Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

Cancers, Journal Year: 2021, Volume and Issue: 13(11), P. 2612 - 2612

Published: May 26, 2021

Conditions such as Alzheimer's (AD) and Parkinson's diseases (PD) are less prevalent in cancer survivors and, overall, is subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk other. In addition epidemiologic data, there also evidence complex biological interconnection, genes, proteins, pathways often showing opposite dysregulation diseases. this narrative review, we focus on possible role played by orexin signaling, which altered patients narcolepsy 1 those AD PD, has been linked β-amyloid brain levels inflammation mouse models cell lines. Taken together, lines depict case inverse comorbidity between disorders, orexins. These considerations therapeutic potential modulation diverse pathologies narcolepsy, cancer.

Language: Английский

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Sleep–Wake Disorders in Alzheimer’s Disease: A Review

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 13(10), P. 1467 - 1478

Published: May 4, 2022

Alzheimer's disease (AD) is a multifactorial disease, and it has become serious health problem in the world. Senile plaques (SPs) neurofibrillary tangles (NFTs) are two main pathological characters of AD. SP mainly consists aggregated β-amyloid (Aβ), NFT formed by hyperphosphorylated tau protein. Sleep–wake disorders prevalent AD patients; however, links mechanisms sleep–wake on pathogenesis remain to be investigated. Here, we referred reviewed some evidence demonstrate relationship between On one hand, may lead increase Aβ production decrease clearance, spreading pathology, as well oxidative stress inflammation. other ApoE4 allele, risk gene for AD, was reported participate disorders. Furthermore, neurotransmitters, such acetylcholine, glutamate, serotonin, melatonin, orexins, their receptors were suggested involved development We discussed possible therapeutic strategies treatment based view sleep regulation. In general, this review explored different views find novel targets diagnosis therapy

Language: Английский

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Orexin dual receptor antagonists, zolpidem, zopiclone, eszopiclone, and cognitive research: A comprehensive dose-response meta-analysis

Frontiers in Human Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Jan. 9, 2023

Background About one-third of adults have trouble sleeping, ranging from occasional difficulty to chronic insomnia, along with maintaining sleep. Many studies reported that the long-term use hypnotics can cause brain dysfunction and damage cognition. Objective The objective study is evaluate whether low, medium, high doses orexin dual receptor antagonists (DORA), zopiclone (ZOP), eszopiclone (ESZ), zolpidem (ZST) impair Methods From beginning through September 20, 2022, PubMed, Embase, Scopus, Cochrane Library, Google Scholar were searched. Randomized controlled trials (RCTs) assessing therapeutic effects DORA, eszopiclone, for sleep cognitive function included. primary outcomes indices related profile, including memory, alertness, execution control function, attention orientation. secondary adverse events. standard mean difference (SMD) was generated continuous variables. Certain data captured figures by GetData 2.26 analyzed using RStudio 4.2. Results Finally, a total 8,702 subjects included in 29 studies. Compared placebo, DSST (Digit Symbol Substitution Test) scores DORA SMD = 0.77; 95% CI: 0.33–1.20; 1.58; 1.11–2.05; 0.85; 0.33–1.36, respectively. at −0.39; 0.85–0.07; −0.88, −2.34–0.58; −0.12, −0.85–0.60, Zopiclone's scale score −0.18; −0.54–0.18. In addition, time (TST) 0.28, −0.15–0.70; 1.36, 0.87–1.86; 2.59, 1.89–3.30, TST 1.01, 0.18–1.83; 1.94, 0.46–3.43; 1.71, 0.86–2.56, relatively 2.03, −0.21–4.27; 2.38, 1.35–3.42; 0.60–2.82. 2.47, 1.36–3.58. Conclusion We recommend as best intervention insomnia because it highly effective inducing without impairing Although has more pronounced effect on sleep, reduce its side effects. Eszopiclone improved quality, but their safety cognition remains be verified.

