Protective effect of a molecular chaperone inducer, paeoniflorin, on the HCl- and ethanol-triggered gastric mucosal injury.

AIMS: We previously found that paeoniflorin, a major constituent of Paeonia lactiflora Pall, could induce heat shock proteins (HSPs) in cultured mammalian cells without apparent toxicity (Yan et al. 2004). We here investigated the induction of HSPs by paeoniflorin in mouse stomach and the effect of paeoniflorin on the HCl- and ethanol-triggered gastric mucosal injury in mouse. MAIN METHODS: Paeoniflorin and quercetin were intraperitoneally administered in mouse and Hsp70 and other proteins in mouse tissues were detected by western blotting. KEY FINDINGS: The intraperitoneal administration of paeoniflorin clearly induced Hsp70 in mouse stomach, and paeoniflorin had a protective effect on the HCl- and ethanol-triggered gastric mucosal injury. When quercetin was injected before paeoniflorin administration, the induction of Hsp70 was suppressed and the protective effect of paeoniflorin was also diminished. Thus, the expression level of Hsp70 was well correlated with the extent of protection against irritant-induced gastric mucosal injury. Oral injection of HCl activated nuclear factor kappa B (NF-κB) and elicited the expression of cyclooxygenase-2 (COX-2) in gastric mucosa. Prior administration of paeoniflorin, however, suppressed these effects. No apparent systemic side effect of paeoniflorin has been observed so far. Hsp70 was also induced in the liver, heart, and brain by paeoniflorin. SIGNIFICANCE: From these results, it is suggested that paeoniflorin and paeoniflorin-containing herbal medicines might be used clinically as HSP inducers for the prevention and treatment of diseases associated with protein conformation and of various other pathological states, such as stress ulcers and irritant- or ischemia-induced injuries.

Restorative effect of repetitive administration of Shaoyao-Gancao-tang on bioavailability of paeoniflorin reduced by antibacterial synthetic drugs treatment in rats.

Paeoniflorin (PF) is an active glucoside in Shaoyao (peony root), and is transformed into an antispasmodic metabolite, paeonimetabolin-I (PM-I), by intestinal bacteria in the gut after oral administration of Shaoyao or Shaoyao-Gancao-tang (SGT, Shakuyaku-Kanzo-To in Japanese). SGT is a pain-relieving traditional Chinese formulation (Kampo-medicine in Japanese) and is often used together with antibacterial synthetic drugs, such as amoxicillin and metronidazole (AMPC-MET), in peptic ulcer therapy. Since the bioavailability of PF in SGT has been reported to be significantly reduced by co-administered antibacterial drugs, we investigated how to minimize this reducing effect of antibacterial treatment in the present study. We found that repetitive administration of SGT starting 24 h after AMPC-MET treatment rapidly restored the plasma PM-I concentration from SGT reduced by AMPC-MET, due to its restorative effect on the decreased PF-metabolizing activity of intestinal bacteria in rat feces. The present findings suggest that it may be clinically useful to administer SGT repetitively, starting 1 or 2 d after treatment with a mixture of AMPC-MET during their combination therapy, to accelerate the recovery of the reduced bioavailability of PF in SGT. Similar administration regimens may also be useful in other combination therapies involving traditional Chinese formulations and antibacterial synthetic drugs to ensure the efficacy of the bioactive glycosides in the formulations.

R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum.

5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 24924 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 X 10(-7) M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 +/- 7% at 3 X 10(-7) M for cisapride and 36 +/- 6% for BRL 24924, also at 3 X 10(-7) M. R 50 595 (10(-7)(-3) X 10(-7) M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 +/- 3.2% at 3 X 10(-8) M. The effects of 5-HT were completely abolished at a concentration of 3 X 10(-7) M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way.(ABSTRACT TRUNCATED AT 250 WORDS)