losartan-potassium and Leukomalacia--Periventricular

Neonatal brain injury (NBI) remains a major contributor to neonatal mortality and long-term neurodevelopmental morbidity. Although therapeutic hypothermia is the only proven treatment to minimize brain injury caused by neonatal encephalopathy in term neonates, it provides incomplete neuroprotection. There are no specific drugs yet proven to prevent NBI in preterm neonates. This review discusses the scientific and emerging clinical trial data for several neuroprotective drugs in development, examining potential efficacy and safety concerns. Drugs with the highest likelihood of success and closest to clinical application include erythropoietin for term and preterm neonates and antenatal magnesium for preterm neonates.

Topics: Adrenal Cortex Hormones; Allopurinol; Anesthetics, Inhalation; Anticonvulsants; Antioxidants; Cerebral Intraventricular Hemorrhage; Cyclooxygenase Inhibitors; Darbepoetin alfa; Erythropoietin; Free Radical Scavengers; Hematinics; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Indomethacin; Infant, Newborn; Leukomalacia, Periventricular; Magnesium; Melatonin; Neuroprotection; Prenatal Care; Topiramate; Xenon

Topics: Adenosine; Brain-Derived Neurotrophic Factor; Erythropoietin; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Leukomalacia, Periventricular; Nitric Oxide; Receptors, N-Methyl-D-Aspartate

To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants.. Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth.. There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group.. Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events.. ClinicalTrials.gov: NCT00413946.

Topics: Bronchopulmonary Dysplasia; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Enterocolitis, Necrotizing; Erythropoietin; Europe; Hematocrit; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Leukocyte Count; Leukomalacia, Periventricular; Neuroprotective Agents; Platelet Count; Recombinant Proteins; Reticulocyte Count; Retinopathy of Prematurity; Sepsis

Topics: Animals; Animals, Newborn; Dose-Response Relationship, Drug; Erythropoietin; Female; Globins; Leukomalacia, Periventricular; Male; Nerve Tissue Proteins; Neuroglobin; Neuroprotection; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Treatment Outcome

In this study, a single intraperitoneal injection of erythropoietin (EPO) loaded oligochitosan nanoparticles (epo-NPs) (average diameter 266 nm) was investigated as a treatment for periventricular leukomalacia (PVL). Nanoparticles were fabricated using a gelation technology process. PVL rats models were prepared to examine the therapeutic efficacy of epo-NPs and analyze the mechanism by which epo-NPs protect white matter. The metabolization of epo-NPs in the liver was also investigated. The pathology and behavioral data show that this single injection of a low quantity of epo-NPs had an excellent therapeutic effect on the rat model of PVL. The EPO release curve in phosphate buffered saline solution was a good fit with the zero-order kinetics distribution and was maintained at around 25% in 48 h. In vivo experiments demonstrated that 50 IU/kg epo-NPs had the same effect as a 5000 IU/kg direct injection of free EPO. Nanoparticles prolonged the time course of EPO metabolization in the liver and the stable release of EPO from the nanoparticles kept the plasma concentration of EPO at around 100 IU/ml during the 8-12h post-injection. Therefore, we suggest that oligochitosan based nanoparticles are an effective vehicle for drug delivery.

Topics: Animals; Animals, Newborn; Behavior, Animal; Brain; Chemistry, Pharmaceutical; Chitin; Chitosan; Disease Models, Animal; Drug Carriers; Drug Compounding; Erythropoietin; GAP-43 Protein; Humans; Infant, Newborn; Injections, Intraperitoneal; Leukomalacia, Periventricular; Liver; Magnetic Resonance Imaging; Nanotechnology; Oligosaccharides; Particle Size; Rats; Solubility; Technology, Pharmaceutical

Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by hypoxia-ischemia and inflammation. Activated microglia trigger white matter damage and play a major role in the development of PVL. Erythropoietin (EPO) and its derivative carbamylated erythropoietin (CEPO) have been shown to be neuroprotective in several brain disease models. Here we investigated whether EPO and CEPO could provide protection in mouse models of PVL induced by hypoxia-ischemia or hypoxia-ischemia-inflammation. We administered EPO or CEPO to mice with PVL, and found that both EPO and CEPO treatments decreased microglia activation, oligodendrocyte damage and myelin depletion. We also noted improved performance in neurological function assays. Inhibited disease progression in PVL mice by EPO or CEPO treatment was associated with decreased poly-(ADP-ribose) polymerase-1 (PARP-1) activity. PARP-1 activity was increased dramatically in activated microglia in untreated mice with PVL. Furthermore, we demonstrated that the neuroprotective properties of EPO and CEPO were diminished after PARP-1 gene depletion. The therapeutic doses of EPO and CEPO used in this study did not interfere with normal oligodendrocyte maturation and myelination. Together, our data demonstrate that EPO and CEPO are neuroprotective in cerebral white matter injury via a novel microglial PARP-1 dependent mechanism, and hold promise as a future treatment for PVL and other hypoxic-ischemic/inflammatory white matter diseases.

Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Erythropoietin; Humans; Hypoxia; Infant, Newborn; Inflammation; Leukomalacia, Periventricular; Mice; Microglia; Myelin Sheath; Neurons; Neuroprotective Agents; Oligodendroglia

One of the pathological hallmarks of periventricular leukomalacia (PVL) is the selective vulnerability of late oligodendrocyte progenitors (preoligodendrocytes; preOLs) to hypoxia-ischemia (H-I). It is unknown whether recombinant human erythropoietin (rhEPO) protects preOLs in vivo.. To develop a rat PVL model in which preOLs are selectively damaged and exhibit similar pathological changes to diffuse-type human PVL, various conditions of H-I were compared in P2-P7 rats (P2 = postnatal day 2). To evaluate the effect of rhEPO on oligoprotection (preOLs), rhEPO was administered to P3 PVL rats.. After counts of NG2-positive and O4-positive cells were performed in P2-P7 rats, right common carotid artery occlusion followed by 6% O(2) for 0-120 min was performed in P2-P4 rats. The mortality and histological alterations after hematoxylin/eosin staining and ED1 immunostaining were assessed 2 days after H-I. Various doses of rhEPO (1-30,000 U/kg i.p.) were administered to PVL rats 15 min before administration of 6% O(2).. Double-positive cells for NG2 and O4 were detected from P2, and their number gradually increased until P7. Although right common carotid artery occlusion with 6% O(2) for 60 min resulted in a relatively high proportion of deaths in P2-P4 rats, typical histological changes in the PVL diffuse component were found in most surviving P3 animals. With 50-100 U/kg rhEPO, the histological damage was attenuated.. Histological changes similar to those seen in the PVL diffuse component were induced by H-I in P3 rats, in which preOLs were gradually developing, and a low dose of rhEPO was effective in the treatment of brain damage induced by H-I.

Topics: Animals; Animals, Newborn; Antigens; Disease Models, Animal; Erythropoietin; Female; Humans; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Immunohistochemistry; Infant, Newborn; Leukomalacia, Periventricular; Oligodendroglia; Pregnancy; Proteoglycans; Rats; Rats, Wistar; Stem Cells

This article reports the results of a study on the relationship between cord blood levels of erythropoietin and periventricular leukomalacia. Cord blood was obtained from 19 infants with gestational age between 27 and 32 weeks. Cystic periventricular leukomalacia was seen in 4 of them. Erythropoietin levels were not different between those with and those without periventricular leukomalacia.

Topics: Erythropoietin; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leukomalacia, Periventricular; Pilot Projects; Premature Birth; Statistics as Topic; Statistics, Nonparametric

Periventricular leukomalacia (PVL), a common neonatal brain white matter (WM) lesion, is frequently associated with cerebral palsy. Growing evidence has indicated that in addition to ischemia/reperfusion injury, cytokine-induced brain injury associated with maternal or fetal infection may also play an important role in the pathogenesis of PVL. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes enhanced expression of the cytokines, i.e., IL-1 beta, TNF-alpha, and IL-6, in fetal brains. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection and repair of the nervous system. In the present study we investigated the effect of EPO on LPS-induced WM injury in Sprague-Dawley rats. LPS (500 microg/kg) suspension in pyrogen-free saline was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. The control group was treated with pyrogen-free saline. They were given 5,000 U/kg recombinant human EPO. Seven-day-old Sprague-Dawley rat pups were divided into four groups: control group, LPS-treated group, prenatal maternal EPO-treated group (5,000 U/kg, intraperitoneally given to pregnant rats at 18 and 19 days of gestation), and postnatal EPO-treated group (5,000 U/kg, intraperitoneally given to 1-day-old rat pups). Cytokine induction in the postnatal 7-day-old (P7) rat brain after maternal administration of LPS was determined by the ELISA method. The proinflammatory cytokine levels (IL-1 beta, TNF-alpha, and IL-6) in P7 rat pup brains were significantly increased in the LPS-treated group as compared with the control group. Prenatal maternal EPO treatment significantly reduced the concentration of TNF-alpha and IL-6 in the newborn rat brain following LPS injection. The concentration of IL-1 beta was decreased in the intrauterine EPO treatment group. Postnatal EPO treatment significantly decreased only the IL-6 concentration in the newborn rat brain following LPS injection. The concentration of cytokines, IL-1 beta and TNF-alpha, was reduced in the postnatal EPO treatment group. We demonstrated here that LPS administration in pregnant rats at gestational day 18 and 19 induced WM injury in P7 progeny characterized by apoptosis. Prenatal maternal and postnatal EPO treatment significantly reduced the number of apoptotic cells in the periventricular WM. Using immunohistochemistry techniques, we investigated the effects of maternal admi

Topics: Animals; Animals, Newborn; Apoptosis; Bacterial Infections; Brain; Brain Diseases; Disease Models, Animal; Erythropoietin; Female; Humans; Infant, Newborn; Interleukin-1beta; Interleukin-6; Leukomalacia, Periventricular; Lipopolysaccharides; Myelin Basic Protein; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Using an established mouse model of human periventricular leukomalacia, we investigated whether EPO could reduce excitotoxic damage. When administered 1 h following intracerebral injection of 10 microg ibotenic acid at day 5 of life, both a single injection of EPO (5000 IU/kg bw) and repetitive administrations of EPO reduced white and gray matter lesion size. The therapeutic window for protection was small as the protective effect of EPO was lost when EPO administration was delayed to 4 h post-insult. EPO-mediated upregulation of EPO-R, but not EPO, mRNA was observed within 4 h of the excitotoxic insult. The EPO effect was gender independent. Minor hematopoetic effects were observed following EPO treatment. We conclude that a single dose of EPO is sufficient to reduce excitotoxic brain injury and may therefore possess therapeutic relevance in the clinical setting.

Topics: Animals; Animals, Newborn; Brain; Cytoprotection; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Female; Glutamic Acid; Humans; Ibotenic Acid; Infant, Newborn; Injections, Intraventricular; Leukomalacia, Periventricular; Male; Mice; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Receptors, Erythropoietin; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Time Factors