Quantitative analysis of the olfactory pathway for drug delivery to the brain

Thorne, Robert G.; Emory, Carolyn; Thomas, Anthony J.; Frey, William H.

doi:10.1016/0006-8993(95)00637-6

Cited by 308 publications

(178 citation statements)

References 19 publications

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“…This different onset of action probably originates from dissimilar pharmacokinetics and targeting efficiencies of intranasally vs ICVadministered drugs (Thorne et al, 1995(Thorne et al, , 2008Shi et al, 2010). As at 30 min after intranasal application of Cy3-NPS, a much weaker signal was observed than after ICV injection, it is possible that, although NPS does reach the brain rapidly after transnasal delivery, it may require additional time to reach its brain target cells in the full concentration required to produce behavioral effects.…”

Section: Discussionmentioning

confidence: 99%

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Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Ionescu

Dine

Yen

et al. 2012

Neuropsychopharmacol

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Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor-ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.

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Section: Discussionmentioning

confidence: 99%

“…As it has been shown that effective concentrations of intranasally applied substances can be detected in the CNS up to 4 h after delivery (Thorne et al, 1995;Jansson and Björk, 2002), we chose this time point for behavioral testing.…”

Section: Intranasally Administered Nps Exerts Strong Anxiolytic Effecmentioning

confidence: 99%

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Ionescu

Dine

Yen

et al. 2012

Neuropsychopharmacol

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“…Intranasally administered peptides may reach the brain along olfactory but also trigeminal pathways [21]. Given that intraneuronal, axonal transport requires hours to days for substances to reach the brain [22], it is more plausible to assume that intranasal insulin, passing through intercellular clefts in the olfactory epithelium, diffuses into the subarachnoidal space and is rapidly delivered to the CSF [15] and brain tissue [21,22] via bulk flow transport through perineural channels as reviewed by Hanson and Frey [21]. The functional efficacy of the intranasal route was corroborated by human studies indicating that intranasal insulin exerts rapid effects on EEG measures comparable to those of i.v.…”

Section: Central Nervous Insulin Effects In Healthy Humansmentioning

confidence: 99%

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Hallschmid

Schultes

2009

Diabetologia

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Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an evergrowing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

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“…A variety of nasal delivery methods are typically used in studies investigating nose-tobrain delivery in rodents, but very few studies specifically and consistently deposit drug on the olfactory epithelium. The most commonly used nasal administration modes are nose drops (18)(19)(20)(21), in which the animal is placed on its back in a supine position while liquid drops are snorted into the nasal cavity, or inserting a soft catheter connected to a microsyringe into the nasal cavity and applying a volume of drug a set distance into the nasal cavity from the naris (11,22). These methods may effectively deliver drug to the nasal cavity; however, they tend to involve a large dose volume resulting in saturation of both the respiratory and olfactory epithelium.…”

Section: Introductionmentioning

confidence: 99%

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Hoekman

2011

AAPS PharmSciTech

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Abstract. Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P=−3.1), and a hydrophobic drug, nelfinavir (log P=6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p<0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p<0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

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Quantitative analysis of the olfactory pathway for drug delivery to the brain

Cited by 308 publications

References 19 publications

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

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