics: Adsorption; Amnesia; Animals; Cerebral Hemorrhage; Disease Models, Animal; Enbucrilate; Erythropoietin; Humans; Lactic Acid; Male; Motor Activity; Nanoparticles; Neuroprotective Agents; Paralysis; Paresis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Wistar; Recombinant Proteins; Stroke; Survival Rate; Weight Loss

Topics: Anemia; Cerebral Hemorrhage; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Hematinics; Humans; Male; Renal Insufficiency, Chronic; Stroke; Tissue Plasminogen Activator

Attention has turned to neurorestorative therapies, including erythropoietin, for experimental ischaemic stroke and head injury. Treatments for intracerebral haemorrhage need to be developed, as this represents a particularly devastating and common form of neurological injury. Aim The aim of this study is to investigate the therapeutic potential of erythropoietin after intracerebral haemorrhage in rats and to measure its effects on mechanisms of recovery and neurogenesis.. Intracerebral haemorrhage was induced in 24 Wistar male rats by intrastriatal infusion of autologous blood. Recombinant human erythropoietin (5000 or 10,000 U/kg BW/day) or saline was administered starting 1 day after intracerebral haemorrhage and continued daily for 1 week (n=8 for each group). To label proliferating cells, 5'-bromo-2' deoxyuridine was injected daily for 13 days after intracerebral haemorrhage. All animals survived for 2 weeks after intracerebral haemorrhage. Functional outcome, area of tissue loss and immunohistochemical staining were measured at 14 days after intracerebral haemorrhage. Global test or anova was used to test the erythropoietin dose effect.. Rats receiving recombinant human erythropoietin after intracerebral haemorrhage exhibited significant improvement in modified neurological severity score and corner test at 14 days (P<0.05). Increased expression of phenotypes of synaptogenesis and proliferating immature neurons were shown by immunohistochemical staining. Only the group receiving a lower dose of recombinant human erythropoietin had significantly less tissue loss compared with the control group (P<0.05). In rats treated with recombinant human erythropoietin, double staining for 5'-bromo-2' deoxyuridine and TUJ1 revealed a subpopulation of cells that express an immature neuronal marker while still dividing.. Erythropoietin improves neurological outcome and increases histochemical parameters of neurogenesis when given after intracerebral haemorrhage in rats. Intriguingly, only the lower dose of recombinant human erythropoietin was effective in reducing tissue loss in the region of intracerebral haemorrhage.

Topics: Animals; Antimetabolites; Brain; Bromodeoxyuridine; Cerebral Hemorrhage; Coloring Agents; Erythropoietin; Humans; Immunohistochemistry; Indicators and Reagents; Linear Models; Male; Nerve Tissue Proteins; Psychomotor Performance; Rats; Rats, Wistar; Recombinant Proteins; Recovery of Function; Tissue Fixation

Intracerebral hemorrhage (ICH) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its long-lasting analog, darbepoetin alfa, have been demonstrated to be neuroprotective in several models of neuronal insult. The objectives of this study were to analyze whether the systemic administration of recombinant human EPO (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery and brain damage in a rat model of ICH.. Experimental ICH was induced in rats by injecting autologous blood into the right striatum under stereotactic guidance. Subsequently, animals underwent placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Animals were killed 14 days after injury.. Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment after injury, as assessed by the neurological tasks performed. rHuEPO- and darbepoetin alfa-treated animals exhibited a restricted brain injury with nearly normal parenchymal architecture. In contrast, the saline-treated group exhibited extensive cerebral cytoarchitectural disruption and edema. The number of surviving NeuN-positive neurons was significantly higher in the rats treated with rHuEPO and darbepoetin alfa compared with those that received saline (P < 0.05).. These results demonstrate that weekly administered darbepoetin alfa confers behavioral and histological neuroprotection after ICH in rats similar to that of daily EPO administration. Administration of EPO and its long-lasting recombinant forms affords significant neuroprotection in an ICH model and may hold promise for future clinical applications.

Topics: Animals; Basal Ganglia Hemorrhage; Blood Transfusion, Autologous; Brain; Brain Edema; Brain Infarction; Cerebral Hemorrhage; Corpus Striatum; Darbepoetin alfa; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Treatment Outcome

