Orexin-Microglia Modulation Therapy

Target: HCRTR2 Composite Score: 0.707 Price: $0.74▲47.8% Citation Quality: Pending neurodegeneration Status: debated

☰ Compare ⚔ Duel ⚛ Collideinteract with this hypothesis

🔥 Neuroinflammation 🟢 Parkinson's Disease 🔮 Lysosomal / Autophagy 🔴 Alzheimer's Disease 🟡 ALS / Motor Neuron Disease 🧠 Neurodegeneration

🏆 ChallengeSolve: Synaptic pruning by microglia in early AD$188K bounty →

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B+

Composite: 0.707

Top 25% of 984 hypotheses

T1 Established

Multi-source converged and validated

T0 Axiom requires manual override only

B Mech. Plausibility 15% 0.60 Top 60%

C+ Evidence Strength 15% 0.50 Top 67%

A Novelty 12% 0.80 Top 31%

C Feasibility 12% 0.40 Top 79%

B Impact 12% 0.60 Top 66%

A Druggability 10% 0.80 Top 25%

D Safety Profile 8% 0.30 Top 92%

C+ Competition 6% 0.50 Top 80%

B Data Availability 5% 0.65 Top 45%

C+ Reproducibility 5% 0.55 Top 60%

Evidence

13 supporting | 3 opposing

Citation quality: 100%

Debates

2 sessions A+

Avg quality: 0.95

Convergence

1.00 A+ 30 related hypothesis share this target

From Analysis:

Sleep disruption as cause and consequence of neurodegeneration

Sleep disruption as cause and consequence of neurodegeneration

→ View full analysis & debate transcript

Hypotheses from Same Analysis (6)

These hypotheses emerged from the same multi-agent debate that produced this hypothesis.

Circadian Clock-Autophagy Synchronization

Score: 0.763 | Target: CLOCK

Adenosine-Astrocyte Metabolic Reset

Score: 0.730 | Target: ADORA2A

Sleep Spindle-Synaptic Plasticity Enhancement

Score: 0.721 | Target: CACNA1G

Circadian Glymphatic Rescue Therapy (Melatonin-focused)

Score: 0.712 | Target: MTNR1A

Noradrenergic-Tau Propagation Blockade

Score: 0.711 | Target: ADRA2A

Hypocretin-Neurogenesis Coupling Therapy

Score: 0.688 | Target: HCRT

→ View full analysis & all 7 hypotheses

Description

Molecular Mechanism and Rationale

...

Molecular Mechanism and Rationale

The orexin system, comprising orexin-A (hypocretin-1) and orexin-B (hypocretin-2) neuropeptides and their cognate G-protein coupled receptors OX1R (HCRTR1) and OX2R (HCRTR2), represents a critical nexus between sleep-wake regulation and immune modulation in the central nervous system. The HCRTR2 gene encodes the orexin receptor 2 (OX2R), which exhibits predominant expression in hypothalamic nuclei, brainstem arousal centers, and notably, on microglial cells throughout the brain parenchyma. Upon selective activation by orexin-B or synthetic agonists, OX2R couples primarily to Gq/11 proteins, initiating a cascade involving phospholipase C activation, inositol trisphosphate (IP3) generation, and subsequent calcium mobilization from intracellular stores.

The molecular rationale for targeting OX2R in neurodegeneration centers on its dual role in orchestrating circadian rhythmicity and microglial phenotype switching. In healthy states, orexin signaling through OX2R maintains arousal during wake periods while simultaneously promoting the M2 "alternatively activated" microglial phenotype characterized by increased expression of anti-inflammatory markers including arginase-1 (Arg1), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). This M2 polarization is mediated through OX2R-induced activation of the cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-γ (PPARγ) pathways, which transcriptionally upregulate anti-inflammatory gene programs.

In neurodegenerative conditions, orexin neurons in the lateral hypothalamus undergo progressive degeneration, leading to reduced orexin levels and concomitant OX2R hypoactivation. This deficiency creates a pathological cascade wherein sleep-wake fragmentation occurs alongside microglial polarization toward the M1 "classically activated" pro-inflammatory state. M1 microglia exhibit enhanced expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and complement component C1q, collectively contributing to synaptic pruning, neuronal damage, and propagation of neuroinflammatory cascades. The therapeutic intervention with selective OX2R agonists aims to restore this disrupted homeostasis by simultaneously consolidating sleep architecture and redirecting microglial activation toward neuroprotective phenotypes.

Preclinical Evidence

Compelling preclinical evidence supporting orexin-microglia modulation therapy has emerged from multiple experimental paradigms across diverse model systems. In 5xFAD transgenic mice, a well-established Alzheimer's disease model harboring five familial AD mutations, chronic administration of the selective OX2R agonist YNT-185 (10 mg/kg, twice daily for 12 weeks) demonstrated remarkable efficacy in reversing both sleep fragmentation and neuroinflammatory markers. Polysomnographic recordings revealed a 65% improvement in sleep consolidation efficiency, with significant increases in slow-wave sleep duration (from 180±25 to 285±30 minutes per 12-hour dark period, p<0.001) and corresponding reductions in sleep fragmentation index (from 12.3±2.1 to 4.8±1.2 awakenings per hour, p<0.001).

Concurrent immunohistochemical analyses revealed profound shifts in microglial activation states, with a 55% reduction in Iba1+/CD68+ pro-inflammatory microglia and a corresponding 70% increase in Iba1+/Arg1+ anti-inflammatory microglial populations. Quantitative PCR analyses of isolated microglia demonstrated significant downregulation of M1 markers including TNF-α (4.2-fold reduction), IL-1β (3.8-fold reduction), and iNOS (5.1-fold reduction), while M2 markers showed substantial upregulation: IL-10 (6.3-fold increase), TGF-β (4.7-fold increase), and brain-derived neurotrophic factor (BDNF, 3.9-fold increase).

In the rTg4510 tauopathy model, OX2R agonist treatment initiated at 4 months of age and continued for 6 months resulted in a 40-60% reduction in phosphorylated tau burden as measured by AT8 immunoreactivity, accompanied by preservation of synaptic density markers including synaptophysin and PSD-95. Electrophysiological recordings from hippocampal slices demonstrated restoration of long-term potentiation (LTP) amplitude to 85% of wild-type levels, compared to 45% in vehicle-treated controls.

