Orexin A

Also known as: Hypocretin-1, OX-A

Evidence: Clinical

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Overview

Hypothalamic neuropeptide (hypocretin-1) acting at OX1R and OX2R to promote wakefulness and arousal; intranasal delivery studied in sleep-deprived primates and narcolepsy models.

Orexin A (hypocretin-1) is a 33-residue hypothalamic neuropeptide acting at the OX1R and OX2R receptors, identified in 1998 (Sakurai et al., 1998; de Lecea et al., 1998). Loss of orexin neurons causes narcolepsy type 1 (Peyron et al., 2000). It crosses the blood-brain barrier from blood by simple diffusion in mice, unlike orexin B (Kastin and Akerstrom, 1999). Intranasal and intravenous dosing improved cognitive performance in sleep-deprived monkeys (Deadwyler et al., 2007). In two small placebo-controlled crossover trials in narcolepsy, 435 nmol intranasally stabilised REM sleep and cut attention errors without increasing wakefulness (Baier et al., 2011; Weinhold et al., 2014), and 500 nmol raised sympathetic nerve activity in healthy men (Meusel et al., 2022). There is no approved orexin peptide product.

Benefits

Wakefulness, Arousal, Sleep regulation

Dosing reference

Research dose: 15 to 30 mcg intranasal (community range; published human intranasal doses were 435 nmol, about 1.5 mg, and 500 nmol, about 1.8 mg)
Range: 15 to 30 mcg, As needed
Reconstitution: 1 mL bacteriostatic water
Common vial sizes: 0.5 mg

Human trials used single intranasal doses of 435 nmol, about 1.5 mg, in narcolepsy with cataplexy (Baier et al., 2011; Weinhold et al., 2014) and 500 nmol, about 1.8 mg, in healthy men (Meusel et al., 2022). That is roughly fifty times the 15 to 30 mcg community figure in the numeric fields. The monkey study used 2.5 to 10 mcg/kg intravenously and an estimated 1 mcg/kg nasally (Deadwyler et al., 2007). Measured effects in healthy men were a rise in muscle sympathetic nerve activity with no change in blood pressure or heart rate (Meusel et al., 2022). Orexin A crosses the blood-brain barrier from blood by diffusion in mice, so other routes are not inert (Kastin and Akerstrom, 1999).

Mechanism

Orexin A (hypocretin-1) is produced by lateral hypothalamic neurons and binds OX1R and OX2R, G-protein-coupled receptors that drive arousal, feeding and autonomic tone (Sakurai et al., 1998; de Lecea et al., 1998). Absence of the peptide in the brain is the lesion behind narcolepsy type 1 with cataplexy (Peyron et al., 2000). Orexin A is lipophilic and enters mouse brain from blood by non-saturable diffusion, reaching parenchyma largely intact, while orexin B is degraded in blood (Kastin and Akerstrom, 1999). Intranasal delivery in humans reproduces central effects: reduced and stabilised REM sleep in narcolepsy (Baier et al., 2011) and increased muscle sympathetic nerve activity without a change in blood pressure or baroreflex sensitivity in healthy men, which the authors read as an upward reset of the vascular baroreflex set point (Meusel et al., 2022).

Evidence

Clinical: at least one published human trial or an approved drug

Orexin A and B and their receptors were identified as hypothalamic neuropeptides regulating feeding (Sakurai et al., 1998; de Lecea et al., 1998)
Narcolepsy type 1 brains show a generalised absence of hypocretin peptides, which established the deficiency as the cause (Peyron et al., 2000)
Intravenous orexin A crosses the mouse blood-brain barrier by simple diffusion, mostly intact; orexin B is degraded in blood and does not (Kastin and Akerstrom, 1999)
In sleep-deprived rhesus monkeys, both intravenous (2.5 to 10 mcg/kg) and nasal delivery improved delayed match-to-sample performance, with nasal more effective than the highest intravenous dose (Deadwyler et al., 2007)
Two placebo-controlled crossover trials in narcolepsy with cataplexy (n=8 and n=14) gave 435 nmol intranasally: REM sleep was reduced and stabilised with fewer direct wake-to-REM transitions, and attention errors fell, but nocturnal wakefulness and daytime sleepiness did not improve (Baier et al., 2011; Weinhold et al., 2014)
Human-trial status: small crossover trials only. Intranasal orexin A at 500 nmol raised resting muscle sympathetic nerve activity in 10 healthy men (Meusel et al., 2022), and daytime sleepiness did not improve in any published trial (Weinhold et al., 2014). No approval anywhere; development has moved to small-molecule orexin receptor agonists

References

Side effects

In the published human trials (n=8, n=14 and n=10) intranasal dosing was tolerated with no serious adverse events reported. The measured physiological effect in healthy men was a rise in resting muscle sympathetic nerve activity, with blood pressure, heart rate and heart rate variability unchanged (Meusel et al., 2022). Beyond those single doses there is no human safety data: no repeat-dose study, no pharmacokinetics and no long-term follow-up. Orexin signalling drives arousal and autonomic tone, so cardiovascular and anxiety effects are plausible class effects rather than observed ones.

Storage

Storage: Frozen (-20°C)
Lyophilized: 12+ months
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not measured in humans; in mice, intravenous orexin A enters brain intact and leaves at the same rate as an albumin marker (Kastin and Akerstrom, 1999)
Bioavailability: Not quantified by any route. Intranasal dosing produces central effects in humans and monkeys (Baier et al., 2011; Deadwyler et al., 2007), and intravenous orexin A crosses the mouse blood-brain barrier by simple diffusion (Kastin and Akerstrom, 1999).
Molecular weight: 3561.1 Da
Sequence: QPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-NH2 (33 residues from HCRT, UniProt O43612, residues 34-66; pyroglutamyl N-terminus, two intrachain disulfide bonds, C-terminal amide)