Flucrypyrim, a novel uterine relaxant, has antinociceptive and anti-inflammatory effects in vivo

Zhongtang Li,Rifang Yang,Yuwen Cong,Yue Cong,Xiaohui Lin,Limei Wang,Lin Guo,Zuyin Yu,Junxing Dong,Xingan Wu

doi:10.1038/srep42040

Abstract

Consequences of primary dsysmenorrhea (PD) can be severe. Increased prostaglandin production leads to uterine contraction and insufficient blood flow to the endometrium causing ischemia and pain symptoms. Protein tyrosine kinase/phosphatase activities contribute to the modulation of uterine contraction. In our previous study, we found the synthetic β-methoxyacrylates compound Fluacrypyrim (FAPM), significantly increased protein tyrosine phosphatases (PTPs) activity, resulting in dephosphorylation of tyrosine kinases. In the present study, we found that FAPM near completely inhibited prostaglandin F2α (PGF2α)-, oxytocin-, acetylcholine-, and high K+-induced uterine contractions in rats in vitro, and decreased rat myometrial myosin light chain (MLC20) phosphorylation induced by PGF2α. A structure–activity relationship assay indicated that the β-methoxyacrylates structure of FAPM is crucial for the inhibition of PGF2α-induced uterine contractions. FAPM caused a concentration-dependent parallel rightward shift of the concentration–response curve induced by oxytocin, dose-dependently reduced the number of abdominal constrictions and increased the latency time in PGF2α- and acetic acid-induced writhing test in mice in vivo. Furthermore, FAPM considerably inhibited the development of Carr-induced rat paw edemas and thexylene-induced mouse ear edemas. Taken together, our results indicate that FAPM exerts antinociceptive and anti-inflammatory effects in vivo with considerable potential as a novel uterine relaxant.

Highlights

Contractions elicited by pervanadate, a protein tyrosine phosphatase inhibitor, which can potentiate contractile receptor-mediated contraction[15,16]
Protein tyrosine kinase/phosphatase activities contribute to the modulation of uterine contractions induced by contractile agonists or stretch via tyrosine phosphorylation and dephosphorylation reactions[12,13,14,15]
We previously reported that fluacrypyrim (FAPM) significantly increases the protein tyrosine phosphatases (PTPs) activity in a dose-dependent manner, inhibiting protein tyrosine phosphorylation which can be reversed by PTP inhibitor sodium pervanadate[20]

Summary

Results

Effects of FAPM and its analogs on PGF2α-induced uterine contractions in the rats. To investigate the in vivo inhibition of PGF2α-induced uterine contraction by FAPM, we first examined the effect of FAPM on PGF2α-induced uterine contraction in vitro. Application of 0.25 μM Ach produced phasic contractions of constant amplitude and frequency, and administration of FAPM along with Ach exerted an inhibitory effect on uterine contractile force and frequency. Administration of FAPM (50, 100 and 200 mg/kg) 1 h before acid injection produced a significant and dose-dependent inhibition of acetic acid-induced abdominal constrictions in mice (Fig. 6a). The FAPM group (200 mg/kg) exhibited the maximum inhibiting effect of acetic acid-induced writhing and the longest latency time (12.2 min) - almost six fold long as that in the vehicle control group (2.2 min). Administration of FAPM (100 and 200 mg/ kg), 1 hour prior to PGF2α injection, highlighted a significant and dose-dependent inhibition of PGF2α -induced abdominal constrictions in mice (Fig. 8a). The FAPM group (200 mg/kg) exhibited the maximum inhibiting effect of PGF2α-induced writhing (Fig. 8a) and a significantly increased latency time (p < 0.01) (Fig. 8b)

Discussion

Materials and Methods

Author Contributions

Additional Information