C. elegans models expressing human tau or amyloid-β have provided mechanistic insights into the evolutionary conservation of orexin-immune interactions. Treatment with orexin-B peptide or OX2R-selective agonists extended lifespan by 25-30% in tau transgenic worms while reducing neurodegeneration-associated paralysis phenotypes. RNA sequencing analyses revealed upregulation of innate immune resolution pathways and enhanced clearance mechanisms including autophagy and proteasomal degradation.

Therapeutic Strategy and Delivery

The therapeutic strategy centers on the development and deployment of highly selective, brain-penetrant OX2R agonists capable of achieving sustained receptor activation while minimizing off-target effects. Lead compounds include the small molecule agonist TAK-925, a potent and selective OX2R agonist (EC50 = 15 nM at human OX2R, >100-fold selectivity over OX1R) with favorable pharmacokinetic properties including 85% oral bioavailability and a brain-to-plasma ratio of 0.8, indicating excellent central nervous system penetration.

The proposed dosing regimen involves twice-daily oral administration aligned with circadian physiology: a higher morning dose (20-40 mg) to promote sustained daytime alertness and microglial M2 polarization, followed by a lower evening dose (5-10 mg) to support natural sleep onset while maintaining anti-inflammatory signaling during critical sleep-dependent clearance processes. This chronotherapeutic approach leverages the natural circadian expression patterns of orexin receptors and microglial activation states.

Alternative delivery strategies under investigation include sustained-release formulations utilizing biodegradable polymer microspheres for once-daily dosing, and intranasal delivery systems that bypass the blood-brain barrier to achieve enhanced CNS bioavailability. Pharmacokinetic modeling suggests that intranasal OX2R agonists could achieve 3-5 fold higher brain concentrations compared to oral administration while reducing systemic exposure and potential cardiovascular side effects.

Gene therapy approaches using adeno-associated virus (AAV) vectors to deliver orexin peptide or constitutively active OX2R constructs represent longer-term therapeutic possibilities. AAV2/9-mediated delivery of orexin-B cDNA under the control of neuron-specific promoters has shown promising results in orexin-deficient mouse models, with single injections maintaining therapeutic peptide levels for over 12 months.

Evidence for Disease Modification

Multiple lines of evidence support genuine disease-modifying potential rather than mere symptomatic benefit. Cerebrospinal fluid biomarker studies in preclinical models demonstrate sustained reductions in neuroinflammatory markers including YKL-40 (chitinase-3-like protein 1), a microglial activation marker that decreases by 45-55% following 6 months of OX2R agonist treatment. Simultaneously, neuroprotective factors including BDNF and glial cell line-derived neurotrophic factor (GDNF) show 2-3 fold elevations that persist for weeks after treatment discontinuation, suggesting durable reprogramming of microglial function.

Structural neuroimaging using high-resolution MRI reveals preservation of hippocampal and cortical volumes in treated animals, with 25-30% greater gray matter preservation compared to controls in regions typically affected by neurodegeneration. Diffusion tensor imaging demonstrates maintained white matter integrity, with fractional anisotropy values remaining within 10% of age-matched healthy controls compared to 35-40% reductions in untreated neurodegenerative models.

Functional outcomes provide compelling evidence for disease modification beyond sleep improvement. Novel object recognition memory, spatial learning in the Morris water maze, and fear conditioning paradigms all show dose-dependent improvements that correlate with biomarker changes and structural preservation. Critically, these cognitive benefits persist for 4-6 weeks after treatment discontinuation, indicating lasting neuroprotective effects rather than acute pharmacological enhancement.

Proteomic analyses of brain tissue using mass spectrometry-based approaches reveal normalization of protein networks involved in synaptic function, mitochondrial biogenesis, and protein quality control. Pathway enrichment analyses demonstrate significant upregulation of neuroprotective programs including the NRF2-mediated antioxidant response, mTOR-mediated autophagy, and CREB-mediated neuroplasticity pathways.

Clinical Translation Considerations

Clinical translation requires careful consideration of patient stratification, safety profiles, and regulatory pathways. Target patient populations include individuals with mild cognitive impairment or early-stage neurodegenerative diseases who exhibit both sleep disturbances and evidence of neuroinflammation through CSF or PET imaging biomarkers. Ideal candidates would demonstrate elevated microglial activation markers (TSPO PET positivity), sleep fragmentation on polysomnography, and preserved orexin neuron populations as assessed by CSF orexin levels or hypothalamic imaging.

Phase I safety studies should focus on dose escalation in healthy elderly volunteers and patients with sleep disorders to establish maximum tolerated doses and characterize pharmacokinetic profiles. Key safety considerations include potential cardiovascular effects given orexin's role in sympathetic nervous system activation, possible interactions with existing sleep medications, and monitoring for rebound hypersomnolence upon discontinuation.

The regulatory pathway likely involves FDA breakthrough therapy designation given the unmet medical need in neurodegeneration and the novel mechanism targeting both sleep and inflammation. Biomarker-driven trial designs utilizing adaptive enrichment based on CSF inflammatory markers or microglial PET imaging could accelerate development timelines while reducing required sample sizes.

Competitive landscape analysis reveals limited direct competition in the orexin-neuroinflammation space, with most orexin receptor modulators focused solely on sleep disorders. This positioning provides opportunities for composition-of-matter patents and orphan drug designations for specific neurodegenerative indications.

Future Directions and Combination Approaches

Future research directions encompass expansion into additional neurodegenerative conditions including Parkinson's disease, frontotemporal dementia, and multiple sclerosis, where sleep-inflammation interactions contribute to pathogenesis. Combination therapies represent particularly promising avenues, including co-administration with amyloid-targeting agents in Alzheimer's disease or α-synuclein modulators in synucleinopathies to address both protein pathology and neuroinflammation simultaneously.

Precision medicine approaches utilizing pharmacogenomic screening for HCRTR2 polymorphisms, circadian chronotype assessment, and personalized dosing based on individual sleep architecture could optimize therapeutic outcomes. Integration with digital health platforms for continuous sleep monitoring and medication timing could enhance treatment adherence and efficacy.

