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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Brain Uptake of the Glucagon-Like Peptide-1 Antagonist Exendin(9-39) after Intranasal Administration

William A. Banks, Matthew J. During and Michael L. Niehoff
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 469-475; DOI: https://doi.org/10.1124/jpet.103.063222
William A. Banks
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Matthew J. During
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Michael L. Niehoff
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Abstract

Exendin, a member of the glucagon-like peptide-1 family, and its antagonist exendin(9-39) affect cognition and neuronal survival after their intranasal delivery. Here, we examined the uptake of radioactively labeled exendin(9-39) (I-Ex) by the olfactory bulbs, brain (minus pineal, pituitary, and olfactory bulb), cerebrospinal fluid, and cervical lymph nodes (C-node) as well as levels in serum after intranasal or intravenous administration. We found that olfactory bulb uptake of I-Ex after intranasal administration was rapid, much greater than after i.v. administration, and was enhanced by about 60% with cyclodextrin (CD). I-Ex was also taken up by the remainder of the brain after intranasal administration, but this uptake was not enhanced by CD, nor did it exceed uptake after i.v. administered I-Ex. Uptake by the olfactory bulb was not dependent on Brownian motion but did involve active processes. Intranasal I-Ex reached the C-node by way of the blood. About one-sixth of the intranasal dose of I-Ex entered the blood. However, the vascular route accounted for little of the intranasal I-Ex that reached the brain and even less that reached the olfactory bulb. I-Ex after intranasal administration was found in the hippocampus, cerebellum, brain stem, and cerebrospinal fluid (CSF). Distribution patterns showed that intranasal I-Ex used the extraneuronal route of CSF rather than brain parenchyma to diffuse throughout the brain. These results show that intranasal administration is an effective means of delivering peptide to the brain, especially the olfactory bulb.

Footnotes

  • This work was supported by Veterans Affairs Merit Review, RO1 NS41863, and RO1 AA12743.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.063222.

  • ABBREVIATIONS: GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; CNS, central nervous system; BBB, blood-brain barrier; I-Ex, radioactively labeled exendin(9-39); C-node, cervical lymph nodes; CSF, cerebrospinal fluid; CD, cyclodextrin; PE, polyethylene; PBS, phosphate-buffered saline; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance; AUC, area under the curve.

    • Received November 19, 2003.
    • Accepted December 31, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Brain Uptake of the Glucagon-Like Peptide-1 Antagonist Exendin(9-39) after Intranasal Administration

William A. Banks, Matthew J. During and Michael L. Niehoff
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 469-475; DOI: https://doi.org/10.1124/jpet.103.063222

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Brain Uptake of the Glucagon-Like Peptide-1 Antagonist Exendin(9-39) after Intranasal Administration

William A. Banks, Matthew J. During and Michael L. Niehoff
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 469-475; DOI: https://doi.org/10.1124/jpet.103.063222
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