Brain Endothelial Cells: Metabolic Flux and Energy Metabolism

McDonald, Cade; Blankenheim, Zachery J; Drewes, Lester R.

doi:10.1007/164_2021_494

Cited by 6 publications

(5 citation statements)

References 61 publications

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“…Altered TJ integrity, altered expression of trophic transporters, inhibition of essential substrate uptake, altered active efflux of molecules, and disrupted angiogenesis all affect ATP demand. 115 ATP is a critical molecule in cellular energy metabolism and serves as an important signaling molecule in intercellular communication. Notably, the AMP/ ATP ratio has been suggested as a link between circadian rhythms and energy metabolism.…”

Section: Atpmentioning

confidence: 99%

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Kim,

Keep,

Zhang

2024

Circulation Research

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The blood-brain barrier (BBB) is a critical interface separating the central nervous system from the peripheral circulation, ensuring brain homeostasis and function. Recent research has unveiled a profound connection between the BBB and circadian rhythms, the endogenous oscillations synchronizing biological processes with the 24-hour light-dark cycle. This review explores the significance of circadian rhythms in the context of BBB functions, with an emphasis on substrate passage through the BBB. Our discussion includes efflux transporters and the molecular timing mechanisms that regulate their activities. A significant focus of this review is the potential implications of chronotherapy, leveraging our knowledge of circadian rhythms for improving drug delivery to the brain. Understanding the temporal changes in BBB can lead to optimized timing of drug administration, to enhance therapeutic efficacy for neurological disorders while reducing side effects. By elucidating the interplay between circadian rhythms and drug transport across the BBB, this review offers insights into innovative therapeutic interventions.

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Section: Atpmentioning

confidence: 99%

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Kim,

Keep,

Zhang

2024

Circulation Research

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“…Expression of the protein transporter TOMM20 was upregulated in eNOS high groups at 7 DPI (Figure S3D), unchanged at 1 MPI (Figure S3E), and downregulated at 12 MPI (Figure S3F). Previous research has demonstrated that, despite having access to sufficient oxygen, BMECs are highly glycolytic (McDonald et al, 2022). The young adult mice, at 7 DPI, protein expression results suggest that MCMV enhances this metabolic preference.…”

Section: Resultsmentioning

confidence: 99%

Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice

Harrison

Morris

Rudman

et al. 2022

Preprint

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Risk factors contributing to dementia are multifactorial. Pathogens as risk factors for dementia is largely correlative with few causal relationships. Here, we demonstrate that intermittent cytomegalovirus (CMV) infection in mice, mimicking human chronic infection and reactivation/reinfection events, alters blood brain barrier (BBB) metabolic pathways. An increase in basal mitochondrial function is observed in brain microvasculature endothelial cells (BMEC) at 12 months post infection but not at earlier time points and is accompanied by elevated levels of superoxide, indicative of oxidative stress. Further, these mice score lower in cognitive assays as compared to age-matched controls. Our data show that repeated systemic infection with CMV, alters BBB metabolic function and impacts cognition. These observations provide mechanistic insights through which pathogens contribute to the progression of pathologies associated with dementia.

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“…While glycolysis plays a major role, oxidative phosphorylation also contributes significantly to the production of total adenosine triphosphate (ATP). 44,45 Seahorse test showed that the elevated metabolic level with the treatment of HP@124 rescues the poor state of ECs, and may promote migration and restore TJs. However, further research is required to verify the association between energy metabolism and BSCB restoration.…”

Section: Discussionmentioning

confidence: 99%

“…Our bioinformatics analysis revealed that the effects on the microvascular endothelial cells were related to the process of metabolism, of which the main way is glucose metabolism, including glycolysis and oxidative phosphorylation. While glycolysis plays a major role, oxidative phosphorylation also contributes significantly to the production of total adenosine triphosphate (ATP) 44,45 …”

Section: Discussionmentioning

confidence: 99%

Thermosensitive hydrogel‐based GPR124 delivery strategy for rebuilding blood‐spinal cord barrier

Shu

Wang

Tao

et al. 2023

Bioengineering & Transla Med

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Spinal cord injury (SCI) causes blood‐spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel‐based G protein‐coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post‐SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post‐SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin‐poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post‐SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.

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Brain Endothelial Cells: Metabolic Flux and Energy Metabolism

Cited by 6 publications

References 61 publications

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice

Thermosensitive hydrogel‐based GPR124 delivery strategy for rebuilding blood‐spinal cord barrier

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