Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin: a pharmacodynamic study DOI Creative Commons
Akiko Ohashi, Eiko Nakamaru‐Ogiso, Hiroshi Matsuoka

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 18, 2024

Abstract Background The levels of brain tetrahydrobiopterin (BH4), a coenzyme tryptophan hydroxylase and tyrosine hydroxylase, regulate the rates monoamine synthesis, including serotonin, dopamine, noradrenaline. attempt to treat congenital or acquired central nervous system (CNS) disorders caused by deficiency with synthetic BH4, 6RBH4, has failed owing its limited permeation through blood-brain barrier (BBB). Sepiapterin (SP), BH4 precursor, is known be rapidly assimilated into cellular BH4-salvage pathway. However, no treatment attempts SP have been made, concerns about ability reach parenchyma when administered peripherally. Therefore, we investigated pharmacodynamics entry CNS following intraperitoneal (ip) administration SP. Methods To assess delivery, derived an equation describing cell-uptake as function dose based on tandem model; BBB cell membranes. We estimated each clearances determining directional component flow: influx (CLin) uptake (CLuptake) were determined in vitro, while pumping plasma (CLout) was calculated using vivo data from previous studies involving direct injection rat ventricle. validate model vivo, various doses mice measured resulting increase in levels. distinguish increases due those exogenous quantification performed 6 hours after administration, had ceased. Results predicted linear SP, clearance CL(plasma→cells) = 5.42–10.2 µL·min-1·g-1. In results showed that suprathreshold (> 13.3 mg/kg, mice, ip) linearly increased concentrations. In this context, reached brain, taken up, AUCplasma 1.3–2.45 µM·min per 1 mg/kg-body. Conclusions Peripheral at practical range dose-dependent manner. could promising therapy enhance synthesis neurotransmitter deficiencies.

Language: Английский

The pathobiology of neurovascular aging DOI
Monica M. Santisteban, Costantino Iadecola

Neuron, Journal Year: 2025, Volume and Issue: 113(1), P. 49 - 70

Published: Jan. 1, 2025

Language: Английский

Citations

4
Diffusion magnetic resonance imaging of cerebrospinal fluid dynamics: Current techniques and future advancements DOI
Adam M. Wright, Yu‐Chien Wu, Li Feng

et al.

NMR in Biomedicine, Journal Year: 2024, Volume and Issue: 37(9)

Published: May 7, 2024

Abstract Cerebrospinal fluid (CSF) plays a critical role in metabolic waste clearance from the brain, requiring its circulation throughout various brain pathways, including ventricular system, subarachnoid spaces, para‐arterial interstitial and para‐venous spaces. The complexity of CSF has posed challenge obtaining noninvasive measurements dynamics. assessment dynamics circulatory pathways is possible using diffusion magnetic resonance imaging (MRI) with optimized sensitivity to incoherent water movement across brain. This review presents an overview both established emerging MRI techniques designed measure their potential clinical applications. discussion offers insights into optimization acquisition parameters enhance specificity metrics on underlying Lastly, we emphasize importance cautious interpretations diffusion‐based imaging, especially when differentiating between tissue‐ fluid‐related changes or elucidating structural versus functional alterations.

Language: Английский

Citations

13
Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge DOI Creative Commons
Shahram Darabi, Enam Alhagh Charkhat Gorgich, Fatemeh Moradi

et al.

IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: 18, P. 191 - 199

Published: Jan. 9, 2025

Language: Английский

Citations

2
Exploring Radial Asymmetry in MR Diffusion Tensor Imaging and Its Impact on the Interpretation of Glymphatic Mechanisms DOI Creative Commons
Adam M. Wright, Yu‐Chien Wu, Nan‐kuei Chen

et al.

Journal of Magnetic Resonance Imaging, Journal Year: 2023, Volume and Issue: 60(4), P. 1432 - 1441

Published: Dec. 29, 2023

Background Diffusion imaging holds great potential for the non‐invasive assessment of glymphatic system in humans. One technique, diffusion tensor along perivascular space (DTI‐ALPS), has introduced ALPS‐index, a novel metric evaluating diffusivity within space. However, it still needs to be established whether observed reduction ALPS‐index reflects axonal changes, common occurrence neurodegenerative diseases. Purpose To determine alterations can influence change ALPS‐index. Study Type Retrospective. Population 100 participants (78 cognitively normal and 22 with mild cognitive impairments) aged 50–90 years old. Field Strength/Sequence 3T; diffusion‐weighted single‐shot spin‐echo echo‐planar sequence, T1‐weighted images (MP‐RAGE). Assessment The ratio two radial diffusivities (i.e., λ2/λ3) across major white matter tracts distinct venous/perivenous anatomy that fulfill (ALPS‐tracts) do not (control tracts) anatomical assumptions were analyzed. Statistical Tests investigate correlation between λ2/λ3 age/cognitive function (RAVLT) while accounting effect age, linear regression was implemented remove age from each variable. Pearson analysis conducted on residuals obtained regression. significance set at p < 0.05. Results λ2 ~50% higher than λ3 demonstrated consistent pattern both ALPS control tracts. Additionally, advancing ( r = −0.39, −0.29, association forceps tract, respectively) decreased memory 0.24, 0.27, respectively). Data Conclusions results unveil widespread asymmetry changes aging neurodegeration. These findings highlight may solely reflect but also incorporate contributions. Level Evidence 3 Technical Efficacy Stage 2