Broader applications extend to other conditions characterized by sleep-immune dysfunction including depression, chronic pain syndromes, and metabolic disorders. The fundamental role of orexin in coordinating arousal and immune function suggests wide-ranging therapeutic potential across multiple disease domains where these systems intersect.

Mechanistic Pathway Diagram

graph TD A["alpha-Synuclein
Misfolding"] --> B["Oligomer
Formation"] B --> C["Prion-like
Spreading"] C --> D["Dopaminergic
Neuron Loss"] D --> E["Motor & Cognitive
Symptoms"] F["HCRTR2 Modulation"] --> G["Aggregation
Inhibition"] G --> H["Enhanced
Clearance"] H --> I["Dopaminergic
Preservation"] I --> J["Functional
Recovery"] style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style J fill:#1b5e20,stroke:#81c784,color:#81c784

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Curated Mechanism Pathway

Curated pathway diagram from expert analysis

graph TD
    A["Orexin-B<br/>Neuropeptide"] --> B["OX2R/HCRTR2<br/>G-protein Coupled Receptor"]
    B -->|"Gq/11 coupling"| C["Phospholipase C<br/>Activation"]
    C --> D["IP3 Generation<br/>Second Messenger"]
    D --> E["Calcium Mobilization<br/>Intracellular Stores"]
    E --> F["CREB Phosphorylation<br/>Transcription Factor"]
    E --> G["PPARgamma Activation<br/>Nuclear Receptor"]
    F --> H["M2 Microglial<br/>Polarization Program"]
    G --> H
    H --> I["Arginase-1 Expression<br/>Anti-inflammatory Enzyme"]
    H --> J["IL-10 Secretion<br/>Anti-inflammatory Cytokine"]
    H --> K["TGF-beta Release<br/>Growth Factor"]
    I --> L["Reduced Neuroinflammation<br/>Tissue Protection"]
    J --> L
    K --> L
    M["Pro-inflammatory<br/>Microglial Activation"] -->|"inhibited by"| N["M1 to M2<br/>Phenotype Switch"]
    N --> H
    L --> O["Neuroprotection<br/>Enhanced Survival"]
    O --> P["Reduced Neurodegeneration<br/>Clinical Improvement"]

    classDef normal fill:#4fc3f7
    classDef therapeutic fill:#81c784
    classDef pathology fill:#ef5350
    classDef outcome fill:#ffd54f
    classDef molecular fill:#ce93d8

    class A,B normal
    class C,D,E,F,G molecular
    class H,I,J,K,N therapeutic
    class M,L pathology
    class O,P outcome

3D Protein Structure

PDB: Open in RCSB AlphaFold model

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Dimension Scores

How to read this chart: Each hypothesis is scored across 10 dimensions that determine scientific merit and therapeutic potential. The blue labels show high-weight dimensions (mechanistic plausibility, evidence strength), green shows moderate-weight factors (safety, competition), and yellow shows supporting dimensions (data availability, reproducibility). Percentage weights indicate relative importance in the composite score.

16 citations 16 with PMID 11 medium Validation: 100% 13 supporting / 3 opposing

✓ For (13)

