Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin

Falcone, Joseph; Salameh, Therese S.; Xiang, Yi; Cordy, Benjamin J.; Mortell, William G.; Kabanov, Alexander V.; Banks, William A.

doi:10.1124/jpet.114.216705

Cited by 70 publications

(45 citation statements)

References 40 publications

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“…The pathway by which GUO applied to the nostril reaches the CNS seems to be reached as fast as only 5 min post-injection. This result is in accordance with other studies, which demonstrated that different drugs could reach maximal CNS concentrations immediately after administration [37,38]. No significant difference was observed in GUO endogenous levels in the brain structures following IN [ 3 H] GUO solution administration in any condition tested in this work.…”

Section: Discussionsupporting

confidence: 82%

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Ramos

Müller

Rocha

et al. 2015

Purinergic Signalling

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In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [ 3 H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO Purinergic Signalling (2016) 12:149-159 DOI 10.1007 Denise Barbosa Ramos and Gabriel Cardozo Muller contributed equally as first authors.Electronic supplementary material The online version of this article (doi:10.1007/s11302-015-9489-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 82%

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Ramos

Müller

Rocha

et al. 2015

Purinergic Signalling

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“…This observation is contradictory to what is observed in muscle where PKC activation leads to increased uptake. The effects observed here are unique to insulin since studies completed with these inhibitors and 125 I-albumin have shown a completely different proffile in regards to uptake into the brain post intranasal administration [37]. …”

Section: Discussionmentioning

confidence: 99%

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh

Bullock

Hujoel

et al. 2015

JAD

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108

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Intranasal insulin has shown effficacy in patients with Alzheimer’s disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory defficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

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“…Daily, intranasal leptin at concentrations of 0.1 or 0.2 mg/kg body weight has been shown to decrease weight and food intake over a 28-day period independent of changes in serum leptin levels (27). Radioactive tracer experiments reveal the hypothalamus and olfactory bulbs contain the greatest amounts of leptin 15-30 min after intranasal leptin administration (3,28). The hippocampus also had increased levels, but these were not different from the total brain average.…”

Section: Leptinmentioning

confidence: 96%

“…However, brain endothelial cells have relatively low expression, and the BBB prevents albumin from crossing in vitro and in vivo. In order to bypass the BBB, recent studies show evidence for the uptake of albumin across the nasal epithelium (3,17). Uptake occurred through a saturable transport system rapidly to all regions of the brain, with the highest levels detected in the striatum and the olfactory bulb.…”

Section: Proteins and Peptides Albuminmentioning

confidence: 99%

“…Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration (2). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain (3)(4)(5). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

Meredith

Salameh

Banks

2015

AAPS J

Self Cite

166

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Abstract. The blood-brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases.

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Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin

Cited by 70 publications

References 40 publications

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

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