Language: Английский

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Involvement of orexin nerves in early stage of Alzheimer's disease model mice and preventive effect of orexin receptor antagonists

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Abstract Background Mild cognitive impairment (MCI) is a condition between healthy cognition and dementia with high probability of progression to Alzheimer’s disease (AD). Elevated levels orexin (OX) have been reported in the cerebrospinal fluid patients MCI AD. Objective To investigate efficacy dual OX receptor antagonists (suvorexant lemborexant) an early-stage AD mouse model (App-KI). Methods The expression gene, suvorexant lemborexant brain after single oral dose, their effects on locomotor activity were investigated wild-type mice. In addition, function App-KI mice was assessed using Y-maze test administration or once day for 60 d. After behavioral test, amyloid-beta quantified hippocampal CA1 region Results gene highest lateral hypothalamus also observed other regions. Drug peaked at 20–40 min 15 declined, still detectable 24 h later. Locomotor reduced administration; however, administration, did not differ from control group. particular, showed that prevented Furthermore, suppressed accumulation Conclusion results suggest effectively suppress early stages

Language: Английский

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Reduction of orexin-expressing neurons and a unique sleep phenotype in the Tg-SwDI mouse model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Feb. 4, 2025

Sleep disturbances are common in Alzheimer’s disease (AD) and AD-related dementia (ADRD). We performed a sleep study on Tg-SwDI mice, cerebral amyloid angiopathy (CAA) model, age-matched wild-type (WT) control mice. The results showed that at 12 months of age, the hemizygous mice spent significantly more time non-rapid eye movement (NREM) (44.6 ± 2.4% versus 35.9 2.5% WT) had much shorter average length wake bout during dark (active) phase (148.5 8.7 s 203.6 13.0 WT). Histological analysis revealed stark decreases orexin immunoreactive (orexin-IR) neuron number soma size these (cell number: 2187 97.1 3318 137.9 WT. size: 109.1 8.1 μm 2 160.4 6.6 WT), while melanin-concentrating hormone (MCH) (MCH-IR) neurons remained unchanged 4256 273.3 4494 326.8 220.1 13.6 202.0 7.8 apoptotic cell death marker cleaved caspase-3 (Caspase-3-IR) percentage orexin-IR was higher than WT controls. This selective loss could be associated with abnormal phenotype Further studies needed to determine cause cells relevant effects cognition impairments this mouse model microvascular amyloidosis.

Language: Английский

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Associations of Cerebrospinal Fluid Orexin‐A, Alzheimer Disease Biomarkers, and Cognitive Performance

Annals of Clinical and Translational Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

ABSTRACT Objective Cerebrospinal fluid (CSF) orexin‐A has been suggested to be a biomarker of Alzheimer disease (AD). In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF is positively associated Aβ42, p‐tau181, total tau (t‐tau) concentrations. However, recent systematic review meta‐analysis did not support differences in between AD controls. this study, we tested the association concentrations, biomarkers, cognitive performance without AD. Methods Two hundred seventy community‐dwelling underwent standardized assessments, sleep monitoring single‐channel electroencephalography test, one night home apnea testing, biofluid imaging measurement within 1 year monitoring, APOE genotyping. Plasma biomarkers were measured by immunoassay or mass spectrometry. was radioimmunoassay. Results levels differ amyloid positivity, status, stage. (Aβ40, t‐tau) even after correction for multiple comparisons. any measure performance. Interpretation This study showed that but pathology We hypothesize due similar mechanisms production/release these proteins sleep–wake activity. Future studies measuring other forms orexin peptides, such as orexin‐B, may provide evidence marker

Language: Английский

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Dual orexin receptor antagonists as promising therapeutics for Alzheimer’s disease

Deleted Journal, Journal Year: 2025, Volume and Issue: 2(1)

Published: March 8, 2025

We examine the relationship between sleep, glymphatics and Alzheimer's disease (AD), recent work questioning glymphatic clearance during sleep. highlight a need for understanding and/or other mechanism of review flow measurement methods. Further, we explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances enhance clearance. Further research could elucidate linkage DORAs, improved reducing pathophysiology.