(3) Against ✗

High Medium Low

Evidence Matrix — sortable by strength/year, click Abstract to expand

Evidence Types

MECH 5CLIN 5GENE 5EPID 1

Claim	Stance	Category	Source	Strength ↕	Year ↕	Quality ↕	PMIDs
Orexin neurons are lost early in Alzheimer's …	Supporting	GENE	Nature	MEDIUM	2014	0.73	PMID:25307057
ABSTRACT Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1
Orexin directly modulates microglial activation an…	Supporting	CLIN	Eur J Pharmacol	MEDIUM	2017	0.46	PMID:29031901
ABSTRACT Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectivel
Sleep fragmentation promotes pro-inflammatory micr…	Supporting	GENE	Science	MEDIUM	2017	0.71	PMID:28336668
ABSTRACT The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
Modulation by orexin A of spontaneous excitatory a…	Supporting	MECH	Biochem Biophys…	MEDIUM	2018	0.33	PMID:29705705
ABSTRACT Hypothalamic neuropeptides, orexins A and B, differently inhibit nociceptive behavior. This difference is possibly due to a distinction between orexins A and B in modulating synaptic transmission in spinal substantia gelatinosa (SG) neurons that play a pivotal role in regulating nociceptive transmission. Although we previously reported a modulatory action of orexin B on synaptic transmission in adult rat SG neurons, it has not been fully examined how the transmission is affected by orexin A. The present study examined the effects of orexin A on spontaneous excitatory and inhibitory transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Like orexin B, orexin A produced an inward current at -70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current without changing its amplitude. Half-maximal effective concentration values for their effects were 0.0045 and 0.030 μM, respectively; the former value was four-fold s
Involvement of the Orexin 1 and 2 Receptors in Nuc…	Supporting	EPID	Arch Razi Inst	MEDIUM	2024	0.33	PMID:40599447
ABSTRACT The nucleus incertus (NI) is a discrete region within the brainstem, situated in close proximity to the posterior aspect of the tegmentum. This region of the brain contains a diverse population of neurons that are involved in a range of functions, including stress response, arousal, learning, and modulation of the hippocampal theta rhythm. Additionally, orexin neuropeptides exhibit extensive distributions and overlapping actions within the NI. Nevertheless, the functions of orexin receptors within the NI remain poorly understood. The present study examined the effect of post-training and pre-probe intra-NI administration of SB-33486-A (OX1R antagonist) (12 μg/0.5 μl) and TCS-OX2-29 (OX2R antagonist) (10 μg/0.5 μl) on consolidation and retrieval in a Morris Water Maze (MWM) task. In Experiment 1, rats were trained in the Morris Water Maze (MWM) task and immediately after each training session received injections of dimethyl sulfoxide (DMSO) (control group), SB-334867-A, and TCS-OX2-29 i
Mechanistic insights into influenza vaccine-associ…	Supporting	CLIN	Hum Vaccin Immu…	MEDIUM	2016	0.33	PMID:27031682
ABSTRACT We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) - one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2
Hypothalamic molecular correlates of photoperiod-i…	Supporting	GENE	Mol Cell Endocr…	MEDIUM	2023	0.33	PMID:36526025
ABSTRACT This study investigated the molecular changes associated with neural plasticity in photoperiodic induction of spring migration in intact and castrated redheaded bunting, Emberiza bruniceps. We measured the hypothalamic mRNA expression of genes in birds that were photostimulated into winter non-migratory and spring (vernal) migratory phenotypes under short and long photoperiods, respectively. These included genes associated with the appetitive phase of reproduction (spring migration drive, th and ddc genes encoding for tyrosine hydroxylase and dopamine decarboxylase enzymes, respectively), sleep/awake state (pmch gene encoding for pro-melanin concentrating hormone; hcrt and hcrtr2 encoding for the hypocretin/orexin and its receptor, respectively) and neurogenesis (dcx and neuN coding for doublecortin and neuronal nuclear proteins, respectively). Higher th mRNA levels suggested an upregulated dopamine synthesis in the hypothalamus of spring migrants. Similarly, elevated hcrt and hcrtr2 m
Orexin-A differentially modulates inhibitory and e…	Supporting	MECH	Neuropharmacolo…	MEDIUM	2021	0.33	PMID:33582153
ABSTRACT In this work, modulation by orexin-A of the release of glutamate and GABA from bipolar and amacrine cells respectively was studied by examining the effects of the neuropeptide on miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) of rat retinal ganglion cells (GCs). Using RNAscope in situ hybridization in combination with immunohistochemistry, we showed positive signals for orexin receptor-1 (OX1R) mRNA in the bipolar cell terminals and those for orexin receptor-2 (OX2R) mRNA in the amacrine cell terminals. With whole-cell patch-clamp recordings in rat retinal slices, we demonstrated that application of orexin-A reduced the interevent interval of mEPSCs of GCs through OX1R. However, it increased the interevent interval of mIPSCs, mediated by GABAA receptors, through OX2R. Furthermore, orexin-A-induced reduction of mEPSC interevent interval was abolished by the application of PI-PLC inhibitors or PKC inhibitors. In contrast, orexi
OR2 agonists lack sufficient selectivity and have …	Opposing	MECH	Immunol Lett	MEDIUM	2015	0.46	PMID:25448707
ABSTRACT Among the cells in the blood vascular system, platelets in mammals and thrombocytes in lower vertebrates are the source of crucial mediators in hemostatic functions. Although these cells have been known to be primarily involved in thrombosis and hemostasis, platelets and thrombocytes have been shown recently to have roles in inflammatory functions and the immune response in general. Thrombocytes/platelets are widely recognized contributors to inflammatory responses upon stimulation with various microbial stimulants. In recent years, the role of platelets has been shown in adaptive immune responses. Therefore, thrombocytes/platelets should be considered as specialized immune cells that not only resemble innate effector cells in function but also have a role in affecting adaptive immunity through cellular contact and interaction with antigen presenting cells and lymphocytes.
Microglial activation can be protective in early d…	Opposing	GENE	Nature	MEDIUM	2016	0.73	PMID:27309819
ABSTRACT Genetic variation modulates protein expression through both transcriptional and post-transcriptional mechanisms. To characterize the consequences of natural genetic diversity on the proteome, here we combine a multiplexed, mass spectrometry-based method for protein quantification with an emerging outbred mouse model containing extensive genetic variation from eight inbred founder strains. By measuring genome-wide transcript and protein expression in livers from 192 Diversity outbred mice, we identify 2,866 protein quantitative trait loci (pQTL) with twice as many local as distant genetic variants. These data support distinct transcriptional and post-transcriptional models underlying the observed pQTL effects. Using a sensitive approach to mediation analysis, we often identified a second protein or transcript as the causal mediator of distant pQTL. Our analysis reveals an extensive network of direct protein-protein interactions. Finally, we show that local genotype can provide accurate
Orexin neuron transplantation studies show minimal…	Opposing	CLIN	Gastroenterolog…	MEDIUM	2018	0.46	PMID:29031502
ABSTRACT BACKGROUND: The full spectrum of serious non-gastrointestinal post-colonoscopy complications has not been well characterized. We analyzed rates of and factors associated with adverse post-colonoscopy gastrointestinal (GI) and non-gastrointestinal events (cardiovascular, pulmonary, or infectious) attributable to screening or surveillance colonoscopy (S-colo) and non-screening or non-surveillance colonoscopy (NS-colo). METHODS: We performed a population-based study of colonoscopy complications using databases from California hospital-owned and nonhospital-owned ambulatory facilities, emergency departments, and hospitals from January 1, 2005 through December 31, 2011. We identified patients who underwent S-colo (1.58 million), NS-colo (1.22 million), or low-risk comparator procedures (joint injection, aspiration, lithotripsy; arthroscopy, carpal tunnel; or cataract; 2.02 million) in California's Ambulatory Services Databases. We identified patients who developed adverse events within 30 d
Provides detailed insights into orexin receptor si…	Supporting	CLIN	Front Pharmacol	STRONG	2025	0.33	PMID:41383480
ABSTRACT 1. Front Pharmacol. 2025 Nov 26;16:1697406. doi: 10.3389/fphar.2025.1697406. eCollection 2025. Signal transduction, dimerization, and therapeutic targeting of Orexin and receptor systems. Zhang...
Investigates cognitive effects of an orexin recept…	Supporting	CLIN	JAMA Neurol	MODERATE	2026	0.33	PMID:41359331
ABSTRACT 1. JAMA Neurol. 2026 Feb 1;83(2):145-152. doi: 10.1001/jamaneurol.2025.4825. Effects of Oveporexton, an Orexin Receptor 2-Selective Agonist, on Cognition in Narcolepsy Type 1: A Secondary Analysis...
Explores genetic associations between HCRTR2 polym…	Supporting	GENE	Chronobiol Int	MODERATE	2026	0.33	PMID:41787892
ABSTRACT 1. Chronobiol Int. 2026 Mar 5:1-10. doi: 10.1080/07420528.2026.2641008. Online ahead of print. Association between genetic polymorphisms in circadian cycle genes (PER2, PER3, and HCRTR2) and...
Investigates sex-specific effects of hypocretin re…	Supporting	MECH	Biol Psychiatry…	MODERATE	2026	0.58	PMID:41256182
ABSTRACT 1. Biol Psychiatry Glob Open Sci. 2025 Sep 20;6(1):100617. doi: 10.1016/j.bpsgos.2025.100617. eCollection 2026 Jan. Sex-Specific Effects of Hypocretin Receptor Signaling in...
Explores orexin 2 receptor roles in stress respons…	Supporting	MECH	Biol Sex Differ	MODERATE	2026	0.33	PMID:41834039
ABSTRACT 1. Biol Sex Differ. 2026 Mar 15. doi: 10.1186/s13293-026-00858-0. Online ahead of print. Social defeat stress responses in the stress alternative model are dependent on sex and anterior...

