BackgroundConcerns have risen regarding the potential side effects of clinical exposure of the pediatric population to inhalational anesthetics, and how they might impact cognitive, learning, and memory functions. However, neither the mechanisms of anesthetic cytotoxicity, nor potential protective strategies, have yet been fully explored. In this study, we examined whether two of the most commonly used inhalational anesthetics, sevoflurane and desflurane, affect neuronal viability and synaptic network assembly between cultured rat cortical neurons.ResultsPrimary rat cortical neuron cultures were exposed to equipotent sevoflurane or desflurane for 1 hour. Neuron viability, synaptic protein expression, mitochondrial morphology, and neurite growth were assayed with immunostaining and confocal microscopy techniques. The effects of anesthetics on the functional development of neural networks were evaluated with whole-cell patch clamp recordings of spontaneous synaptic currents. Our results demonstrate that an acute exposure to sevoflurane and desflurane inhibits the development of neurite processes, impacts the mitochondria, and compromises synaptic proteins - concomitant with a reduction in synaptic function in mature networks. Interestingly, pretreatment of neurons with a mitochondrial division inhibitor (Mdivi-1) not only protected mitochondria integrity but also played a protective role against anesthetic-induced structural and functional neurotoxicity.ConclusionsWe show that Mdivi-1 likely plays a protective role against certain harmful effects of general anesthetics on primary rat neuronal cultures. In addition, Mdivi-1 alone plays a direct role in enhancing growth and modulating synaptic activity. This study highlights the importance of further study into possible protective agents against anesthetic neurotoxicity.
Preterm birth (<37 weeks of gestation) significantly increases the risk of neonatal mortality and morbidity. As many as half of all preterm births occur following spontaneous preterm labour. Since in such cases there are no known reasons for the initiation of labour, treatment of preterm labour (tocolysis) has sought to stop labour contractions and delay delivery. Despite some success, the use of cyclooxygenase (COX) inhibitors is associated with maternal/fetal side effects, and possibly increased risk of preterm birth. Clinical use of these drugs predates the collection of molecular and biochemical evidence in vitro, examining the expression and activity of COX enzymes in pregnant uterine tissues with and without labour. Such evidence is important to the rationale that COX enzymes are, or are not, appropriate targets for the tocolysis. The current study systematically searched existing scientific evidence to address the hypothesis that COX expression/activity is increased with the onset of human labour, in an effort to determine whether there is a rationale for the use of COX inhibitors as tocolytics. Our review identified 44 studies, but determined that there is insufficient evidence to support or refute a role of COX-1/-2 in the onset of preterm labour that supports COX-targeted tocolysis.
BackgroundPreterm labour, a condition characterized by regular uterine contractions and cervical dilation prior to 37 weeks of pregnancy can result in premature birth of babies that may not be fully developed and/or possess serious health problems such as cerebral palsy and learning disabilities. Is associated with an increase in uterine prostaglandins (PGs) synthesis by cyclooxygenase (COX) enzymes which promotes inflammatory and contractile processes that drive labour. For this reason, COX inhibitors (e.g. indomethacin) have been used to treat/prevent preterm labour. Despite limited success, tocolysis by COX‐inhibition carries serious adverse fetal effects due to inhibition of prostaglandin‐dependent developmental homeostatic functions. The more recent discovery of a second, inducible COX isoform, COX‐2, presented an opportunity to spare homeostatic prostaglandin by selective inhibition of COX‐2. However, subsequent clinical studies have called into question the appropriateness of COX‐2 selective inhibition. This study reviewed the molecular evidence concerning the role of COX‐2 in human parturition that underpins the rationale of use of COX‐2 inhibitors in the treatment of preterm labour and presents evidence of COX‐2 gene expression in term and preterm human myometrium.MethodsFor our systematic literature review, we