Please use this identifier to cite or link to this item:
https://repository.monashhealth.org/monashhealthjspui/handle/1/35977
Title: | Evaluation of 3K3A-Activated Protein C to Treat Neonatal Hypoxic Ischemic Brain Injury in the Spiny Mouse. | Authors: | LaRosa D.A.;Wong F.Y.;Walker D.W.;Dickinson H.;Brew N.;Goss M.G.;Ellery S.J.;Hale N. | Institution: | (Ellery, Goss, Brew, Dickinson, Hale, LaRosa, Walker, Wong) The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Melbourne 3168, Australia (Ellery, Dickinson, LaRosa, Walker) Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia (LaRosa) Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, United States (Walker) School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia (Wong) Department of Paediatrics, Monash University, Clayton, Australia (Wong) Monash Newborn, Monash Medical Centre, Clayton, Melbourne, Australia | Issue Date: | 12-Feb-2019 | Copyright year: | 2019 | Publisher: | Springer New York LLC (E-mail: barbara.b.bertram@gsk.com) | Place of publication: | United States | Publication information: | Neurotherapeutics. 16 (1) (pp 231-243), 2019. Date of Publication: 15 Jan 2019. | Journal: | Neurotherapeutics | Abstract: | Neonatal hypoxic ischemic encephalopathy (HIE) resulting from intrapartum asphyxia is a global problem that causes severe disabilities and up to 1 million deaths annually. A variant form of activated protein C, 3K3A-APC, has cytoprotective properties that attenuate brain injury in models of adult stroke. In this study, we compared the ability of 3K3A-APC and APC (wild-type (wt)) to attenuate neonatal brain injury, using the spiny mouse (Acomys cahirinus) model of intrapartum asphyxia. Pups were delivered at 38 days of gestation (term = 39 days), with an intrapartum hypoxic insult of 7.5 min (intrapartum asphyxia cohort), or immediate removal from the uterus (control cohort). After 1 h, pups received a subcutaneous injection of 3K3A-APC or wild-type APC (wtAPC) at 7 mg/kg, or vehicle (saline). At 24 h of age, pups were killed and brain tissue was collected for measurement of inflammation and cell death using RT-qPCR and histopathology. Intrapartum asphyxia increased weight loss, inflammation, and apoptosis/necrosis in the newborn brain. 3K3A-APC administration maintained body weight and ameliorated an asphyxia-induced increase of TGFbeta1 messenger RNA expression in the cerebral cortex, immune cell aggregation in the corpus callosum, and cell death in the deep gray matter and hippocampus. In the cortex, 3K3A-APC appeared to exacerbate the immune response to the hypoxic ischemic insult. While wtAPC reduced cell death in the corpus callosum and hippocampus following intrapartum asphyxia, it increased markers of neuro-inflammation and cell death in control pups. These findings suggest 3K3A-APC administration may be a useful therapy to reduce cell death and neonatal brain injury associated with HIE.Copyright © 2018, The American Society for Experimental NeuroTherapeutics, Inc. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1007/s13311-018-0661-0 | PubMed URL: | 30225791 [http://www.ncbi.nlm.nih.gov/pubmed/?term=30225791] | ISSN: | 1933-7213 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35977 | Type: | Article | Subjects: | transforming growth factor beta1/ec [Endogenous Compound] unclassified drug *3k3a activated protein C/dt [Drug Therapy] *3k3a activated protein C/pd [Pharmacology] *newborn hypoxia/dt [Drug Therapy] nonhuman priority journal reverse transcription polymerase chain reaction sex difference survival rate tissue preparation TUNEL assay *activated protein C/dt [Drug Therapy] *activated protein C/pd [Pharmacology] *cytoprotective agent/dt [Drug Therapy] *cytoprotective agent/pd [Pharmacology] immunoglobulin enhancer binding protein/ec [Endogenous Compound] Acomys Acomys cahirinus adult animal experiment animal model apoptosis article body weight body weight loss brain cortex cell aggregation cell death cerebrovascular accident comparative study controlled study corpus callosum *drug screening female gene expression gestational age gray matter hippocampus histopathology housekeeping gene *hypoxic ischemic encephalopathy/dt [Drug Therapy] image analysis immunocompetent cell male microglia mortality rate mouse neuroapoptosis neuropathology newborn messenger RNA/ec [Endogenous Compound] comparative study controlled study corpus callosum *drug screening female gene expression gestational age gray matter hippocampus body weight Article apoptosis animal model animal experiment adult Acomys cahirinus Acomys cell death cerebrovascular accident survival rate tissue preparation TUNEL assay brain cortex body weight loss cell aggregation histopathology housekeeping gene *hypoxic ischemic encephalopathy / *drug therapy image analysis immunocompetent cell male microglia mortality rate mouse neuroapoptosis neuropathology newborn *newborn hypoxia / *drug therapy nonhuman priority journal reverse transcription polymerase chain reaction sex difference |
Appears in Collections: | Articles |
Show full item record
Items in Monash Health Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.