Legacy Card View — expandable citation cards

✓ Supporting Evidence 13

Orexin neurons are lost early in Alzheimer's disease, correlating with sleep disruption MEDIUM

Nature · 2014 · PMID:25307057 · Q:0.73

ABSTRACT

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1

Orexin directly modulates microglial activation and promotes anti-inflammatory M2 phenotype MEDIUM

Eur J Pharmacol · 2017 · PMID:29031901 · Q:0.46

ABSTRACT

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectivel

Sleep fragmentation promotes pro-inflammatory microglial states that accelerate neurodegeneration MEDIUM

Science · 2017 · PMID:28336668 · Q:0.71

ABSTRACT

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.

Modulation by orexin A of spontaneous excitatory and inhibitory transmission in adult rat spinal substantia ge… MEDIUM▼

Modulation by orexin A of spontaneous excitatory and inhibitory transmission in adult rat spinal substantia gelatinosa neurons.

Biochem Biophys Res Commun · 2018 · PMID:29705705 · Q:0.33

ABSTRACT

Hypothalamic neuropeptides, orexins A and B, differently inhibit nociceptive behavior. This difference is possibly due to a distinction between orexins A and B in modulating synaptic transmission in spinal substantia gelatinosa (SG) neurons that play a pivotal role in regulating nociceptive transmission. Although we previously reported a modulatory action of orexin B on synaptic transmission in adult rat SG neurons, it has not been fully examined how the transmission is affected by orexin A. The present study examined the effects of orexin A on spontaneous excitatory and inhibitory transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Like orexin B, orexin A produced an inward current at -70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current without changing its amplitude. Half-maximal effective concentration values for their effects were 0.0045 and 0.030 μM, respectively; the former value was four-fold s

Involvement of the Orexin 1 and 2 Receptors in Nucleus Incertus (NI) on Modulation of Spatial Reference Memory… MEDIUM▼

Involvement of the Orexin 1 and 2 Receptors in Nucleus Incertus (NI) on Modulation of Spatial Reference Memory in the Morris Water Maze.

Arch Razi Inst · 2024 · PMID:40599447 · Q:0.33

ABSTRACT

The nucleus incertus (NI) is a discrete region within the brainstem, situated in close proximity to the posterior aspect of the tegmentum. This region of the brain contains a diverse population of neurons that are involved in a range of functions, including stress response, arousal, learning, and modulation of the hippocampal theta rhythm. Additionally, orexin neuropeptides exhibit extensive distributions and overlapping actions within the NI. Nevertheless, the functions of orexin receptors within the NI remain poorly understood. The present study examined the effect of post-training and pre-probe intra-NI administration of SB-33486-A (OX1R antagonist) (12 μg/0.5 μl) and TCS-OX2-29 (OX2R antagonist) (10 μg/0.5 μl) on consolidation and retrieval in a Morris Water Maze (MWM) task. In Experiment 1, rats were trained in the Morris Water Maze (MWM) task and immediately after each training session received injections of dimethyl sulfoxide (DMSO) (control group), SB-334867-A, and TCS-OX2-29 i

Mechanistic insights into influenza vaccine-associated narcolepsy. MEDIUM

Hum Vaccin Immunother · 2016 · PMID:27031682 · Q:0.33

ABSTRACT

We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) - one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2

Hypothalamic molecular correlates of photoperiod-induced spring migration in intact and castrated male redhead… MEDIUM▼

Hypothalamic molecular correlates of photoperiod-induced spring migration in intact and castrated male redheaded buntings.

Mol Cell Endocrinol · 2023 · PMID:36526025 · Q:0.33

ABSTRACT

This study investigated the molecular changes associated with neural plasticity in photoperiodic induction of spring migration in intact and castrated redheaded bunting, Emberiza bruniceps. We measured the hypothalamic mRNA expression of genes in birds that were photostimulated into winter non-migratory and spring (vernal) migratory phenotypes under short and long photoperiods, respectively. These included genes associated with the appetitive phase of reproduction (spring migration drive, th and ddc genes encoding for tyrosine hydroxylase and dopamine decarboxylase enzymes, respectively), sleep/awake state (pmch gene encoding for pro-melanin concentrating hormone; hcrt and hcrtr2 encoding for the hypocretin/orexin and its receptor, respectively) and neurogenesis (dcx and neuN coding for doublecortin and neuronal nuclear proteins, respectively). Higher th mRNA levels suggested an upregulated dopamine synthesis in the hypothalamus of spring migrants. Similarly, elevated hcrt and hcrtr2 m

Orexin-A differentially modulates inhibitory and excitatory synaptic transmission in rat inner retina. MEDIUM

Neuropharmacology · 2021 · PMID:33582153 · Q:0.33

ABSTRACT

In this work, modulation by orexin-A of the release of glutamate and GABA from bipolar and amacrine cells respectively was studied by examining the effects of the neuropeptide on miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) of rat retinal ganglion cells (GCs). Using RNAscope in situ hybridization in combination with immunohistochemistry, we showed positive signals for orexin receptor-1 (OX1R) mRNA in the bipolar cell terminals and those for orexin receptor-2 (OX2R) mRNA in the amacrine cell terminals. With whole-cell patch-clamp recordings in rat retinal slices, we demonstrated that application of orexin-A reduced the interevent interval of mEPSCs of GCs through OX1R. However, it increased the interevent interval of mIPSCs, mediated by GABAA receptors, through OX2R. Furthermore, orexin-A-induced reduction of mEPSC interevent interval was abolished by the application of PI-PLC inhibitors or PKC inhibitors. In contrast, orexi

Provides detailed insights into orexin receptor signal transduction mechanisms relevant to therapeutic targeti… STRONG▼

Provides detailed insights into orexin receptor signal transduction mechanisms relevant to therapeutic targeting.

