Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

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-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-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-α (TNFα) and interleukin (IL)-1β, 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 TNFα and IL-1β 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.

Anti-inflammatory and utero-relaxant effect of α-bisabolol on the pregnant human uterus

“…cAMP is the most common endogenous second messenger that plays a key role in the regulation of several biologic responses in humans, such as the inflammation of immune cells [ 3 23 ]. Many cell-surface receptors are coupled to a signal-transducing G protein.…”

“…The explants were incubated at 37℃ in a 5% CO 2 humidified atmosphere for 3 h, with the samples then transferred to 24 new well plates containing fresh culture medium. The uterine explants were incubated with increasing concentrations of 560, 860 and 1,200 µM of α-bisabolol and 10 µM of forskolin, both with and without 10 µg/ml of LPS for 24 h, as recommended [ 3 ]. All compounds were dissolved in DMSO.…”

“…During the inflammation associated with infection, prostaglandins are simultaneously released with Nitric oxide, and their overproduction could be detrimental [ 2 ]. The secretion of inflammatory cytokines by fetal and maternal tissues, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), are associated with the release of prostaglandins, which promote uterine contractions, thus contributing to embryonic and fetal expulsion [ 3 ]. Some mechanisms involved in uterine relaxation are associated with the production of some second messengers, such as cyclic adenosine monophosphate (cAMP), which actives the cAMP-dependent protein kinase A (PKA).…”

“…Some mechanisms involved in uterine relaxation are associated with the production of some second messengers, such as cyclic adenosine monophosphate (cAMP), which actives the cAMP-dependent protein kinase A (PKA). PKA is responsible for the phosphorylation and inhibition of key proteins involved in uterine contractions [ 3 ]. Currently, tocolytic drugs, such as nitric oxide donors, calcium channel blockers, oxytocin receptor blockers, beta-adrenoceptor agonists and cyclo-oxygenase inhibitors [ 4 ], are used for the treatment of preterm birth as a first-line therapy [ 2 4 ].…”

“…Moreover, they are widely used for tocolysis, despite the fact that their use has not been approved by pharmaceutical agencies or ones from the United States, and that their use has been strongly associated with several serious adverse effects in both mother and fetus [ 5 6 ]. Due to the growing importance of the discovery and development of new drugs for the pharmacological treatment of preterm birth associated with inflammation and infection, it is necessary to identify new molecular targets involved in uterine contractions and inflammation [ 3 7 ]. (−)-α-Bisabolol (IUPAC name: (2R)-6-methyl-2-[(1R)-4-methylcyclohex-3-en-1-yl] hept-5-en-2-ol) is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation of essential oil from plants, such as Vanillosmopsis erythropappa and Matricaria chamomilla and has been associated with anti-inflammatory and antibacterial properties, and is thought to be beneficial for skin-care [ 8 9 ].…”