| Transport across the blood-brain barrier of pluronic leptin. | |
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MedLine Citation:
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PMID: 20053933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Leptin is a peptide hormone produced primarily by adipose tissue that acts as a major regulator of food intake and energy homeostasis. Impaired transport of leptin across the blood-brain barrier (BBB) contributes to leptin resistance, which is a cause of obesity. Leptin as a candidate for the treatment of this obesity is limited because of the short half-life in circulation and the decreased BBB transport that arises in obesity. Chemical modification of polypeptides with amphiphilic poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic) is a promising technology to improve efficiency of delivery of polypeptides to the brain. In the present study, we determined the effects of Pluronic P85 (P85) with intermediate hydrophilic-lipophilic balance conjugated with leptin via a degradable SS bond [leptin(ss)-P85] on food intake, clearance, stability, and BBB uptake. The leptin(ss)-P85 exhibited biological activity when injected intracerebroventricularly after overnight food deprivation and 125I-leptin(ss)-P85 was stable in blood, with a half-time clearance of 32.3 min (versus 5.46 min for leptin). 125I-Leptin(ss)-P85 crossed the BBB [blood-to-brain unidirectional influx rate (K(i)) = 0.272 +/- 0.037 microl/g x min] by a nonsaturable mechanism unrelated to the leptin transporter. Capillary depletion showed that most of the 125I-leptin(ss)-P85 taken up by the brain reached the brain parenchyma. Food intake was reduced when 3 mg of leptin(ss)-P85 was administered via tail vein in normal body weight mice [0-30 min, p < 0.0005; 0-2 h, p < 0.001]. These studies show that the structure based Pluronic modification of leptin increased metabolic stability, reduced food intake, and allowed BBB penetration by a mechanism-independent BBB leptin transporter. |
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Authors:
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Tulin O Price; Susan A Farr; Xiang Yi; Serguei Vinogradov; Elena Batrakova; William A Banks; Alexander V Kabanov |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-01-06 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 333 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-03-22 Completed Date: 2010-04-22 Revised Date: 2013-01-28 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 253-63 Citation Subset: IM |
Affiliation:
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Geriatric Research, Education, and Clinical Center, VA Medical Center, John Cochran Division, 915 N. Grand Blvd., St. Louis, MO 63106, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood-Brain Barrier / metabolism* Brain / blood supply, metabolism Capillaries / metabolism Eating / drug effects Endothelium, Vascular / metabolism Injections, Intravenous Injections, Intraventricular Leptin / administration & dosage, chemistry, pharmacokinetics* Male Mice Poloxamer / chemistry, pharmacokinetics* Tissue Distribution |
| Grant Support | |
ID/Acronym/Agency:
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R01 AG029839-04/AG/NIA NIH HHS; R01 AG029839-05/AG/NIA NIH HHS; R01 NS051334/NS/NINDS NIH HHS; R01 NS051334-01A1/NS/NINDS NIH HHS; R01 NS051334-02/NS/NINDS NIH HHS; R01 NS051334-03/NS/NINDS NIH HHS; R01 NS051334-05/NS/NINDS NIH HHS; R01-NS051334/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Leptin; 0/pluronic P105; 106392-12-5/Poloxamer |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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