Language: Английский

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Sleep abnormalities are associated with greater cognitive deficits and disease activity in Huntington’s disease: a 12-year polysomnographic study

Brain Communications, Journal Year: 2025, Volume and Issue: 7(2)

Published: Jan. 1, 2025

Increasing evidence suggests that the sleep pathology associated with neurodegenerative diseases can in turn exacerbate both cognitive deficits and underlying pathobiology of these conditions. Treating may therefore bear significant, even disease-modifying, potential for conditions, but how best when to do so remains undetermined. Huntington's disease, by virtue being an autosomal dominant disease presenting mid-life, presents a key 'model' condition through which advance this field. To date, however, there has been no clinical longitudinal study abnormalities robust interrogation their association onset, markers activity. Here, we present first such study. gene carriers (n = 28) age- sex-matched controls 21) were studied at baseline 10- 12-year follow-up. All premanifest stratified follow-up into 'prodromal/manifest' versus 'premanifest' groups. Objective assessed two-night inpatient polysomnography 2-week domiciliary actigraphy, was explored against Montreal Cognitive Assessment, Trail A/B task, Symbol Digit Modalities Task (SDMT), Hopkins Verbal Learning (HVLT) Montgomery-Asberg Depression Rating Scale (MADRS) scores, plus serum neurofilament light levels. Statistical analysis incorporated cross-sectional ANOVA, repeated measures linear models regressions adjusted multiple confounders including stage. Fifteen phenoconverted prodromal/early manifest completion. At follow-up, showed more frequent stage changes (P ≤ 0.001, ηp 2 0.62) higher levels maintenance insomnia (defined wake after P 0.002, 0.52). The latter finding corroborated nocturnal motor activity patterns on actigraphy 0.004, 0.32). Greater greater (Trail A R 0.78; SDMT 0.008, 0.63; B 0.013, 0.60) 0.015, 0.39). Longitudinal modelling suggested instability accrues from early phase, whereas emerges closer phenoconversion. Baseline able discriminate those who within period remained (area under curve 0.81, 0.024). These results demonstrate premanifest/early are suggest former bears value predicting while is deficits. Intervention studies interrogate causation could not only benefit patients also help provide fundamental proof-of-concept findings wider sleep-neurodegeneration

Language: Английский

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CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer’s disease: progress and prospects

Frontiers in Cellular Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: April 7, 2025

CRISPR/Cas9 technology has revolutionized genetic and biomedical research in recent years. It enables editing modulation of gene function with an unparalleled precision effectiveness. Among the various applications prospects this technology, opportunities it offers unraveling molecular underpinnings a myriad central nervous system diseases, including neurodegenerative disorders, psychiatric conditions, developmental abnormalities, are unprecedented. In review, we highlight CRISPR/Cas9-based therapeutics as promising strategy for management Alzheimer's disease transformative impact on AD research. Further, emphasize role generating accurate models identification novel therapeutic targets, besides CRISPR-based therapies aimed at correcting AD-associated mutations modulating processes. Furthermore, delivery systems reviewed potential non-viral nanotechnology-based carriers overcoming critical limitations effective is discussed. Overall, review highlights promise intricate processes underlying development AD, discusses its limitations, ethical concerns several challenges efficient across BBB, ensuring specificity, avoiding off-target effects. This article can be helpful better understanding based approaches way forward utilizing enormous targeted, gene-specific treatments that could change trajectory debilitating incurable illness.

Language: Английский

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Dysregulation of the orexin/hypocretin system is not limited to narcolepsy but has far‐reaching implications for neurological disorders

European Journal of Neuroscience, Journal Year: 2020, Volume and Issue: 53(4), P. 1136 - 1154

Published: Dec. 9, 2020

Neuropeptides orexin A and B (OX-A/B, also called hypocretin 1 2) are released selectively by a population of neurons which projects widely into the entire central nervous system but is localized in restricted area tuberal region hypothalamus, caudal to paraventricular nucleus. The OX prominently targets brain structures involved regulation wake-sleep state switching, orchestrates multiple physiological functions. degeneration dysregulation promotes narcoleptic phenotypes both humans animals. Hence, this review begins with already proven involvement narcolepsy, it mainly discusses new pre-clinical clinical insights role three major neurological disorders characterized sleep impairment have been recently associated dysfunction, such as Alzheimer's disease, stroke Prader Willi syndrome, emerged over past 10 years be strongly dysfunction should more considered future. In light these disorders, conceivable speculate that integrity necessary for healthy functioning body.

Language: Английский

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