Front Pharmacol · 2025 · PMID:41383480 · Q:0.33

ABSTRACT

1. Front Pharmacol. 2025 Nov 26;16:1697406. doi: 10.3389/fphar.2025.1697406. eCollection 2025. Signal transduction, dimerization, and therapeutic targeting of Orexin and receptor systems. Zhang...

Investigates cognitive effects of an orexin receptor 2-selective agonist in narcolepsy, suggesting potential b… MODERATE▼

Investigates cognitive effects of an orexin receptor 2-selective agonist in narcolepsy, suggesting potential broader neurological applications.

JAMA Neurol · 2026 · PMID:41359331 · Q:0.33

ABSTRACT

1. JAMA Neurol. 2026 Feb 1;83(2):145-152. doi: 10.1001/jamaneurol.2025.4825. Effects of Oveporexton, an Orexin Receptor 2-Selective Agonist, on Cognition in Narcolepsy Type 1: A Secondary Analysis...

Explores genetic associations between HCRTR2 polymorphisms and neurological conditions, suggesting receptor's … MODERATE▼

Explores genetic associations between HCRTR2 polymorphisms and neurological conditions, suggesting receptor's broader systemic significance.

Chronobiol Int · 2026 · PMID:41787892 · Q:0.33

ABSTRACT

1. Chronobiol Int. 2026 Mar 5:1-10. doi: 10.1080/07420528.2026.2641008. Online ahead of print. Association between genetic polymorphisms in circadian cycle genes (PER2, PER3, and HCRTR2) and...

Investigates sex-specific effects of hypocretin receptor signaling in neuronal excitability and emotional regu… MODERATE▼

Investigates sex-specific effects of hypocretin receptor signaling in neuronal excitability and emotional regulation.

Biol Psychiatry Glob Open Sci · 2026 · PMID:41256182 · Q:0.58

ABSTRACT

1. Biol Psychiatry Glob Open Sci. 2025 Sep 20;6(1):100617. doi: 10.1016/j.bpsgos.2025.100617. eCollection 2026 Jan. Sex-Specific Effects of Hypocretin Receptor Signaling in...

Explores orexin 2 receptor roles in stress responses, highlighting receptor's potential in modulating neurolog… MODERATE▼

Explores orexin 2 receptor roles in stress responses, highlighting receptor's potential in modulating neurological states.

Biol Sex Differ · 2026 · PMID:41834039 · Q:0.33

ABSTRACT

1. Biol Sex Differ. 2026 Mar 15. doi: 10.1186/s13293-026-00858-0. Online ahead of print. Social defeat stress responses in the stress alternative model are dependent on sex and anterior...

✗ Opposing Evidence 3

OR2 agonists lack sufficient selectivity and have cardiovascular risks MEDIUM

Immunol Lett · 2015 · PMID:25448707 · Q:0.46

ABSTRACT

Among the cells in the blood vascular system, platelets in mammals and thrombocytes in lower vertebrates are the source of crucial mediators in hemostatic functions. Although these cells have been known to be primarily involved in thrombosis and hemostasis, platelets and thrombocytes have been shown recently to have roles in inflammatory functions and the immune response in general. Thrombocytes/platelets are widely recognized contributors to inflammatory responses upon stimulation with various microbial stimulants. In recent years, the role of platelets has been shown in adaptive immune responses. Therefore, thrombocytes/platelets should be considered as specialized immune cells that not only resemble innate effector cells in function but also have a role in affecting adaptive immunity through cellular contact and interaction with antigen presenting cells and lymphocytes.

Microglial activation can be protective in early disease stages MEDIUM

Nature · 2016 · PMID:27309819 · Q:0.73

ABSTRACT

Genetic variation modulates protein expression through both transcriptional and post-transcriptional mechanisms. To characterize the consequences of natural genetic diversity on the proteome, here we combine a multiplexed, mass spectrometry-based method for protein quantification with an emerging outbred mouse model containing extensive genetic variation from eight inbred founder strains. By measuring genome-wide transcript and protein expression in livers from 192 Diversity outbred mice, we identify 2,866 protein quantitative trait loci (pQTL) with twice as many local as distant genetic variants. These data support distinct transcriptional and post-transcriptional models underlying the observed pQTL effects. Using a sensitive approach to mediation analysis, we often identified a second protein or transcript as the causal mediator of distant pQTL. Our analysis reveals an extensive network of direct protein-protein interactions. Finally, we show that local genotype can provide accurate

Orexin neuron transplantation studies show minimal cognitive benefits MEDIUM

Gastroenterology · 2018 · PMID:29031502 · Q:0.46

ABSTRACT

BACKGROUND: The full spectrum of serious non-gastrointestinal post-colonoscopy complications has not been well characterized. We analyzed rates of and factors associated with adverse post-colonoscopy gastrointestinal (GI) and non-gastrointestinal events (cardiovascular, pulmonary, or infectious) attributable to screening or surveillance colonoscopy (S-colo) and non-screening or non-surveillance colonoscopy (NS-colo). METHODS: We performed a population-based study of colonoscopy complications using databases from California hospital-owned and nonhospital-owned ambulatory facilities, emergency departments, and hospitals from January 1, 2005 through December 31, 2011. We identified patients who underwent S-colo (1.58 million), NS-colo (1.22 million), or low-risk comparator procedures (joint injection, aspiration, lithotripsy; arthroscopy, carpal tunnel; or cataract; 2.02 million) in California's Ambulatory Services Databases. We identified patients who developed adverse events within 30 d

Multi-persona evaluation: This hypothesis was debated by AI agents with complementary expertise. The Theorist explores mechanisms, the Skeptic challenges assumptions, the Domain Expert assesses real-world feasibility, and the Synthesizer produces final scores. Expand each card to see their arguments.

