Olfactory dysfunction in patients with narcolepsy with cataplexy is restored by intranasal Orexin A (Hypocretin-1)

Abstract

Until recently, olfactory dysfunction was an unknown feature of narcolepsy. Orexin A, also called hypocretin-1, is abnormally decreased or undetectable in the cerebrospinal fluid of narcoleptic patients with cataplexies. As hypothalamic orexin-containing neurons project throughout the entire olfactory pathway, from the olfactory mucosa to the olfactory cortex, disturbed orexinergic transmission may crucially be involved in impaired olfactory performance of narcolepsy patients. In our study we analysed the olfactory performance (threshold, discrimination, identification and sum score of these measurements, the TDI score) of narcoleptic patients with cataplexies (n = 10) and of age-, gender-, BMI- and smoker/non-smoker-matched healthy controls (n = 10). We then in a double-blind, randomized, placebo-controlled cross-over design applied orexin A intranasally to seven of the patients and measured 2-phenyl-ethyl alcohol (PEA) single-staircase odour detection thresholds. Compared to the controls, patients showed significantly lower scores for olfactory threshold (patients: median 8.0, range 4.0-10.5; controls: median 9.4, range 7.5-13.3; P < 0.05), discrimination (patients: median 12.5, range 10-15; controls: median 15.0, range 12-16; P < 0.005), identification (patients: median 13.0, range 10-16; controls: median 14.0, range 13-16; P < 0.05) and TDI score (patients: median 33.4, range 30-36; controls: median 38.4, range 35-43; P < 0.0001). In all patients, the PEA olfactory threshold score increased after administration of orexin A (median 11.5, range 6.5-13.25) compared to placebo (median 7.75, range 6.25-11.25; P < 0.05). Our results support the hypothesis that mild olfactory dysfunction is an intrinsic symptom of narcolepsy with cataplexies. The observation that intranasal orexin A restores olfactory function is in favour of this hypothesis. Furthermore, our data support that the pathophysiological mechanism underlying olfactory dysfunction in narcolepsy is the lack of CNS orexin.

Food consumption and activity levels increase in rats following intranasal Hypocretin-1

“…Intranasal HC also improves cognitive ability following sleep deprivation in nonhuman primates [13]. Three recent clinical trials show that IN HC restores olfactory function and is beneficial for sleep and attention in narcolepsy [14][15][16].…”

Models for narcolepsy with cataplexy drug discovery

“…Unfortunately, this delivery method presented a similar brain concentration, when compared with the intravenous administration [36]. Likewise, when administered to narcoleptic patients, this approach restored only the olfactory dysfunction [37].…”

Therapeutics of Narcolepsy

“…153 Successful intranasal hypocretin administration has been demonstrated in both laboratory animals and human subjects with narcolepsy. 8,154 In a small patient cohort, intranasal hypocretin improved olfactory function and cognitive disturbances associated with narcolepsy. Notwithstanding the difficulties administering already prepared compounds, hypocretin-based therapy could well revolutionize the treatment of narcolepsy in the future.…”

“…1e7 In addition to this classic tetrad, individuals with narcolepsy may exhibit sleep disruption and fragmentation, report memory disturbances, and display automatisms. 8 Cataplexy is the most specific sign and is considered pathognomonic; the other symptoms accompany an assortment of sleep disorders and also occur in the general population.…”