Endocannabinoid System in First Trimester Placenta: Low FAAH and High CB1 Expression Characterize Spontaneous Miscarriage

Trabucco, Elisabetta; Acone, Gennaro; Marenna, A.; Pierantoni, Riccardo; Cacciola, Giovanna; Chioccarelli, Teresa; Mackie, Ken; Fasano, Silvia; Colacurci, Nicola; Meccariello, Rosaria; Cobellis, Gilda; Cobellis, Luigi

doi:10.1016/j.placenta.2009.03.015

Cited by 84 publications

(74 citation statements)

References 44 publications

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“…A lower enzymatic Endocannabinoid system and preterm labor activity of FAAH has been described in peripheral lymphocytes from women who subsequently spontaneously miscarried (Maccarrone et al 2000). Accordingly, placental tissues from spontaneously miscarrying women are characterized by very low FAAH levels (Trabucco et al 2009). Conversely, there is a lack of data regarding the participation of FAAH on the pathophysiology of preterm labor.…”

Section: Discussionmentioning

confidence: 99%

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Bariani¹,

Rubio²,

Cella³

et al. 2015

Reproduction

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Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolaminespecific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth.

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Section: Discussionmentioning

confidence: 99%

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Bariani¹,

Rubio²,

Cella³

et al. 2015

Reproduction

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“…homoeostasis are related to infertility and miscarriages (Paria et al 1996, Wang et al 2003, Schuel 2006, Fonseca et al 2010. The metabolic enzymes of AEA (NAPE-PLD and FAAH) have already been characterized in human placenta (Kenney et al 1999, Park et al 2003, Helliwell et al 2004, Habayeb et al 2008, Trabucco et al 2009, Taylor et al 2011, and it has also been reported that AEA induces a decrease in BeWo cell viability through the activation of CB2 receptor (Habayeb et al 2008). On the other hand, only a few studies have examined a possible role for …”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the involvement of this molecule in human placentation is not clear, though some members of the ECS in this organ have been described. In fact, CB1 and CB2 receptors and the main metabolic enzymes of AEA, fatty acid amide hydrolase (FAAH) and N-arachidonoylphosphatidylethanolamine-phospholipase D (NAPE-PLD), have been described to be present in first-trimester and term placentas, as well as in BeWo cells (Kenney et al 1999, Park et al 2003, Helliwell et al 2004, Habayeb et al 2008, Trabucco et al 2009, Taylor et al 2011. Furthermore, AEA induces a decrease in the viability of BeWo cells, a cell model of cytotrophoblasts, via CB2 receptor (Habayeb et al 2008), suggesting a role for the ECS during placentation.…”

Section: Introductionmentioning

confidence: 99%

2-Arachidonoylglycerol effects in cytotrophoblasts: metabolic enzymes expression and apoptosis in BeWo cells

Costa¹,

Fonseca²,

Keating³

et al. 2014

Reproduction

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The major endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a member of the endocannabinoid system (ECS) that participates in cell proliferation and apoptosis, important events for the homoeostasis of biological systems. The formation of placenta is one of the most important stages of pregnancy and its development requires highly regulated proliferation, differentiation and apoptosis of trophoblasts. Anomalies in these processes are associated with gestational pathologies. In this work, we aimed to study the involvement of 2-AG in cytotrophoblast cell turnover. We found that 2-AG biosynthetic (diacylglycerol lipase A) and degradative (monoacylglycerol lipase) enzymes are expressed in human cytotrophoblasts and in BeWo cells. We also found that 2-AG induces a decrease in cell viability in a time-and concentration-dependent manner and exerts antiproliferative effects. The loss of cell viability induced by a 48-h treatment with 2-AG (10 mM) was accompanied by chromatin fragmentation and condensation, morphological features of apoptosis. Additionally, 2-AG induced an increase in caspase 3/7 and 9 activities, a loss of mitochondrial membrane potential (Djm) and an increase in reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation, suggesting the activation of the mitochondrial pathway. Moreover, whereas Djm loss and ROS/RNS generation were significantly attenuated by the antagonists of both the cannabinoid receptors 1 and 2 (CB1 and CB2), the increase in caspase 3/7 and 9 activities and loss of cell viability were reversed only by the antagonist of CB2 receptor; the blockage of the eCB membrane transporter and the depletion of cholesterol failed to reverse the effects of 2-AG. Therefore, this work supports the importance of cannabinoid signalling during cytotrophoblast cell turnover and that its deregulation may be responsible for altered placental development and poor pregnancy outcomes.

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“…51 Conversely, CB2 expression is relatively unchanged throughout the first trimester, 53 and its expression in the second and third trimester remains to be determined. Recently, we were the first to publish evidence that eCBs and synthetic cannabinoids stimulate fetal membrane production of PGE 2 in a CB1-dependent manner.…”

Section: Endocannabinoids and Early Prediction Of Preterm Labor Riskmentioning

confidence: 98%

“…48 Also, FAAH protein and mRNA expression, as well as FAAH activity in peripheral lymphocytes, were found to be markedly reduced in women who conceived unassisted but subsequently miscarried spontaneously, or failed to maintain pregnancy in the first trimester after undergoing in vitro fertilisation, compared to gestational age-matched women undergoing voluntary pregnancy termination. [49][50][51][52] This suggests that high plasma anandamide concentrations may be associated with uterine activation and labor onset and, therefore, may be surrogate biomarkers for placental dysfunction and/or poor pregnancy outcome.…”

Section: Endocannabinoids and Early Prediction Of Preterm Labor Riskmentioning

confidence: 99%

Eicosanoids as Diagnostics for Preterm Labor

McKirdy¹,

Rice

Mitchell

2013

Reproductive Biology Insights

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Despite continuing significant research efforts and an increasing prevalence of preterm labor (PTL) worldwide, a comprehensive understanding of the mechanisms involved remains to be established; such is the complexity of the interactions involved. Closing the knowledge gaps in this field would afford an opportunity to improve mortality and morbidity rates on a global scale. Early identification of pregnancies at risk of PTL would increase the possibility of delaying birth (where appropriate) prior to initiation of labor. This requires identification of appropriate biomarkers that are readily detectable in easily obtained clinical samples. A family of arachidonic acid metabolites, called eicosanoids. Eicosanoids have shown promise as possible diagnostic biomarkers for PTL. The inherent problems of antibody cross-reactivity in immunoassay methods has, however, resulted in possible misinterpretation of past results. The following mini-review outlines the necessity of such diagnostic targets and the problem with previous research methods and also summarizes recent findings in the field.

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Endocannabinoid System in First Trimester Placenta: Low FAAH and High CB1 Expression Characterize Spontaneous Miscarriage

Cited by 84 publications

References 44 publications

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

2-Arachidonoylglycerol effects in cytotrophoblasts: metabolic enzymes expression and apoptosis in BeWo cells

Eicosanoids as Diagnostics for Preterm Labor

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