title: PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement.
abstract: OBJECTIVE
  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-CCK(9), produced a significantly longer anorectic effect than unmodified CCK(9). The present study assessed the dose-dependency of this response and the effect of two selective CCK(1) receptor antagonists, with different abilities to cross the blood-brain barrier (BBB), on PEG-CCK(9)-induced anorexia.
  
  
  METHODS
  Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 microg kg(-1)) of CCK(9) or PEG-CCK(9) in male Wistar rats. Devazepide (100 microg 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-CCK(9) (6 microg kg(-1)) and food intake was monitored.
  
  
  RESULTS
  In PEG-CCK(9)-treated rats, a clear dose-dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK(9), only the initial intensity was dose-dependent. Intraperitoneal administration of devazepide or 2-NAP, injected immediately prior to PEG-CCK(9), completely abolished the anorectic effect of PEG-CCK(9).
  
  
  CONCLUSIONS
  The duration of the anorexia for PEG-CCK(9) was dose-dependent, suggesting that PEGylation of CCK(9) increases its circulation time. Both devazepide and 2-NAP completely abolished the anorectic effect of i.p. PEG-CCK(9) indicating that its anorectic effect was solely due to stimulation of peripheral CCK(1) receptors.
authors.affiliation: Interdisciplinary Research Center, Katholieke Universiteit Leuven, Kortrijk, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Verbaeys
authors.forename: F
authors.initials: F
authors.lastname: León-Tamariz
authors.forename: J
authors.initials: J
authors.lastname: Buyse
authors.forename: M
authors.initials: M
authors.lastname: De Cuyper
authors.forename: H
authors.initials: H
authors.lastname: Pottel
authors.forename: M
authors.initials: M
authors.lastname: Van Boven
authors.forename: M
authors.initials: M
authors.lastname: Cokelaere
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D001067:Appetite Depressants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001812:Blood-Brain Barrier; D002766:Cholecystokinin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D020109:Devazepide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D009282:Naphthalenesulfonates / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D043886:Receptor, Cholecystokinin A / Q000187:drug effects* / Q000378:metabolism; D012527:Satiation / Q000187:drug effects*
chemical_list: D001067:Appetite Depressants; D003692:Delayed-Action Preparations; D009282:Naphthalenesulfonates; D010446:Peptide Fragments; D043886:Receptor, Cholecystokinin A; C053399:cholecystokinin 9; C080661:N-(2-naphthalenesulfonyl)aspartyl-(2-phenethyl)amide; D001224:Aspartic Acid; D011092:Polyethylene Glycols; D002766:Cholecystokinin; D020109:Devazepide