PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

• Published in: British journal of pharmacology 2007-10, Vol.152 (3), p.396-403
• Main Authors: Verbaeys, I, León‐Tamariz, F, Buyse, J, Cuyper, M, Pottel, H, Boven, M, Cokelaere, M
• Format: Article
• Language: English
• Subjects: 2‐NAP; Animals; anorexia; Anorexia - chemically induced; Appetite Depressants - administration & dosage; Appetite Depressants - chemistry; Appetite Depressants - pharmacokinetics; Appetite Depressants - pharmacology; Aspartic Acid - analogs & derivatives; Aspartic Acid - pharmacology; Biological and medical sciences; Blood-Brain Barrier; CCK1 receptor antagonists; cholecystokinin; Cholecystokinin - administration & dosage; Cholecystokinin - chemistry; Cholecystokinin - pharmacokinetics; Cholecystokinin - pharmacology; Delayed-Action Preparations; devazepide; Devazepide - pharmacology; Dose-Response Relationship, Drug; dose–response; Eating - drug effects; Injections, Intraperitoneal; Male; Medical sciences; Naphthalenesulfonates - pharmacology; PEGylated cholecystokinin; Peptide Fragments - administration & dosage; Peptide Fragments - chemistry; Peptide Fragments - pharmacokinetics; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Rats; Rats, Wistar; Receptor, Cholecystokinin A - drug effects; Receptor, Cholecystokinin A - metabolism; Research Papers; Satiation - drug effects
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707390

Background and purpose: Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short‐lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG‐CCK9, produced a significantly longer anorectic effect than unmodified CCK9. The present study assessed the dose–dependency of this response and the effect of two selective CCK1 receptor antagonists, with different abilities to cross the blood‐brain barrier (BBB), on PEG‐CCK9‐induced anorexia. Experimental approach: Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 μg kg−1) of CCK9 or PEG‐CCK9 in male Wistar rats. Devazepide (100 μg kg−1), which penetrates the BBB or 2‐NAP (3 mg kg−1), which does not cross the BBB, were coadministered i.p. with PEG‐CCK9 (6 μg kg−1) and food intake was monitored. Key results: In PEG‐CCK9‐treated rats, a clear dose‐dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK9, only the initial intensity was dose‐dependent. Intraperitoneal administration of devazepide or 2‐NAP, injected immediately prior to PEG‐CCK9, completely abolished the anorectic effect of PEG‐CCK9. Conclusions and implications: The duration of the anorexia for PEG‐CCK9 was dose‐dependent, suggesting that PEGylation of CCK9 increases its circulation time. Both devazepide and 2‐NAP completely abolished the anorectic effect of i.p. PEG‐CCK9 indicating that its anorectic effect was solely due to stimulation of peripheral CCK1 receptors. British Journal of Pharmacology (2007) 152, 396–403; doi:10.1038/sj.bjp.0707390; published online 9 July 2007