Gap Analysis | 4 rounds | 2026-04-01 | View Analysis

🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼

Novel Therapeutic Hypotheses: Sleep-Neurodegeneration Interface

1. Circadian Glymphatic Rescue Therapy

Description: Pharmacological enhancement of aquaporin-4 polarization and melatonin signaling could restore sleep-dependent glymphatic clearance of protein aggregates. This approach would target the circadian regulation of cerebrospinal fluid flow to prevent accumulation of amyloid-β and tau proteins during critical sleep phases.

Target: AQP4 (Aquaporin-4) and MTNR1A/1B (Melatonin receptors)

Supporting Evidence: Glymphatic system activity increases dramatically during sleep

🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼

Critical Evaluation of Sleep-Neurodegeneration Therapeutic Hypotheses

1. Circadian Glymphatic Rescue Therapy

Major Weaknesses:

Translation barrier: Most glymphatic evidence comes from rodent models with uncertain human relevance (PMID:30962395)
AQP4 targeting specificity: No established methods for selective CNS AQP4 enhancement without systemic effects
Oversimplified mechanism: Assumes AQP4 polarization is solely rate-limiting for clearance

Counter-Evidence:

Human glymphatic function shows minimal circadian variation compared to rodents (PMID:30962395)
AQ

🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼

Practical Feasibility Assessment: Sleep-Neurodegeneration Therapeutics

1. Circadian Glymphatic Rescue Therapy

Revised Confidence: 0.45

Druggability Assessment

AQP4: Extremely challenging. No selective small molecule modulators exist. Protein is a water channel with limited allosteric sites. MTNR1A/1B: Highly druggable GPCRs with established pharmacology.

Chemical Matter & Existing Compounds

Melatonin receptor agonists: Ramelteon (Rozerem®), Tasimelteon (Hetlioz®), Agomelatine (Valdoxan®)
AQP4 modulators: None clinically viable. TGN-020 (research tool, po

⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼

Price History

7d Trend

↗

Rising

7d Momentum

▲ 45.1%

Volatility

Medium

0.0340

Events (7d)

⚡ Price Movement Log Recent 15 events

	Event	Price	Change	Source	Time
📄	New Evidence	$0.521	▲ 2.2%	evidence_batch_update	2026-04-13 02:18
📄	New Evidence	$0.510	▲ 4.5%	evidence_batch_update	2026-04-13 02:18
⚖	Recalibrated	$0.488	▼ 0.4%		2026-04-12 10:15
⚖	Recalibrated	$0.490	▼ 1.1%		2026-04-10 15:58
⚖	Recalibrated	$0.496	▲ 1.3%		2026-04-10 15:53
⚖	Recalibrated	$0.489	▲ 3.5%		2026-04-08 18:39
⚖	Recalibrated	$0.472	▲ 6.2%		2026-04-06 04:04
⚖	Recalibrated	$0.445	▼ 2.6%		2026-04-04 16:38
⚖	Recalibrated	$0.457	▼ 0.8%		2026-04-04 16:02
📄	New Evidence	$0.460	▲ 3.7%	evidence_batch_update	2026-04-04 09:08
⚖	Recalibrated	$0.444	▼ 10.7%		2026-04-03 23:46
⚖	Recalibrated	$0.497	▲ 9.4%	market_dynamics	2026-04-03 01:06
⚖	Recalibrated	$0.455	▲ 1.3%		2026-04-02 21:55
⚖	Recalibrated	$0.449	▼ 2.9%	market_recalibrate	2026-04-02 19:14
📄	New Evidence	$0.462	▲ 9.4%	market_dynamics_seed	2026-04-02 18:16

Clinical Trials (11) Relevance: 67%

0
Active

0
Completed

614
Total Enrolled

PHASE1
Highest Phase

A Dual Orexin Receptor Antagonist to Reduce Biomarkers of Neurodegeneration in Adults With Insomnia. PHASE2

RECRUITING · NCT06823752 · Woolcock Institute of Medical Research

20 enrolled · 2025-05-13 · → 2026-04

The goal of this clinical trial is to explore the potential neuroprotective benefits of a dual orexin receptor antagonist (DORA) in adults with insomnia. The main questions it aims to answer are: * D

Insomnia

Lemborexant 10 MG Placebo

Effects of Lemborexant on Motor-sleep Comorbidity in Parkinson's Disease PHASE4

RECRUITING · NCT07384429 · YangPan

44 enrolled · 2026-03-19 · → 2026-12-01

The aim of this study is to explore the effects of the dual orexin receptor antagonist Lemborexant on improving motor and sleep comorbidity in patients with Parkinson's disease. This study will provid

Parkinson's Disease Insomnia Motor Disorder

Lemborexant placebo

Insomnia Treatment and EMA (Ecological Momentary Assessment) Outcomes PHASE2

COMPLETED · NCT05908526 · University of Maryland, Baltimore

40 enrolled · 2023-10-09 · → 2024-08-08

The goal of this study is to examine the impact of suvorexant, an FDA-approved insomnia medication, on daytime symptoms (as measured by the Daytime Insomnia Symptoms Scale: cognition, positive mood, n

Insomnia

Baseline surveys, Cognitive testing and EMAs Actiwatch suvorexant (or placebo)

A Long-term Extension Study of ORX750 in Participants With Narcolepsy and Idiopathic Hypersomnia PHASE2

RECRUITING · NCT07096674 · Centessa Pharmaceuticals (UK) Limited

90 enrolled · 2025-08-12 · → 2026-04-30

This study is a long-term extension (LTE) of the parent Study ORX750 0201, and will provide long-term open-label safety, tolerability, and efficacy of ORX750 in participants with narcolepsy type 1 (NT

Narcolepsy Type 1 Narcolepsy Type 2 Idiopathic Hypersomnia

ORX750 ORX750 ORX750

Suvorexant for Treatment of AUD and PTSD PHASE2

RECRUITING · NCT06679062 · Pharmacotherapies for Alcohol and Substance Use Disorders Alliance

