Orexin-A
preclinicalAlso known as: Hypocretin-1
Orexin-A (hypocretin-1) is a 33-amino-acid neuropeptide produced primarily in the lateral hypothalamus, acting as an endogenous ligand for the G-protein-coupled orexin receptors OX1 and OX2. Its mechanism of action involves binding to these receptors to modulate neuronal excitability, particularly in brain regions regulating sleep-wake cycles, arousal, and reward processing. OX1 receptor activation preferentially enhances calcium signaling, while OX2 receptor activation influences both calcium and cAMP pathways, collectively promoting wakefulness, suppressing rapid eye movement (REM) sleep, and stabilizing transitions between sleep states. Key preclinical research, including studies referenced in 2006, has demonstrated that orexin-A administration in rodent models increases wakefulness and locomotor activity, while orexin neuron loss or receptor antagonism induces narcolepsy-like symptoms. Further investigations have linked orexin-A to energy homeostasis, stress responses, and addiction-related behaviors, with evidence that central orexin-A infusion can enhance cognitive performance and vigilance under conditions of sleep deprivation. These findings underscore its critical role in maintaining arousal and its dysregulation in disorders such as narcolepsy type 1. Clinically, orexin-A has been explored as a potential therapeutic target for narcolepsy, hypersomnia, and other conditions involving excessive daytime sleepiness. However, its clinical utility remains limited due to poor blood-brain barrier permeability and rapid degradation, necessitating intranasal or intracerebroventricular delivery in experimental settings. Ongoing research focuses on orexin receptor agonists and stabilizers to harness its wake-promoting effects without invasive administration. For research purposes only — not medical advice.
Key data
C152H243N47O44S4Research & studies
Orexin expression increased at 4000 m altitude but decreased at higher altitudes.; Exogenous orexin A reduced infarct size and improved microcirculation blood flow.; Orexin A elevated blood oxygen saturation and attenuated systemic oxidative stress and inflammation.; 4000 m altitude promotes orexin expression, attenuating cerebral ischaemia-reperfusion injury.
Acute sleep deprivation caused cognitive deficits and reduced orexin-A expression in AD mice.; Proteomic analysis identified 1380 modulated proteins, including 105 AD-associated and 6 involved in amyloid-beta clearance.; Molecular dynamics simulations showed orexin-A binds amyloid-beta with high affinity and inhibits its aggregation.; Orexin-A may modulate amyloid-beta aggregation and circadian dysfunction, offering a potential therapeutic target for AD.
iNPH patients had the highest CSF orexin-A levels (263.31 ± 56.89 pg/mL).; NFPA, iNPH, and moderate-to-severe AD patients had higher orexin-A levels than controls (p < 0.001).; mAD and bv-FTD patients showed no significant difference in orexin-A levels compared to controls.; mAD patients had lower CSF orexin-A concentrations than all other patient groups.
Orexin-A decreases the number of wake-REM transitions and total REM sleep time.; Orexin-A does not increase wake time.; Orexin-A fails to alleviate daytime sleepiness.; Orexin deficiency is not the only factor in narcolepsy type 1 pathophysiology.
CSF Orexin-A levels were lower in PD patients versus controls (mean difference -59.21, 95% CI: -89.10 to -29.32).; Mean OXA concentration in PD patients was 281.52 (95% CI: 226.65-336.40).; Lower OXA levels were within the normal range, indicating a potential but not significant orexinergic disruption.
Intranasal orexin-A reduced mortality and improved cognitive and emotional deficits in septic mice.; Orexin-A attenuated cerebral edema, blood-brain barrier disruption, and ultrastructural brain damage.; Orexin-A decreased pro-inflammatory factors IL-1β and TNF-α and inhibited microglial activation.; The protective effects were mediated via OXR2 receptor and downregulation of the RAS/MAPK pathway.
Frequently asked questions
What is Orexin-A?
Orexin-A (hypocretin-1) is a 33-amino-acid neuropeptide produced primarily in the lateral hypothalamus, acting as an endogenous ligand for the G-protein-coupled orexin receptors OX1 and OX2. Its mechanism of action involves binding to these receptors to modulate neuronal excitability, particularly in brain regions regu
How does Orexin-A work?
33-aa hypothalamic neuropeptide acting on OX1/OX2 receptors to promote wakefulness and arousal.
What is the research status of Orexin-A?
Orexin-A is currently classified as preclinical, with 2,017 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of Orexin-A?
Orexin-A has a molecular weight of approximately 3561.1 g/mol (formula C152H243N47O44S4).
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