The Orexin/Hypocretin System, the Peptidergic Regulator of Vigilance, Orchestrates Adaptation to Stress

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 448 - 448

Published: Feb. 17, 2024

The orexin/hypocretin neuropeptide family has emerged as a focal point of neuroscientific research following the discovery that this plays crucial role in variety physiological and behavioral processes. These neuropeptides serve powerful neuromodulators, intricately shaping autonomic, endocrine, responses across species. Notably, they master regulators vigilance stress responses; however, their roles food intake, metabolism, thermoregulation appear complementary warrant further investigation. This narrative review provides journey through evolution our understanding orexin system, from its initial to promising progress made developing derivatives. It goes beyond conventional boundaries, striving synthesize multifaceted activities orexins. Special emphasis is placed on domains such response, fear, anxiety, learning, which authors have contributed literature with original publications. paper also overviews advancement pharmacology, already yielded some successes, particularly treatment sleep disorders.

Language: Английский

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Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 100, P. 129629 - 129629

Published: Jan. 30, 2024

Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery CVN766, a potent 1 receptor antagonist that has greater than 1000-fold selectivity over 2 demonstrates low off target hits in diversity screen. In agreement with its vitro ADME data, CVN766 demonstrated moderate vivo clearance rodents displayed good brain permeability occupancy. This drug candidate is currently investigated clinical trials schizophrenia related conditions.

Language: Английский

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Synthesis and Characterization of a New Carbon-11 Labeled Positron Emission Tomography Radiotracer for Orexin 2 Receptors Neuroimaging

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 215 - 222

Published: Jan. 1, 2024

Purpose: Orexin receptors (OXRs) play a crucial role in modulating various physiological and neuropsychiatric functions within the central nervous system (CNS). Despite their significance, precise of OXRs brain remains elusive. Positron emission tomography (PET) imaging is instrumental unraveling CNS functions, development specific PET tracers for current research focus. Methods: The study investigated MDK-5220, an OX2R-selective agonist with promising binding properties (EC 50 on OX 2 R: 0.023 μM, Ki hOX 0.14 μM). Synthesized characterized as R probe, [ 11 C]MDK-5220 was evaluated its potential tracer. Biodistribution studies mice were conducted to assess selectivity, particular attention interaction P-glycoprotein (P-gp) blood-brain barrier. Results: exhibited attributes demonstrating robust selectivity biodistribution studies. However, observed P-gp impacted uptake. this limitation, presents itself candidate further development. Discussion: provides insights into functionality probe. highlights consideration future modifications enhance findings pave way innovative tracer propel ongoing systems, contributing deeper understanding CNS. Conclusion: emerges despite challenges related interaction. This lays foundation exploration probes targeting OXRs, opening avenues advancing our brain. Keywords: synthesis characterization, orexin-2 receptor, positron tomography, carbon-11 labeling, neuroimaging

Language: Английский

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The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Clinical and Translational Neuroscience, Journal Year: 2024, Volume and Issue: 8(1), P. 11 - 11

Published: Feb. 2, 2024

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of glymphatic system, which mainly active during sleep. Changes in sleep circadian are present not only overt neurodegenerative diseases but also their early, prodromal, preclinical phases, supporting they precede (and contribute to) development This narrative review provides brief overview rhythm disruption neurodegeneration, highlights changes addresses future perspectives, particular, whether able to predict neurodegeneration potential actionability prevent or modulate diseases.

Language: Английский

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Rethinking the Role of Orexin in the Regulation of REM Sleep and Appetite

Nutrients, Journal Year: 2023, Volume and Issue: 15(17), P. 3679 - 3679

Published: Aug. 22, 2023

Orexin plays a significant role in the modulation of REM sleep, as well regulation appetite and feeding. This review explores, first, current evidence on orexin sleep wakefulness highlights that should be considered essentially neurotransmitter inhibiting and, to much lesser extent, wake promoting agent. Subsequently, relationship between orexin, is examined detail, shedding light their interconnected nature both physiological conditions diseases (such narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, night syndrome). Understanding intricate vital for unraveling complex mechanisms underlying sleep-wake patterns metabolic control. Further research this field encouraged order pave way novel therapeutic approaches disorders associated with dysregulation.

