Article

Intranasal Delivery to the Central Nervous System: Mechanisms and Experimental Considerations

Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of Pharmaceutical Sciences (Impact Factor: 3.01). 11/2009; 99(4):1654-73. DOI: 10.1002/jps.21924
Source: PubMed

ABSTRACT The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review.

Download full-text

Full-text

Available from: William H. Frey 2nd, Jul 07, 2015
2 Followers
 · 
353 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Repeated, extreme, or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes. Stressors can precipitate the onset of psychiatric diseases, or exacerbate pre-existing disorders including various anxiety and mood disorders. As stressors can negatively impact human psychiatric health, it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure. Elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to, or recovery from, stress-related psychiatric disease. Herein, we will review the evidence for neuropeptide Y as an endogenous mediator of resilience and its potential relevance for the treatment of stress-related psychiatric diseases.
    01/2015; 1:33-43. DOI:10.1016/j.ynstr.2014.09.007
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Melanocortin receptor four (MC4R) is implicated in regulation of stress-related functions. We previously demonstrated that intranasal infusion of MC4R antagonist HS014, shortly before single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), lessened development of anxiety- and depression-like behavior depending on the dose. Here we evaluated effects of HS014 on SPS-elicited changes in HPA axis and expression of several genes of interest in mediobasal hypothalamus, hippocampus and locus coeruleus. Rats were given intranasal infusion of HS014 (3.5 ng or 100 μg) and 30 min later subjected to SPS stressors. Short-term responses of HS014 rats in comparison with vehicle-treated, evident 30 min following SPS stressors, included smaller rise in plasma corticosterone (100 μg HS014), absence of induction of CRH mRNA in mediolbasal hypothalamus and of mRNA for TH and DBH in locus coeruleus. Long-term responses found 7 days after SPS stressors, included lower induction CRH mRNA levels in the mediobasal hypothalamus without effect on mRNAs for the glucocorticoid receptor (GR) and FKBP5, a component of GR co-chaperone complex; and no induction of GR protein in ventral hippocampus. Thus, antagonism of MC4R prior to SPS attenuates development of several abnormalities in gene expression in regions implicated in PTSD.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 08/2014; 131(6). DOI:10.1111/jnc.12847 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A variety of compounds distribute into brain when placed at the cribriform plate by intranasal administration (i.n.). Here, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into brain after i.n. administration. We labeled bovine serum albumin with 125I (I-Alb) and studied its uptake into 11 brain regions and entry into blood from 5 min to 6 h after i.n. administration. I-Alb was present throughout the brain at 5 min. Several regions showed distinct peaks in uptake that ranged from 5 min (parietal cortex) to sixty min (midbrain). About 2-4% of the i.n. I-Alb entered the blood stream. The highest levels occurred in olfactory bulb and striatum. Distribution was dose-dependent with less being taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid phase stimulator phorbol 12-myristate 13-acetate, but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered distribution of radioactive leptin given by i.n. administration, decreasing uptake into blood and by cerebellum and increasing uptake by the hypothalamus. We conclude that I-Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration.
    Journal of Pharmacology and Experimental Therapeutics 07/2014; 351(1). DOI:10.1124/jpet.114.216705 · 3.86 Impact Factor