Abstract
Galanin-like peptide (GALP) shows potential as a therapeutic in the treatment of obesity and related conditions. In this study, we compared the uptake by brain regions and peripheral tissues of radioactively iodinated GALP (I-GALP) after intranasal (i.n.), i.v., and i.c.v. administration. I-GALP was stable in blood and brain during the 10-min study time regardless of route of administration, and similar levels were achieved in cerebrospinal fluid after i.v. and i.n. administration. However, levels in most brain regions were approximately 4 to 10 times higher and uptake by spleen, representative of peripheral tissues, approximately 10% as high after i.n. than i.v. administration. Thus, i.n. administration provided about a 40- to 100 fold improvement in targeting brain versus peripheral tissues compared with i.v. administration. Uptake of I-GALP by whole brain after i.n. administration was inhibited by approximately 50% by 1 μg/mouse of unlabeled GALP, thus demonstrating a saturable component to uptake. Combining I-GALP with cyclodextrins increased brain uptake approximately 3-fold. Selectivity for brain region uptake was also seen with route of administration and with use of cyclodextrins. The hippocampus had the greatest uptake after i.c.v. administration, the cerebellum after i.v. administration, the hypothalamus with i.n. administration without cyclodextrins, the hypothalamus and olfactory bulb (OB) after i.n. administration with α-cyclodextrin, and the OB after i.n. administration with dimethyl-β cyclodextrin. These studies show that intranasal administration is an effective route of administration for the delivery of GALP to the brain and that targeting among brain regions may be possible with the use of various cyclodextrins.
Footnotes
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This study was supported by Veterans Affairs Merit Review and National Institutes of Health Grants R01 NS050547 and R01 NS051334 (to W.A.B.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132381.
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ABBREVIATIONS: GALP, galanin-like peptide; GALR, galanin receptor; BBB, blood-brain barrier; OB, olfactory bulb; i.n., intranasal; I-GALP, 131I-GALP; LR, lactated Ringer's solution; BSA, bovine serum albumin; WBr, whole brain; ant brain, anterior one third of the brain; %Inj/ml, percentage of the injected dose present in a milliliter of serum; %Inj/g, percentage of the injected dose taken up per gram of brain tissue; B-CD, dimethyl-β-cyclodextrin; A-CD, α-cyclodextrin; CD, cyclodextrin; CSF, cerebrospinal fluid; TCA, trichloroacetic acid; ANOVA, analysis of variance; CNS, central nervous system.
- Received September 30, 2007.
- Accepted February 11, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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