Language: Английский

Citations

22
The microcirculation, the blood-brain barrier and the neurovascular unit in health and Alzheimer’s Disease. The aberrant pericyte is a central player. DOI Creative Commons
Yasmin Amy Divecha, Sanketh Rampes,

S. W. Tromp

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: 77(3), P. 100052 - 100052

Published: March 13, 2025

High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation the brain microenvironment, and its separation from variable potentially neurotoxic contents blood, brought about central nervous system barriers. Evidence clinical preclinical studies implicates microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation key to understanding disease (AD), identifying drug targets, developing treatment strategies, improving prescribing vulnerable population. This review has 2 parts: part 1 describes blood flow, extracellular fluid drainage, neurovascular unit components with an emphasis on barrier, summarizes how each aspect altered AD. Discussing structures separately allows us conclude that aberrant pericytes are early contributor AD Pericytes have multiple functions including maintenance integrity control capillary stalling, coupling, intramural periarterial glia-lymphatic (glymphatic) consequently tau clearance. vasoactive, express cholinergic adrenergic receptors, exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion linked pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) loops cause pericyte which contributes even initiates degeneration. We pathophysiology, interesting therapeutic target AD, emerging role regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation dysfunction circulation (including cerebrospinal fluid, interstitial fluid) occurs disease. player pericyte. fundamental implications pathophysiology development therapies.

Language: Английский

Citations

1
Bis(2-ethylhexyl)-tetrabromophthalate Poses a Higher Exposure Risk and Induces Gender-Specific Metabolic Disruptions in Zebrafish Liver DOI

Kaiyu Fu,

Biran Zhu, Yumiao Sun

et al.

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: 58(11), P. 4937 - 4947

Published: March 6, 2024

Bis(2-ethylhexyl)-tetrabromophthalate (TBPH), a typical novel brominated flame retardant, has been ubiquitously identified in various environmental and biotic media. Consequently, there is an urgent need for precise risk assessment based on comprehensive understanding of internal exposure the corresponding toxic effects specific tissues. In this study, we first investigated toxicokinetic characteristics TBPH different tissues using classical pseudo-first-order model. We found that was prone to accumulate liver rather than gonad, brain, muscle both female male zebrafish, highlighting higher liver. Furthermore, long-term at environmentally relevant concentrations led increased visceral fat accumulation, signaling potential abnormal function. Hepatic transcriptome analysis predominantly implicated glycolipid metabolism pathways. However, alterations profile associated genes biochemical indicators revealed gender-specific responses following exposure. Besides, histopathological observations as well inflammatory response confirmed development nonalcoholic fatty disease, particularly zebrafish. Altogether, our findings highlight liver, enhancing metabolic-disrupting with

Language: Английский

Citations

5
Transmantle pressure under the influence of free breathing: non-invasive quantification of the aqueduct pressure gradient in healthy adults DOI Creative Commons
Pan Liu, K. P. Owashi,

Heimiri Monnier

et al.

Fluids and Barriers of the CNS, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 3, 2025

Language: Английский

Citations

0
Cardiac and respiratory activities induce temporal changes in cerebral blood volume, balanced by a mirror CSF volume displacement in the spinal canal DOI Creative Commons
Pan Liu, K. P. Owashi,

Heimiri Monnier

et al.

NeuroImage, Journal Year: 2024, Volume and Issue: 305, P. 120988 - 120988

Published: Dec. 25, 2024

Language: Английский

Citations

2
Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions DOI

BaoLing Chen,

Wanlin Yang, Yuqi Luo

et al.

Journal of Neurology, Journal Year: 2023, Volume and Issue: 270(11), P. 5251 - 5273

Published: July 21, 2023

Language: Английский

Citations

4
Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin DOI Creative Commons
Akiko Ohashi, Eiko Nakamaru‐Ogiso, Hiroshi Matsuoka

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 8, 2024

Abstract Tetrahydrobiopterin (BH4) is an essential coenzyme for tryptophan and tyrosine hydroxylases, making brain monoamine biosynthesis BH4-dependent. Peripheral administration of BH4 successfully replenishes hepatic in hereditary deficiency enables the function another BH4-dependent enzyme, phenylalanine hydroxylase. However, replenishment has been unsuccessful decades because cannot effectively cross blood–brain barrier (BBB). Sepiapterin, a highly membrane-permeable precursor BH4, tested but abandoned due to extensive conversion before reaching brain. This study re-examines whether peripherally administered sepiapterin can (i) reach brain, (ii) BBB, (iii) be taken up by cells, (iv) increase levels. As result, reached when dose was above threshold. All subsequent steps were positive. Sepiapterin dose-dependently increased levels, 3–4 times baseline levels over 6 hours at practical doses. In addition, we quantified analyzed permeability across potential barriers using knowledge transporters responsible permeation cell membranes confirmed that these results theoretically consistent. suggests may promising treatment synthesis various neurotransmitter deficiencies.

Language: Английский

Citations

1