ORCID Profile
0000-0002-4958-6140
Current Organisation
RMIT University
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Publisher: Wiley
Date: 17-08-2023
DOI: 10.1113/JP284191
Abstract: Fetal growth restriction (FGR) is a complex obstetric issue describing a fetus that does not reach its genetic growth potential. The primary cause of FGR is placental dysfunction resulting in chronic fetal hypoxaemia, which in turn causes altered neurological, cardiovascular and respiratory development, some of which may be pathophysiological, particularly for neonatal life. The brainstem is the critical site of cardiovascular, respiratory and autonomic control, but there is little information describing how chronic hypoxaemia and the resulting FGR may affect brainstem neurodevelopment. This review provides an overview of the brainstem‐specific consequences of acute and chronic hypoxia, and what is known in FGR. In addition, we discuss how brainstem structural alterations may impair functional control of the cardiovascular and respiratory systems. Finally, we highlight the clinical and translational findings of the potential roles of the brainstem in maintaining cardiorespiratory adaptation in the transition from fetal to neonatal life under normal conditions and in response to the pathological environment that arises during development in growth‐restricted infants. This review emphasises the crucial role that the brainstem plays in mediating cardiovascular and respiratory responses during fetal and neonatal life. We assess whether chronic fetal hypoxaemia might alter structure and function of the brainstem, but this also serves to highlight knowledge gaps regarding FGR and brainstem development. image
Publisher: MDPI AG
Date: 27-10-2021
Abstract: There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine hosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.
Publisher: MDPI AG
Date: 02-02-2021
DOI: 10.3390/NU13020490
Abstract: Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research “road forward” to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.
Publisher: MDPI AG
Date: 26-01-2020
DOI: 10.3390/IJMS21030806
Abstract: Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-ecl sia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27–40 weeks’ gestation from women with early-onset PE (n = 20) and gestation-matched normotensive control pregnancies (n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT), the creatine transporter (SLC6A8), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings total creatine content of PE placentae was 38% higher than controls (p 0.01). mRNA expression of GATM (p 0.001), GAMT (p 0.001), SLC6A8 (p = 0.021) and BBCK (p 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation.
Publisher: Wiley
Date: 02-11-2018
DOI: 10.1113/JP277151
Publisher: MDPI AG
Date: 30-12-2020
DOI: 10.3390/NU13010089
Abstract: Maternal diet is critical for offspring development and long-term health. Here we investigated the effects of a poor maternal diet pre-conception and during pregnancy on metabolic outcomes and the developing hypothalamus in male and female offspring at birth. We hypothesised that offspring born to dams fed a diet high in fat and sugar (HFSD) peri-pregnancy will have disrupted metabolic outcomes. We also determined if these HFSD-related effects could be reversed by a shift to a healthier diet post-conception, in particular to a diet high in omega-3 polyunsaturated fatty acids (ω3 PUFAs), since ω3 PUFAs are considered essential for normal neurodevelopment. Unexpectedly, our data show that there are minimal negative effects of maternal HFSD on newborn pups. On the other hand, consumption of an ω3-replete diet during pregnancy altered several developmental parameters. As such, pups born to high-ω3-fed dams weighed less for their length, had reduced circulating leptin, and also displayed sex-specific disruption in the expression of hypothalamic neuropeptides. Collectively, our study shows that maternal intake of a diet rich in ω3 PUFAs during pregnancy may be detrimental for some metabolic developmental outcomes in the offspring. These data indicate the importance of a balanced dietary intake in pregnancy and highlight the need for further research into the impact of maternal ω3 intake on offspring development and long-term health.
Publisher: MDPI AG
Date: 15-07-2021
DOI: 10.3390/NU13072418
Abstract: The authors would like to correct a typographical error in their recently published paper [...]
Publisher: Wiley
Date: 03-06-2022
DOI: 10.1113/JP282840
Abstract: Prophylactic creatine treatment may reduce hypoxic brain injury due to its ability to sustain intracellular ATP levels thereby reducing oxidative and metabolic stress responses during oxygen deprivation. Using microdialysis, we investigated the real‐time in vivo effects of fetal creatine supplementation on cerebral metabolism following acute in utero hypoxia caused by umbilical cord occlusion (UCO). Fetal sheep (118 days’ gestational age (dGA)) were implanted with an inflatable Silastic cuff around the umbilical cord and a microdialysis probe inserted into the right cerebral hemisphere for interstitial fluid s ling. Creatine (6 mg kg −1 h −1 ) or saline was continuously infused intravenously from 122 dGA. At 131 dGA, a 10 min UCO was induced. Hourly microdialysis s les were obtained from −24 to 72 h post‐UCO and analysed for percentage change of hydroxyl radicals ( • OH) and interstitial metabolites (lactate, pyruvate, glutamate, glycerol, glycine). Histochemical markers of protein and lipid oxidation were assessed at post‐mortem 72 h post‐UCO. Prior to UCO, creatine treatment reduced pyruvate and glycerol concentrations in the microdialysate outflow. Creatine treatment reduced interstitial cerebral • OH outflow 0 to 24 h post‐UCO. Fetuses with higher arterial creatine concentrations before UCO presented with reduced levels of hypoxaemia ( and ) during UCO which associated with reduced interstitial cerebral pyruvate, lactate and • OH accumulation. No effects of creatine treatment on immunohistochemical markers of oxidative stress were found. In conclusion, fetal creatine treatment decreased cerebral outflow of • OH and was associated with an improvement in cerebral bioenergetics following acute hypoxia. image Fetal hypoxia can cause persistent metabolic and oxidative stress responses that disturb energy homeostasis in the brain. Creatine in its phosphorylated form is an endogenous phosphagen therefore, supplementation is a proposed prophylactic treatment for fetal hypoxia. Fetal sheep instrumented with a cerebral microdialysis probe were continuously infused with or without creatine‐monohydrate for 10 days before induction of 10 min umbilical cord occlusion (UCO 131 days’ gestation). Cerebral interstitial fluid was collected up to 72 h following UCO. Prior to UCO, fetal creatine supplementation reduced interstitial cerebral pyruvate and glycerol concentrations. Fetal creatine supplementation reduced cerebral hydroxyl radical efflux up to 24 h post‐UCO. Fetuses with higher arterial creatine concentrations before UCO and reduced levels of systemic hypoxaemia during UCO were associated with reduced cerebral interstitial pyruvate, lactate and • OH following UCO. Creatine supplementation leads to some improvements in cerebral bioenergetics following in utero acute hypoxia.
