Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins.
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 mug/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 alpha-cyclodextrin, and the OB after i.n. administration with dimethyl-beta 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.
Nonaka
Naoko
N
Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, John Cochran Division, 915 N. Grand Blvd., St. Louis, MO 63106, USA. bankswa@slu.edu.
Farr
Susan A
SA
Kageyama
Haruaki
H
Shioda
Seiji
S
Banks
William A
WA
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004333:Drug Administration Routes; D044089:Galanin-Like Peptide / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009830:Olfactory Bulb / Q000378:metabolism; D013154:Spleen / Q000378:metabolism
D003505:Cyclodextrins; D044089:Galanin-Like Peptide