Language: Английский

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Analysis of the finasteride treatment and its withdrawal in the rat hypothalamus and hippocampus at whole-transcriptome level

Journal of Endocrinological Investigation, Journal Year: 2024, Volume and Issue: 47(10), P. 2565 - 2574

Published: March 17, 2024

Abstract Purpose As reported in patients treated for androgenetic alopecia with finasteride (i.e., a blocker of the enzyme 5 alpha-reductase) and an animal model, side effects affecting sexual, psychiatric, neurological, physical domains, may occur during treatment persist drug suspension. The etiopathogenesis these has been poorly explored. Therefore, we performed genome-wide analysis brain adult male rat. Methods Animals were 20 days) (1mg/rat/day). 24 h after last 1 month suspension, RNA sequencing was hypothalamus hippocampus. Data analyzed by differential expression Gene-Set Enrichment Analyses (GSEA). Results obtained showed that 186 genes 171 up- 15 downregulated) 19 17 2 differentially expressed hippocampus, respectively. Differential at withdrawal failed to identify dysregulated genes. Several gene-sets enriched areas both time points. Conclusion Some be TTR , DIO2 CLDN1 CLDN2 SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL ) GSEA, suggest potential link specific previously observed such as depression, anxiety, disturbance memory attention, sleep disturbance. These data provide important background future experiments aimed confirming pathological role

Language: Английский

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The Flavonoids and Monoterpenes from Citrus unshiu Peel Contained in Ninjinyoeito Synergistically Activate Orexin 1 Receptor: A Possible Mechanism of the Orexigenic Effects of Ninjinyoeito

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 533 - 533

Published: April 5, 2025

Cancer cachexia, often observed in patients with advanced-stage cancer, is characterized by the loss of body weight and appetite. The Japanese herbal medicine Ninjinyoeito (NYT), which composed 12 crude components, has been used as a therapeutic Japan to improve anorexia fatigue, are commonly cancer cachexia. We have previously reported that Citrus unshiu peel (CUP) contained NYT can enhance food intake activating orexin 1 receptor (OX1R). Using CellKey™ system, offers detection OXR activity intracellular impedance changes, CUP were found activate OX1R, turn was inhibited SB-674042, selective OX1R antagonist. Among flavonoids CUP, nobiletin hesperidin, but not naringin, activated OX1R. Furthermore, some monoterpenes including limonene linalool, terpineol, In addition, synergistically when added simultaneously. However, neither nor induced OX2R activity. results collectively suggested activates OX2R, These findings could provide evidence supporting potential

Language: Английский

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Exploring the Toxicity and Therapeutic Potential of A. dahurica and A. pubescens in Zebrafish Larvae: Insights into Anxiety Treatment Mechanisms

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2884 - 2884

Published: March 22, 2025

This study assessed the toxicity and therapeutic potential of Angelica dahurica pubescens using Danio rerio (zebrafish) larvae. Toxicity was evaluated through mortality, malformations, gene expression changes related to stress HPA axis. A. demonstrated low (LD50 (50% lethal dose) >200 µg/mL), with no significant malformations at 15-30 µg/mL, although higher doses caused edemas heart defects. exhibited toxicity, 100% mortality 200 µg/mL severe malformations. Both species showed cardiotoxicity, slowing rates after prolonged exposure. Gene studies suggested had stress-protective effects, increasing nr3c1 expression, while dose-dependent lower concentrations having anxiolytic properties stress. Interestingly, diazepam unexpected changes, highlighting influence environmental dosage factors. In conclusion, both show for anxiety, showing promising effects concentrations. However, requires careful management due its risks. Further are needed optimize applications fully understand mechanisms action.

Language: Английский

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Structure and function of neocortical layer 6b

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Sept. 6, 2023

Cortical layer 6b is considered by many to be a remnant of the subplate that forms during early stages neocortical development, but its role in adult not well understood. Its neuronal complement has only recently become subject systematic studies, and axonal projections synaptic input structures have remained largely unexplored despite decades research into function. In recent years, however, (L6b) attracted increasing attention functional beginning elucidated. this review, I will attempt provide an overview what currently known about excitatory inhibitory neurons layer, their pre- postsynaptic connectivity, implications. Similarities differences between different cortical areas highlighted. Finally, are highly responsive several neuropeptides such as orexin/hypocretin, neurotensin cholecystokinin, some cases exclusively. They also strongly controlled neurotransmitters acetylcholine norepinephrine. The interaction these neuromodulators with L6b microcircuitry consequences discussed.

Language: Английский

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Insomnia and the Orexinergic Pathway in the Link with Psychopathology: Effects of DORAs in Insomnia Comorbid with Mental Disturbances

Current Sleep Medicine Reports, Journal Year: 2024, Volume and Issue: 10(2), P. 119 - 131

Published: April 18, 2024

Language: Английский

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