Naringin Exhibits in vivo Prokinetic Activity via Activation of Ghrelin Receptor in Gastrointestinal Motility Dysfunction Rats

Abstract

Background and Purpose: Poncirus fructus (PF), also known as the dried immature fruit of Poncirus trifoliata (L.) Raf., has long been used as a cure for the treatment of various gastrointestinal disorders in eastern Asia. Recently, it was reported that naringin, a flavonoid constituent of the PF extract, causes the activation of ghrelin receptor in vitro. Although the ghrelin receptor is involved in the enhancement of intestinal motility, there are no studies as yet involving in vivo action of naringin. Therefore, the purpose of the present study is to investigate whether naringin exhibits a prokinetic effect in vivo. Methods: We measured the intestinal transit rate in rats with gastrointestinal motility dysfunction (GMD) and performed a pharmacokinetic analysis of naringin to investigate the effect of naringin on prokinetic activity in vivo. Results: The results of this study show that the aqueous extract of PF and its constituent naringin have a strong prokinetic activity in GMD rats via activation of the ghrelin receptor. Surprisingly, pharmacokinetic analysis revealed that naringin has low bioavailability (11%), implying that the prokinetic effect of naringin was largely due to the local activation of ghrelin receptor in the intestine rather than a systemic effect after absorption. Indeed, it turned out that intravenous administration of naringin led to a lower prokinetic effect than when administrated orally to rats, indicating that naringin prefers to act on the intestinal wall rather than getting absorbed into the systemic circuit. This local mode of action might be advantageous for preventing possible systemic side effects since naringin is not well absorbed into the system circuit. Conclusions: Naringin exhibits an in vivo prokinetic activity by a preferable local activation of ghrelin receptor. Moreover, we propose that naringin could play a role as a leading compound for the development of ghrelin receptor-based prokinetic agents.

Natural dietary compound naringin prevents azoxymethane/dextran sodium sulfate-induced chronic colorectal inflammation and carcinogenesis in mice

“…This local mode of action might be advantageous for preventing possible systemic side effects since naringin is not well absorbed into the system circuit. 28 We thus suggest that the advantage of naringin being superior to aspirin might be its low side effects. Naringin could be developed as a potential therapeutic agent for prevention colitis and reduction the risk of colonic cancers.…”

Preclinical Evidence for the Pharmacological Actions of Naringin: A Review

“…Moreover, naringin (400 mg/ kg) has also been shown to prevent the development of gastric ulcers following ethanol ingestion in rats, presumably by mechanisms not involving prostaglandins [204]. In another model of gastrointestinal motility dysfunction, naringin (50 mg/kg, orally and 5 mg/kg, i. v.) has been shown to exhibit in vivo prokinetic activity via activation of ghrelin receptors [205].…”

Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction

“…PF‐W (1 mg/mL) specifically activates GHSR, resulting in increased intracellular Ca 2+ (Figure ; Jang, Kim, Oh, et al, ). Further, in vivo studies have revealed that coadministration of a GHSR antagonist (CST‐8) with PF‐W decreases the intestinal transit rate in rats with GI motility dysfunction, thereby verifying the involvement of GHSR in the prokinetic action of PF‐W (Jang, Kim, & Shim, ). B. J. Kim, Kim, et al () revealed that PF (2–5 μg/mL, methanol extract) induces both external Ca 2+ influx and Ca 2+ release from internal stores in the interstitial cells of Cajal, leading to oscillations in intracellular Ca 2+ responsible for pacemaker activity.…”

“…The prokinetic effect of naringin was further verified by an in vivo study, in which oral administration of naringin (50 mg/kg) restored the impaired intestinal transit rate in rats with GI motility dysfunction. Moreover, naringin‐induced prokinetic effect was further suppressed by cotreatment with a GHSR antagonist, CST‐8 (Jang, Kim, & Shim, ). These results suggest that naringin, a major prokinetic constituent in the PF‐W extract, exerts its prokinetic effect through GHSR activation.…”