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

Baier, PC; Weinhold, Sara Lena; Huth, Verena; Gottwald, B; Ferstl, Roman; Hinze-Selch, D.

doi:10.1055/s-0029-1240078

Cited by 13 publications

(18 citation statements)

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“…In a study of 130 individuals with narcolepsy, using Sniffin' Sticks, a quarter had mild/moderate olfactory impairment [62]. Olfactory dysfunction in narcolepsy has been reported to be reversed by intranasal orexin A (hypocretin 1) [63]. Animal studies have observed that orexin neurons are glucose-sensing, being inhibited by glucose [64]; thus, hyperglycaemia in people with diabetes may affect olfactory function through actions on orexin neurons in the lateral hypothalamus.…”

Section: Putative Mechanisms For Olfactory Dysfunction In Diabetesmentioning

confidence: 99%

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

et al. 2017

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The increasing global prevalence of diabetes mellitus presents a significant challenge to healthcare systems today. Although diabetic retinopathy, nephropathy and neuropathy are well-established complications of diabetes, there is a paucity of research examining the impact of dysglycaemia on the olfactory system. Olfaction is an important sense, playing a role in the safety, nutrition and quality of life of an individual, but its importance is often overlooked when compared with the other senses. As a result, olfactory dysfunction is often underdiagnosed. The present review article aims to present and discuss the available evidence on the relationship between diabetes and olfaction. It also explores the associations between olfactory dysfunction and diabetes complications that could explain the underlying pathogenesis. Finally, it summarizes the putative pathological mechanisms underlying olfactory dysfunction in diabetes that require further investigation.

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Section: Putative Mechanisms For Olfactory Dysfunction In Diabetesmentioning

confidence: 99%

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

et al. 2017

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“…We also recognize the limitations of translating these findings into clinical applications due to the obvious differences between rodents and humans. Despite species-specific differences, peptides and proteins have been successfully delivered intranasally and are effective in nonhuman primates (Deadwyler et al, 2007;Thorne et al, 2008) as well as in humans (Born et al, 2002;Gozes and Divinski, 2007;Baier et al, 2008;Reger et al, 2008). Although it will be important to evaluate the risk of adverse systemic effects and rebound congestion from repeated use of nasal decongestants (O'Donnell, 1995), a potential advantage of vasoconstrictor formulations is the ability to use intranasal treatments in patient populations with nasal congestion due to colds or allergies.…”

Section: Downloaded Frommentioning

confidence: 99%

“…HC was selected as a model peptide to evaluate intranasal targeting to the CNS using a vasoconstrictor formulation. Recent reports indicate that intranasal administration of HC significantly improves performance in sleep-deprived nonhuman primates (Deadwyler et al, 2007) and olfactory function in patients with narcolepsy (Baier et al, 2008). With a molecular weight that is 10-fold less than that of HC, D-KTP is a considerably smaller peptide that would be expected to enter the nasal vasculature and be affected by a vasoconstrictor to a greater extent than HC.…”

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confidence: 99%

Novel Vasoconstrictor Formulation to Enhance Intranasal Targeting of Neuropeptide Therapeutics to the Central Nervous System

Dhuria

Hanson²,

Frey³

2008

J Pharmacol Exp Ther

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The intranasal route of drug administration is noninvasive, convenient, and rapidly targets therapeutics to the central nervous system (CNS) using olfactory and trigeminal neural pathways connecting the nasal passages to the brain. The purpose of this research was to enhance intranasal drug targeting to the CNS by incorporating a vasoconstrictor [phenylephrine (PHE)] into nasal formulations containing therapeutic neuropeptides [hypocretin-1 (HC) or the dipeptide L-Tyr-D-Arg (D-KTP)]. Concentrations in CNS tissues, peripheral tissues, and blood were determined at 30 min following intravenous or intranasal administration of 125 I-labeled neuropeptides with and without PHE. Compared with intranasal controls, inclusion of 1% PHE in nasal formulations significantly reduced absorption into the blood for HC (65% reduction) and D-KTP (56% reduction), whereas it significantly increased deposition into the olfactory epithelium by ϳ3-fold for both. PHE (1%) significantly increased delivery to the olfactory bulbs for HC (2.1-fold) and D-KTP (3.0-fold), whereas it significantly reduced concentrations in the trigeminal nerve for HC (65% reduction) and D-KTP (39% reduction) and in most remaining brain regions by ϳ50% for both. The dramatic reduction in blood concentrations with PHE contributed to brain-to-blood concentration ratios that were significantly increased for HC throughout the brain (1.6 -6.8-fold) compared with intranasal controls. For D-KTP, 1% PHE significantly increased ratios only in the olfactory bulbs (5.3-fold). With a 5% PHE formulation, D-KTP ratios were significantly increased to additional brain areas (1.5-16-fold). Vasoconstrictor nasal formulations may have particular relevance for CNS therapeutics with adverse side effects where it would be advantageous to limit systemic exposure.It has been reported that greater than 98% of small-molecule and nearly 100% of large-molecule central nervous system (CNS) drugs developed by the pharmaceutical industry do not cross the blood-brain barrier (Pardridge, 2005). Intracerebroventricular or intraparenchymal drug administration can directly deliver therapeutics to the brain; however, these methods are invasive, inconvenient, and impractical for the numbers of individuals requiring therapeutic interventions for treating CNS disorders. Intranasal drug administration is a noninvasive and convenient means to rapidly target therapeutics of varying physical and chemical properties to the CNS. Although the exact mechanisms underlying intranasal delivery to the CNS are not well understood, the olfactory and trigeminal neural pathways connecting the nasal passages to the CNS are clearly involved (Thorne et al

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“…Patients with narcolepsy type 1 have lower levels of hypocretin-1 and consequent inferior olfactory threshold, less olfactory discrimination, and these findings improved after nasal hypocretin-1 administration 10 . In recent and interesting paper published by van Holst et al 1 , all patients with gustatory and hyposmia complains were excluded from original study.…”

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confidence: 99%

Human hypocretin-deficient narcolepsy - aberrant food choice due to impaired taste?

2017

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Authors demonstrate that patients with narcolepsy type 1 (N1) have more tendency of eat salty snacks after satiety than health volunteers. A few mechanisms to explain the weight gain have been discussed in narcolepsy. The hypocretin-1 deficiency can influence the olfactory system. The olfactory system should be modulated through hypocretin-1 via connections from the hypothalamic to other brain regions. Likewise, hypocretin-1 can be synthesized locally in our olfactory mucosa with possible private role modulating the olfactory. In experimental studies, different kinds of smell influence the preference for type of diet. Olfactory and taste sensations help control of appetite and regulate the quantity and quality of foods that will be chosen. N1 patients have lower levels of hypocretin-1 and consequent inferior olfactory threshold, less olfactory discrimination, and these findings improved after nasal hypocretin-1 administration. It is possible that the hyposmia influenced the quality and quantity of food by narcoleptic patients. We suggest that a complementary analysis of olfactory function should be done concomitant with food preferences to compare narcoleptic patients with and without hypocretin-1 deficiency.

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

Cited by 13 publications

References 0 publications

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

Novel Vasoconstrictor Formulation to Enhance Intranasal Targeting of Neuropeptide Therapeutics to the Central Nervous System

Human hypocretin-deficient narcolepsy - aberrant food choice due to impaired taste?

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