The protective mechanism of recombinant human erythropoietin (rhEPO) on blood-brain barrier (BBB) after brain injury is associated with the attenuation of neuro-inflammation. We hypothesize that rhEPO treatment after intracerebral hemorrhage (ICH) modulates matrix metalloproteinase (MMP) activity, maintains BBB integrity, and reduces BBB breakdown-associated inflammation. Adult male 129S2/sv mice were subjected to autologous whole blood-induced ICH. rhEPO or saline was administered intraperitoneally immediately after surgery and for 3 more days until day of sacrifice. BBB permeability was measured by Evans blue leakage, and edema was assessed by brain water content. Immunofluorescence and Western blotting were performed to detect expression of tight junction marker occludin, type IV collagen, MMPs, tissue inhibitor of metalloproteinase (TIMP), and glial fibrillary acidic protein, rhEPO prevented Evans blue leakage, reduced brain edema, and preserved expression of occludin and collagen IV. rhEPO treatment decreased MMP-2 expression, increased TIMP-2 expression, and reduced the number of reactive astrocytes in the brain compared to saline control. We conclude that rhEPO reduces MMP activity, BBB disruption, and the glial cell inflammatory reaction 3 days after ICH. Our study provides additional evidence for the mechanism of rhEPO's neurovascular protective effects and a potential clinical application in the treatment of ICH.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Cerebral Hemorrhage; Collagen Type IV; Disease Models, Animal; Erythropoietin; Evans Blue; Glial Fibrillary Acidic Protein; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Membrane Proteins; Mice; Occludin; Permeability; Recombinant Proteins; Time Factors; Tissue Inhibitor of Metalloproteinases

Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.

Topics: Animals; Apoptosis; Biomarkers; Body Water; Brain; Brain Edema; Cell Death; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Enzyme Activation; Enzyme Inhibitors; Erythropoietin; Male; Nerve Degeneration; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Recovery of Function; Signal Transduction; STAT3 Transcription Factor; Treatment Outcome

Hypoxia induces transcription of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) genes. We set up the hypothesis that elevated intracranial pressure in patients with hydrocephalus triggers release of VEGF and EPO into cerebrospinal fluid (CSF).. VEGF and EPO concentrations, measured in 57 CSF aliquots obtained from infants and children with hydrocephalus undergoing surgery or therapeutic taps, were significantly elevated compared with those in 41 CSF aliquots of sex- and age-matched children undergoing routine diagnostic lumbar puncture for unrelated reasons ( P<0.001 and P=0.015, respectively). In hydrocephalus samples, median (interquartile range) VEGF concentrations were 135 (35-410) pg/ml, and 4 of 57 hydrocephalus samples had a VEGF concentration below the detection limit (1 pg/ml), compared with 38 of 41 control samples. Erythropoietin was undetectable (<0.1 pg/ml) in 34 of 57 hydrocephalus samples and in 34 of 41 controls.. We conclude that conditions necessitating surgical intervention in hydrocephalus patients result in increased CSF concentrations of VEGF and EPO.

Topics: Brain Neoplasms; Cerebral Hemorrhage; Child, Preschool; Endothelial Growth Factors; Erythropoietin; Female; Humans; Hydrocephalus; Infant; Lymphokines; Male; Reference Values; Spinal Dysraphism; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

This study analyses the factors affecting mobilisation and engraftment in autologous peripheral blood progenitor cell transplantation according to the number of CD34(+) re-infused.. A total of 190 patients underwent mobilisation with G-CSF alone (n=113) or in combination with chemotherapy (n=77). A total of 116 patients (61%) were autografted with <2 x 10(6) CD34(+) cells/kg and 74 patients were transplanted with >2 x 10(6) CD34(+) cells/kg. Rates of granulocyte and platelet recovery were estimated using the product-limit method of Kaplan-Meier and compared using a log-rank test. The Cox regression model was used for the multivariate analysis of factors influencing engraftment. Differences between cohorts were evaluated by one-way ANOVA or Mann-Whitney tests, and multivariate analysis was performed using a stepwise lineal regression.. Neutrophil and platelet engraftment was significantly longer with <2 x 10(6)/CD34(+)/kg (12 vs 10 days, P=0.014 and 16 vs 13 days, P=0.0001 respectively). Platelet recovery was affected by exposure to alkylating agents (P=0.04), refractory disease (P=0.02) and AML (P=0.0001), but only the last two variables remained significant in Cox regression (P<0.01). Granulocyte engraftment was longer in CML (univariate, P=0.04) and in refractory disease (multivariate, P=0.02). In patients re-infused with >2 x 10(6)/CD34(+)/kg, the Cox model did not identify prognostic factors for haematopoietic recovery.. Although mobilisation schedules and disease status influenced not only the yield of progenitor cells, but also the engraftment kinetics, the number of CD34(+) re-infused was the main predictor of haematopoietic recovery. While engraftment succeeded in most of the cases, the re-infusion of >2 x 10(6)/CD34(+)/kg resulted in significantly shorter recovery times.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Caspase 14; Caspases; Cerebral Hemorrhage; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Erythropoietin; Etoposide; Female; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Infections; Leukapheresis; Life Tables; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Transplantation Conditioning; Transplantation, Autologous