Inhibition of insulin degrading enzyme by racecadotril in the brain of wistar rats

J. P. Lee, K. C. Cheng, H. H. Chung, H. T. Wu, C. T. Chen, J. T. Cheng

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i.c.v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K ATP channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i.c.v. pretreatment with insulin antibody or glibenclamide. Also, i.c.v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K ATP channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain.

Original languageEnglish
Pages (from-to)489-493
Number of pages5
JournalHormone and Metabolic Research
Volume43
Issue number7
DOIs
Publication statusPublished - May 11 2011
Externally publishedYes

Keywords

  • blood glucose
  • cerebral insulin
  • K channels
  • rececadotril
  • thiorphan

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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