Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-Ischaemia: Simulating Brain Energetics

Moroz, Tracy; Hapuarachchi, Tharindi; Bainbridge, Alan; Price, David L.; Cady, Ernest B.; Baer, E.; Broad, Kevin D.; Ezzati, M; Thomas, David L.; Golay, Xavier; Robertson, Nicola J.; Cooper, Chris E.; Tachtsidis, Ilias

doi:10.1007/978-1-4614-7411-1_45

Cited by 4 publications

(2 citation statements)

References 3 publications

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“…Thus, it is not surprising that a significant percentage of studies on neonatal brain injury employ the piglet model [ 40 ]. However, while few computational studies have used the piglet model to analyze the effect of neonatal brain injury on cerebral blood flow and metabolism [ 41 – 43 ], computational approaches to study intracellular signaling in normal and injured states has not been performed in this model. Since this approach has generated novel insights into neuronal function based on data from rodent models [ 44 – 46 ], our study represents a significant step in building computational models of intracellular signaling with greater translational relevance to human disease and injury conditions.…”

Section: Discussionmentioning

confidence: 99%

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury

Kratimenos

Vij

Vidva³

et al. 2022

J Neurodevelop Disord

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Background Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca2+-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca2+/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca2+-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. Methods We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2–3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca2+-influx, and Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca2+/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. Results Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca2+ level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca2+-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca2+-influx and Bax expression to similar levels as pre-treatment. Conclusions Our model identifies new dynamics of critical components in the Ca2+/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities.

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Section: Discussionmentioning

confidence: 99%

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury

Kratimenos

Vij

Vidva³

et al. 2022

J Neurodevelop Disord

View full text Add to dashboard Cite

show abstract

“…Thus, it is not surprising that a signi cant percentage of studies on neonatal brain injury employ the piglet model [39]. However, while few computational studies have used the piglet model to analyze the effect of neonatal brain injury on cerebral blood ow and metabolism [40][41][42], computational approaches to study intracellular signaling in normal and injured states has not been performed in this model. Since this approach has generated novel insights into neuronal function based on data from rodent models [43][44][45], our study represents a signi cant step in building computational models of intracellular signaling with greater translational relevance to human disease and injury conditions.…”

Section: Discussionmentioning

confidence: 99%

Computational Analysis of Cortical Neuronal Excitotoxicity in a Large Animal Model of Neonatal Brain Injury

Kratimenos

Vij

Vidva³

et al. 2021

Preprint

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Background: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca2+-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca2+/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca2+-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. Methods: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3 day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2]groups) for biochemical analysis of ATP production, Ca2+-influx, and Ca2+/CaM-dependent protein kinase kinase 2(CaMKK2) expression. We then used SimBiology to build a computational model of the Ca2+/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning.Results: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca2+ level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca2+-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca2+-influx and Bax expression to similar levels as pre-treatment. Conclusions: Our model identifies new dynamics of critical components in the Ca2+/CaM-Src signaling pathway leading to neuronal injury and provides an essential framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities.

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Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-Ischaemia: Simulating pH Changes

Hapuarachchi

Moroz

Bainbridge

et al. 2013

Oxygen Transport to Tissue XXXV

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We describe the extension of a computational model of blood flow and metabolism in the piglet brain to investigate changes in neonatal intracellular brain pH during hypoxia-ischemia (HI). The model is able to simulate near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) measurements obtained from HI experiments conducted in piglets. We adopt a method of using 31P-MRS data to estimate of intracellular pH and compare measured pH and oxygenation with their modelled counterparts. We show that both NIRS and MRS measurements are predicted well in the new version of the model.

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Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-Ischaemia: Simulating Brain Energetics

Cited by 4 publications

References 3 publications

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury

Computational Analysis of Cortical Neuronal Excitotoxicity in a Large Animal Model of Neonatal Brain Injury

Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-Ischaemia: Simulating pH Changes

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