Magdalena Kotańska1, Kamil Mika2, Karolina Reguła2, Katarzyna Szczepańska3, Małgorzata Szafarz4, Marek Bednarski2, Agnieszka Olejarz-Maciej3, Katarzyna Nowak4, Gniewomir Latacz3, Szczepan Mogilski5, Kamil J Kuder3, Katarzyna Kieć-Kononowicz3, Jacek Sapa2. 1. Department of Pharmacological Screening, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland. Electronic address: magda.dudek@uj.edu.pl. 2. Department of Pharmacological Screening, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland. 3. Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. 4. Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Krakow, Poland. 5. Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland.
Abstract
AIMS: Histamine H3 receptors ligands act anorectic by blocking the H3 autoreceptors in the CNS, that results in increased synthesis and disinhibition of histamine release. Histamine further influencing H1 receptors participates in the leptin-dependent inhibition of food intake. It also affects the peripheral metabolism by increasing white adipose tissue lipolysis. Thus, ligands such as KSK19 with significant antagonistic properties at the H3 receptor might serve as an useful treatment for obesity. MATERIALS AND METHODS: To induce obesity, female CD-1 mice were fed a high-fat diet for 14 weeks. The test compound at the doses of 10 or 15 mg/kg, i.p. was administrated for 21 days. Glucose and insulin tolerance tests was performed at the beginning of week 15. At the end of study, amount of intraperitoneal fat pads, AlAT, IL-6 and TNF-α plasma levels were determined. RESULTS: Animals fed with high-fat diet and treated with test compound at the dose of 15 mg/kg showed significantly less weight gain, than mice from the control group. The use of KSK19 for 21 days in obese mice also significantly improved glucose tolerance and insulin resistance. In the tested doses KSK19 did not affect locomotor activity neither in lean nor in obese mice after single i.p. administration, but spontaneous activity increased during three hour after twentieth administrations. CONCLUSION: KSK19 is a strong, selective histamine H3 receptor antagonist with a favorable influence on body weight after multiple administration at the dose of 15 mg/kg. Moreover it significantly improves glucose tolerance.
AIMS: Histamine H3 receptors ligands act anorectic by blocking the H3 autoreceptors in the CNS, that results in increased synthesis and disinhibition of histamine release. Histamine further influencing H1 receptors participates in the leptin-dependent inhibition of food intake. It also affects the peripheral metabolism by increasing white adipose tissue lipolysis. Thus, ligands such as KSK19 with significant antagonistic properties at the H3 receptor might serve as an useful treatment for obesity. MATERIALS AND METHODS: To induce obesity, female CD-1mice were fed a high-fat diet for 14 weeks. The test compound at the doses of 10 or 15 mg/kg, i.p. was administrated for 21 days. Glucose and insulin tolerance tests was performed at the beginning of week 15. At the end of study, amount of intraperitoneal fat pads, AlAT, IL-6 and TNF-α plasma levels were determined. RESULTS: Animals fed with high-fat diet and treated with test compound at the dose of 15 mg/kg showed significantly less weight gain, than mice from the control group. The use of KSK19 for 21 days in obesemice also significantly improved glucose tolerance and insulin resistance. In the tested doses KSK19 did not affect locomotor activity neither in lean nor in obesemice after single i.p. administration, but spontaneous activity increased during three hour after twentieth administrations. CONCLUSION: KSK19 is a strong, selective histamine H3 receptor antagonist with a favorable influence on body weight after multiple administration at the dose of 15 mg/kg. Moreover it significantly improves glucose tolerance.
Authors: Christian J M I Klein; Thomas Budiman; Judith R Homberg; Dilip Verma; Jaap Keijer; Evert M van Schothorst Journal: Front Behav Neurosci Date: 2022-04-07 Impact factor: 3.617
Authors: Magdalena Kotańska; Anna Dziubina; Małgorzata Szafarz; Kamil Mika; Karolina Reguła; Marek Bednarski; Małgorzata Zygmunt; Anna Drabczyńska; Jacek Sapa; Katarzyna Kieć-Kononowicz Journal: PLoS One Date: 2020-06-18 Impact factor: 3.240