Publisher: Hindawi Limited
Date: 29-01-2022
DOI: 10.1155/2022/3255296
Abstract: Near-term acute hypoxia in utero can result in significant fetal brain injury, with some brain regions more vulnerable than others. As mitochondrial dysfunction is an underlying feature of the injury cascade following hypoxia, this study is aimed at characterizing mitochondrial function at a region-specific level in the near-term fetal brain after a period of acute hypoxia. We hypothesized that regional differences in mitochondrial function would be evident, and that prophylactic creatine treatment would mitigate mitochondrial dysfunction following hypoxia thereby reducing fetal brain injury. Pregnant Border-Leicester/Merino ewes with singleton fetuses were surgically instrumented at 118 days of gestation (dGa term is ~145 dGA). A continuous infusion of either creatine ( n = 15 6 mg/kg/h) or isovolumetric saline ( n = 16 1.5 ml/kg/h) was administered to the fetuses from 121 dGa. After 10 days of infusion, a subset of fetuses (8 saline-, 7 creatine-treated) were subjected to 10 minutes of umbilical cord occlusion (UCO) to induce a mild global fetal hypoxia. At 72 hours after UCO, the fetal brain was collected for high-resolution mitochondrial respirometry and molecular and histological analyses. The results show that the transient UCO-induced acute hypoxia impaired mitochondrial function in the hippoc us and the periventricular white matter and increased the incidence of cell death in the hippoc us. Creatine treatment did not rectify the changes in mitochondrial respiration associated with hypoxia, but there was a negative relationship between cell death and creatine content following treatment. Irrespective of UCO, creatine increased the proportion of cytochrome c bound to the inner mitochondrial membrane, upregulated the mRNA expression of the antiapoptotic gene Bcl2, and of PCG1-α, a driver of mitogenesis, in the hippoc us. We conclude that creatine treatment prior to brief, acute hypoxia does not fundamentally modify mitochondrial respiratory function, but may improve mitochondrial structural integrity and potentially increase mitogenesis and activity of antiapoptotic pathways.
Publisher: Wiley
Date: 31-05-2021
DOI: 10.1113/JP281266
Abstract: Brief episodes of severe fetal hypoxia can arise in late gestation as a result of interruption of normal umbilical blood flow Systemic parameters and blood chemistry indicate complete recovery within 1–2 hours, although the long‐term effects on fetal brain functions are unknown Fetal sheep were subjected to umbilical cord occlusion (UCO) for 10 min at 131 days of gestation, and then monitored intensively until onset of labour or delivery ( days of gestation) Normal patterns of fetal behaviour, including breathing movements, episodes of high and low voltage electorcortical activity, eye movements and postural (neck) muscle activity, were disrupted for 3–10 days after the UCO Preterm labour and delivery occurred in a significant number of the pregnancies after UCO compared to the control (sham‐UCO) cohort. Complications arising from antepartum events such as impaired umbilical blood flow can cause significant fetal hypoxia. These complications can be unpredictable, as well as difficult to detect, and thus we lack a detailed understanding of the (patho)physiological changes that occur between the antenatal in utero event and birth. In the present study, we assessed the consequences of brief (∼10 min) umbilical cord occlusion (UCO) in fetal sheep at ∼0.88 gestation on fetal plasma cortisol concentrations and fetal behaviour [electrocortical (EcoG), electo‐oculargram (EOG), nuchal muscle electromyography (EMG) and breathing activities] in the days following UCO. UCO caused a rapid onset of fetal hypoxaemia, hypercapnia, and acidosis however, by 6 h, all blood parameters and cardiovascular status were normalized and not different from the control (Sham‐UCO) cohort. Subsequently, the incidence of fetal breathing movements decreased compared to the control group, and abnormal behavioural patterns developed over the days following UCO and leading up to the onset of labour, which included increased high voltage and sub‐low voltage ECoG and EOG activities, as well as decreased nuchal EMG activity. Fetuses subjected to UCO went into labour 7.9 ± 3.6 days post‐UCO (139.5 ± 3.2 days of gestation) compared to the control group fetuses at 13.6 ± 3.3 days post‐sham UCO (144 ± 2.2 days of gestation P 0.05), despite comparable increases in fetal plasma cortisol and a similar body weight at birth. Thus, a single transient episode of complete UCO late in gestation in fetal sheep can result in prolonged effects on fetal brain activity and premature labour, suggesting persisting effects on fetal cerebral metabolism.
Publisher: Wiley
Date: 21-07-2018
DOI: 10.1113/JP275595
Publisher: Wiley
Date: 02-06-2018
DOI: 10.1113/JP274950
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/IJMS22094296
Abstract: Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland—the adrenarche—and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which in iduals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.
No related grants have been discovered for David Walker.