searched MEDLINE and EMBASE databases to identify papers reporting molecular evidence of COX enzyme expression and activity in gestational tissues at term and preterm. Two independent reviewers evaluated abstracts, and qualifying references were reviewed in full text. Data were extracted using a standardized questionnaire. COX‐2 gene expression analysis was conducted on samples of myometrium and decidua from women at term (after 37 weeks) and preterm (below 37 weeks) of gestation, with and without labour using reverse transcriptase‐polymerase chain reaction technique (RT‐PCR).ResultsThirty‐five studies were included in the review. Eight studies on fetal membranes (amnion and chorion) reported significantly higher COX expression or activity with labour. However, in the myometrium and decidua, which are the most relevant therapeutic target tissues for uterine contraction, nine reported no labour‐associated differences COX expression. In the myometrium, four studies reported higher levels of COX mRNA with labour, but did not consider protein expression. Our data show spatial (upper versus lower segment) and temporal (labour versus non‐labour) demonstrate differences in COX‐2 expression; at term, expression of COX‐2 is higher in lower segment myometrium and decidua samples from women in term labour (n=16) compared to term non‐labour (n=18), but no significant differences were observed for upper segment samples. Similarly, COX‐2 expression was higher in lower segment preterm labourThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
INTRODUCTION: Uterine contractions in labour are produced by activation of receptors such as FP (PGF2α) and OXTR (oxytocin). Such receptors signal via Gαq proteins that can be selectively turned off by the regulator of G-protein signaling 2 (RGS2). RGS2 expression can be upregulated by Gαs-coupled receptor signaling. PGE2 elicits various uterine effects, some via activation of Gαs-coupled receptors. In primary human myometrial cells, PGE2 enhances RGS2 expression that attenuates subsequent oxytocin-stimulated calcium responses associated with contraction. RGS2 expression is higher in preterm non-labour versus labour human myometrium, suggesting that RGS2 promotes quiescence in the pregnant uterus. To directly study whether RGS2 dampens uterine contraction, we analyzed the ex vivo contractility of pregnant mouse uteri. We hypothesize that loss of RGS2 expression enhances oxytocin and PGF2α-stimulated uterine contractility. METHODS: Wildtype (WT) and RGS2 knockout (KO) female mice (8-14 weeks) were time-mated and euthanized on days 15-20 of pregnancy or during active labour (n=5-11 per group). Uteri were snap frozen for RNA/protein expression analysis by qPCR and western blot. Uterine sections from d18-19 were dissected into longitudinal strips for ex vivo contractility measurement. Tissues were submerged in Krebs-Henseleit buffer and tied to force transducers to measure isometric force development. Tissues were treated with or without 1μM PGE2 for 2 hours. In parallel, pretreated and non-pretreated tissues were exposed to increasing concentrations of oxytocin or PGF2α (0.1-10uM). All tissues were treated with 100mM KCl to determine the maximum contraction at the end of the experiment. Data were analyzed by ANOVA (Bonferroni post-hoc), or Student’s t-test, as appropriate. RESULTS: RGS2 expression in WT uteri sharply decreases at day 19 (p<0.05), remaining low during labour. OXTR and FP receptor expression increase at day 19 (p<0.01 and p<0.05, respectively) and are sustained through labour. Compared to WT, uteri from KO mice produced larger oxytocin-stimulated contractile amplitudes (p<0.05), and more frequent PGF2α-stimulated contractions (p<0.05). PGE2 pretreatment enhanced RGS2 expression in WT uteri, which reduced the peak amplitudes and integrals elicited by subsequent oxytocin treatment, compared to non-pretreated uteri (p<0.05). CONCLUSION: RGS2 may play a pro-quiescent role in pregnancy, since RGS2 loss enhances uterine contractility. Concomitant upregulation of pro-contractile receptors and RGS2 downregulation may facilitate labour activation. This mechanisms may be involved in the etiology of spontaneous preterm labour; loss of RGS2 expression observed in human preterm labour may allow for early contractile activation. Understanding RGS2’s role in quiescence is important to developing more effective strategies for managing preterm labour.
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