Orexin A

Cerebrospinal fluid hypocretin-1 (orexin-A) was measured by radioimmunoassay in patients with narcolepsy and control subjects. Hypocretin-1 was undetectable in 7 of 9 narcoleptic patients, whereas it was present at normal concentrations in all controls and in patients with other neurological disorders. The findings provided the first direct human evidence that impaired hypocretin/orexin neurotransmission underlies narcolepsy, establishing low CSF hypocretin-1 as a diagnostic biomarker of the disease.

Researchers measured orexin (also called hypocretin), a brain chemical that keeps us awake, in the spinal fluid of people with narcolepsy. Almost all of the narcolepsy patients had essentially no detectable orexin, while healthy people had normal levels. This showed that narcolepsy is caused by a lack of orexin, and that measuring it can help diagnose the condition.

Post-mortem analysis of human narcoleptic brains showed a near-complete, generalized absence of hypocretin (orexin) peptides and hypocretin-producing neurons in the hypothalamus, while related neuronal markers such as melanin-concentrating hormone were preserved, indicating selective loss of orexin neurons rather than global hypothalamic degeneration. A rare early-onset case carried a mutation in the preprohypocretin gene that impaired peptide processing and trafficking. Together the data implicate targeted destruction of hypocretin neurons, likely acquired, as the basis of most human narcolepsy.

By examining the brains of deceased people who had narcolepsy, scientists found that the specific cells that make orexin were almost entirely gone, while neighboring brain cells were intact. In one child with unusually early narcolepsy, a genetic mutation disrupted orexin production. This confirmed that narcolepsy usually results from the loss of the small population of brain cells that produce orexin.

In sleep-deprived rhesus monkeys, both intravenous and intranasal administration of orexin-A reversed sleep-deprivation-induced deficits on a short-term memory task, restoring performance toward non-deprived baseline levels. PET imaging showed sleep deprivation altered regional brain metabolism, and orexin-A normalized activity in relevant cortical and subcortical regions; intranasal delivery achieved these effects without significant systemic exposure. The results demonstrate that exogenous orexin-A, particularly via the nasal route, can counter cognitive impairment from sleep loss.

Scientists kept monkeys awake and then tested their memory, which normally worsens after sleep loss. Giving the monkeys orexin-A, either by injection or as a nasal spray, restored their memory performance to near-normal and reversed sleep-deprivation-related changes in brain activity. This suggested orexin-A, especially delivered through the nose, might one day help counter the mental fog caused by missing sleep.