Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy

Ellery, Stacey J.; LaRosa, Domenic A.; Cullen‐McEwen, Luise A.; Brown, Russell D.; Snow, Rod J.; Walker, David W.; Kett, Michelle M; Dickinson, Hayley

doi:10.1038/pr.2016.268

Cited by 16 publications

(14 citation statements)

References 42 publications

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“…At 1 month of age, male intrapartum asphyxia offspring had a permanent loss of nephrons. Compensatory hypertrophy of remaining nephrons was apparent in this cohort, but despite this, at 3 months of age (young adult), GFR in male asphyxia offspring was significantly lower than controls ( 136 ). It is of interest that cardiac structure and function in spiny mouse neonates was unaltered by intrapartum asphyxia.…”

Section: Preclinical Models Of Birth Asphyxiamentioning

confidence: 59%

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

et al. 2017

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Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable.

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Section: Preclinical Models Of Birth Asphyxiamentioning

confidence: 59%

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

et al. 2017

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“…Intrapartum asphyxia was induced at 38 days of gestation (term at 39 days) as previously described [17][18][19][20][21][22]. Briefly, pregnant dams were killed via cervical dislocation.…”

Section: Housing Facility and Animal Carementioning

confidence: 99%

“…This study used the precocial spiny mouse to study the effects of intrapartum asphyxia on the brain [17][18][19][20][21][22]. The spiny mouse differs from conventional laboratory rodents (mice, rats) in that considerable brain maturation (including the beginnings of myelination) occurs in utero before birth [47]; hence, acute hypoxia delivered during the intrapartum period can be used as a model of oxygen starvation that occurs at birth in some human pregnancies.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

“…Using a well-validated model of intrapartum asphyxia in the spiny mouse [17][18][19][20][21][22], we investigated the effects of 3K3A-APC treatment on the neuropathology that follows brief asphyxia, in comparison with vehicle (saline) or wtAPC treatments. Specifically, our aim was to assess the cerebral effects of 3K3A-APC in both the gray and white matter by examining markers of neuro-inflammation and cell death.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of 3K3A-Activated Protein C to Treat Neonatal Hypoxic Ischemic Brain Injury in the Spiny Mouse

et al. 2019

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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 TGFβ1 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.

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“…The primary aim was to determine if fetal growth restriction occurred when only the gestation-related increase of uterine blood flow was prevented in the spiny mouse, and if so, to take advantage of the in utero development of this small laboratory rodent and eventually to use a number of validated physiological and behavioral tests available for this species. [23][24][25][26] Our secondary aim was to improve on existing rodent models of IUGR and induce a more subtle insult that might improve fetal survival. Studies of reduced fetal growth in spiny mice will now proceed toward characterization of the multi-organ pathology, the assessment of antenatal or postnatal strategies to improve multi-organ growth and development, and the potential for promoting long-term health in IUGR babies.…”

Section: Future Directionsmentioning

confidence: 99%

Description of a method for inducing fetal growth restriction in the spiny mouse

Dickinson

Ellery

Davies‐Tuck

et al. 2017

J Dev Orig Health Dis

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Intrauterine or fetal growth restriction (IUGR) is a major complication of pregnancy and leads to significant perinatal morbidities and mortality. Typically, induction of IUGR in animals involves the complete occlusion or ablation of vessels to the uterus or placenta, acutely impairing blood flow and fetal growth, usually with high fetal loss. We aimed to produce a model of reduced fetal growth in the spiny mouse with minimal fetal loss. At 27 days gestational age (term is 38-39 days), a piece of silastic tubing was placed around the left uterine artery to prevent the further increase of uterine blood flow with advancing gestation to induce IUGR (occluded). Controls were generated from sham surgeries without placement of the tubing. Dams were humanely euthanized at 37 days gestational age and all fetuses and placentas were weighed and collected. Of the 17 dams that underwent surgery, 15 carried their pregnancies to 37 days gestational age and 95% of fetuses survived to this time. The difference in fetal body weight between occluded and control was ~21% for fetuses in the left uterus side: there were no differences for fetuses in the right uterus side. Offspring from the occluded group had significantly lower brain, liver, lung, kidney and carcass weights compared with shams. Preventing the gestation-related increase of uterine blood flow induced significant growth restriction in the fetal spiny mouse, with minimal fetal loss. This technique could be readily adapted for other small animal.

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Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy

Abstract: Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced acute kidney injury and the emergence of chronic kidney disease.

Cited by 16 publications

References 42 publications

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

Evaluation of 3K3A-Activated Protein C to Treat Neonatal Hypoxic Ischemic Brain Injury in the Spiny Mouse

Description of a method for inducing fetal growth restriction in the spiny mouse

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