The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

  • Munoz-Perez, Victor Manuel (Center for Research on Reproductive Biology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of Hidalgo's State) ;
  • Fernandez-Martinez, Eduardo (Center for Research on Reproductive Biology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of Hidalgo's State) ;
  • Ponce-Monter, Hector (Center for Research on Reproductive Biology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of Hidalgo's State) ;
  • Ortiz, Mario I. (Center for Research on Reproductive Biology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of Hidalgo's State)
  • Received : 2017.03.09
  • Accepted : 2017.04.04
  • Published : 2017.07.01
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Abstract

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4- dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)- 3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-$F2{\alpha}$ ($PGF2{\alpha}$)-induced phasic, $K^+$-induced tonic, and $Ca^{2+}$-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ ($TNF{\alpha}$) and interleukin (IL)-$1{\beta}$, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced $TNF{\alpha}$ and $IL-1{\beta}$ uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

Keywords

References

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