Lack of tolerance development with long-term administration of PEGylated cholecystokinin.
Cholecystokinin (CCK) is a short acting satiating peptide hormone produced in the proximal small intestine. Daily CCK injection in rats initially inhibits food intake, but after several days, food intake is no longer affected, suggesting development of tolerance. Previously, we covalently coupled CCK to a 10kDa polyethylene glycol (mPEG-OH) and showed that this conjugate, PEG-CCK(9), produced a significantly longer anorectic effect than unmodified CCK(9). The present study examined whether tolerance to the anorectic effect develops during long-term administration of PEG-CCK(9). For 14 consecutive days, male Wistar rats (n=12) received a daily i.p injection of 8microgkg(-1) of PEG-CCK(9) and a control group received a daily control injection of mPEG-OH. Body weight and food intake were monitored daily during the experiment. Effects on the pancreas were investigated. On each day, injection of PEG-CCK(9) induced an anorectic effect lasting 3-6h, but failed to significantly reduce daily total food intake compared to controls. The body weight gain of the PEG-CCK(9)-treated animals was not different from controls. The PEG-CCK(9)-treated group had a significantly higher pancreas weight, mainly due to hyperplasia. In conclusion, PEG-CCK(9) continued to have a daily suppressive effect on food intake when administered for 14 consecutive days, showing there was no development of tolerance.
Verbaeys
Isabelle
I
Interdisciplinary Research Center, Katholieke Universiteit Leuven, Campus Kortrijk, Belgium. isabelle.verbaeys@kuleuven-kortrijk.be
León-Tamariz
Fabián
F
Buyse
Johan
J
Decuypere
Eddy
E
Pottel
Hans
H
Cokelaere
Marnix
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002766:Cholecystokinin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004361:Drug Tolerance; D005247:Feeding Behavior / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D010179:Pancreas / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
D011092:Polyethylene Glycols; D002766:Cholecystokinin