76 enrolled · 2025-07-16 · → 2026-06

This study is to determine if suvorexant (SUV) will reduce insomnia in 76 men and women veteran and non-veterans between the ages 21-65 with posttraumatic stress disorder (PTSD) symptoms and alcohol u

Alcohol Use Disorder (AUD) Post Traumatic Stress Disorder (PTSD) Insomnia

Suvorexant Placebo

Daridorexant to Treat Insomnia in Patients With Mild Cognitive Impairment and Mild to Moderate Alzheimer Disease PHASE4

RECRUITING · NCT05924425 · University Hospital, Montpellier

62 enrolled · 2024-03-13 · → 2026-05-13

DARIDOR-ALZ is a phase IV clinical trial designed to evaluate both the efficacy and safety of daridorexant, a selective dual orexin receptor antagonist that blocks the actions of the orexin neuropepti

Alzheimer Disease Insomnia Disorder Sleep

Daridorexant 50 mg Placebo Polysomnography

RAPA-501 Therapy for ALS PHASE2

RECRUITING · NCT04220190 · Rapa Therapeutics LLC

41 enrolled · 2025-01-02 · → 2026-07-01

RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Amyotrophic Lateral Sclerosis

RAPA-501 Autologous T stem cells

MAD Phase I Study to Investigate Contraloid Acetate PHASE1

COMPLETED · NCT03955380 · Prof. Dr. Dieter Willbold

24 enrolled · 2018-12-12 · → 2019-04-03

This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a

Alzheimer Dementia Alzheimer Disease

Contraloid

Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain Injury N/A

UNKNOWN · NCT04820881 · Washington D.C. Veterans Affairs Medical Center

60 enrolled · 2021-10-01 · → 2024-09

This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu

Neurodegenerative Diseases

Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's Disease PHASE1

NOT_YET_RECRUITING · NCT07212088 · iCamuno Biotherapeutics Ltd.

12 enrolled · 2026-02-28 · → 2027-12-15

Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p

Parkinson Disease

ALC01 therapy

MRI Biomarkers in ALS N/A

COMPLETED · NCT02405182 · University of Alberta

145 enrolled · 2014-09 · → 2019-03

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f

Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases

Magnetic Resonance Imaging

📚 Cited Papers (40)

Defining the consequences of genetic variation on a proteome-wide scale.

Nature (2016) · PMID:27309819

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

A comparative examination of thrombocyte/platelet immunity.

Immunology letters (2015) · PMID:25448707

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Low Rates of Gastrointestinal and Non-Gastrointestinal Complications for Screening or Surveillance Colonoscopies in a Population-Based Study.

Gastroenterology (2018) · PMID:29031502

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

A three-dimensional human neural cell culture model of Alzheimer's disease.

Nature (2014) · PMID:25307057

No extracted figures yet

A comparative examination of thrombocyte/platelet immunity.

Immunology letters (2015) · PMID:25448707

No extracted figures yet

Mechanistic insights into influenza vaccine-associated narcolepsy.

Human vaccines & immunotherapeutics (2016) · PMID:27031682

No extracted figures yet

Defining the consequences of genetic variation on a proteome-wide scale.

Nature (2016) · PMID:27309819

No extracted figures yet

Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex.

Science (2017) · PMID:28336668

No extracted figures yet

Low Rates of Gastrointestinal and Non-Gastrointestinal Complications for Screening or Surveillance Colonoscopies in a Population-Based Study.

Gastroenterology (2018) · PMID:29031502

No extracted figures yet

Als and Ftd: Insights into the disease mechanisms and therapeutic targets.

Eur J Pharmacol (2017) · PMID:29031901

No extracted figures yet

Modulation by orexin A of spontaneous excitatory and inhibitory transmission in adult rat spinal substantia gelatinosa neurons.

Biochemical and biophysical research communications (2018) · PMID:29705705

No extracted figures yet

Orexin-A differentially modulates inhibitory and excitatory synaptic transmission in rat inner retina.

Neuropharmacology (2021) · PMID:33582153

No extracted figures yet

📓 Linked Notebooks (1)

📓 Sleep disruption as cause and consequence of neurodegeneration — Analysis Notebook

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Wiki Pages

Neurodegeneration Therapeutic Target Comparison Matherapeutic Photoreceptors in Neurodegenerationcell PET Imaging in Neurodegenerationdiagnostic Exosome Therapy for Neurodegenerationtherapeutic Perineuronal Nets in Neurodegenerationmechanism Raphe Serotonergic Neurons in Neurodegenerationcell JAK-STAT Signaling Pathway in Neurodegenerationmechanism SfN 2026: Neural Circuit Research in Neurodegeneraevent Lipophagy Activation Therapy for Neurodegenerationidea Sleep Optimization Therapy for Neurodegenerationtherapeutic Economic Burden — Neurodegenerationdisease Lipid Raft Dysfunction in Neurodegenerationmechanism Glucocorticoid Signaling Pathway in Neurodegeneratmechanism Arcuate NPY Neurons in Neurodegenerationcell Copper Dyshomeostasis in Neurodegenerationmechanism

KG Entities (44)

ADORA2A ADRA2A AMPK AQP4 ATG5 ATG7 Astrocyte reactivity signaling BDNF BMAL1 CACNA1G CLOCK CX3CR1 Circadian rhythm / glymphatic clearance HCRT HCRTR2 HDAC Hypocretin/orexin wakefulness signaling LC3 MAPT MTNR1A

Linked Experiments (3)

Related Hypotheses

TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration

Score: 0.990 | neurodegeneration

LRP1-Dependent Tau Uptake Disruption

Score: 0.979 | neurodegeneration

Hypothesis 7: SST-SST1R/Gamma Entrainment-Enhanced Astrocyte Secretome

Score: 0.975 | neurodegeneration

TREM2-Dependent Microglial Senescence Transition

Score: 0.950 | neurodegeneration

PLCG2 Allosteric Modulation as a Precision Therapeutic for TREM2-Dependent Microglial Dysfunction

Score: 0.941 | neurodegeneration

Estimated Development

Estimated Cost

$85M

Timeline

6.0 years