Tocolytic Effect of Δ9-Tetrahydrocannabinol in Mice Model of Lipopolysaccharide—Induced Preterm Delivery: Role of Nitric Oxide

Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy) methyl) piperidine- 1-carboxylate (JZL184), is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p.)) of JZL184, in a murine model of lipopolysaccharide (LPS) -induced acute lung injury (ALI) 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL) and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone) blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

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“…The doses and the treatments were based on the following past literature: for JZL184 [7][8], for AM281 [16] and for AM630 [17][18]. …”

Section: Methodsmentioning

confidence: 99%

Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice

et al. 2013

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“…In earlier studies, the stimulation of the CB receptor led to the relaxation of the skeletal muscles 37,38 , smooth muscles of blood vessels 39 , and uterine smooth muscles 40 . Therefore, the stimulation of the CB receptors in the uterus was described as tocolysis 41 . As a result, a decrease in level of the receptors could lead to preterm uterine contractions and PTB.…”

Section: Discussionmentioning

confidence: 99%

Premature delivery and cannabinoid receptor expression in the placenta after delivery: an observational study.

Feduniw¹,

Woś²,

Pogoda³

et al. 2020

Preprint

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Objective: To investigate the relationship between cannabinoid receptor expression within the placenta after delivery and the problem of preterm delivery. Design, setting, and participants: The retrospective, observational study was conducted on a multicenter material of 150 women. The study group included 115 women after premature delivery. The control group consisted of 35 women after term delivery. Methods. To determine the expression of cannabinoid receptors after the end of the third stage of labour, several sections were taken from the placenta. RNA isolation, reverse transcription, and Real-Time PCR were performed to assess the expression of the cannabinoid receptors in the placenta. Results: Cannabinoid receptor type 2 expression was lower in the placentas of women after preterm delivery. Urinary tract infections and bleeding at any stage of pregnancy occurred statistically more frequently in the study group and correlated with cannabinoid receptor type 2 expression. In the study group, the history of preterm labor, history of intrauterine fetal deaths, pregnancies terminated by a Caesarean section, and uterine tenderness correlated with lower expression of cannabinoid receptor type 2 and 1a. Conclusions: Cannabinoid receptors mRNA were present in human placental tissue during pregnancy. Decreased cannabinoid receptor type 2 expression in preterm delivered placentas should be further investigated, as perinatal endocannabinoid receptor expression could serve as a predicting tool of preterm birth. For example, liquid-based cytology could be used as a noninvasive perinatal method of measuring the expression level of cannabinoid receptors in decidual cells during pregnancy. KEYWORDS: Cannabinoid receptor; CB2; endocannabinoid system; preterm delivery; PTB

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“…However, if phytocannabinoids alter this dynamic process remains unclear and needs to be further investigated. It has been shown that chronic administration of ∆9-THC before LPS exposure at GD 15 significantly reduced LPS-induced preterm births and increased gestational duration, an effect reversed by the CB1 antagonist AM281, and NOS inhibitor administration [ 211 ]. ∆9-THC and CBD were also found to be effective in alleviating the LPS-induced cytokine storm in human macrophages trough the modulation of NPRL3 inflammasome and STAT3 signaling [ 212 ].…”

Section: The Role Of Endocannabinoids In Low-grade Inflammation and M...mentioning

confidence: 99%

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

Rava

Trezza

2023

IJMS

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In recent years, Cannabis use/misuse for treating pregnancy-related symptoms and other chronic conditions has increased among pregnant women, favored by decriminalization and/or legalization of its recreational uses in addition to its easy accessibility. However, there is evidence that prenatal Cannabis exposure might have adverse consequences on pregnancy progression and a deleterious impact on proper neurodevelopmental trajectories in the offspring. Maternal Cannabis use could interfere with the complex and finely controlled role performed by the endocannabinoid system in reproductive physiology, impairing multiple gestational processes from blastocyst implantation to parturition, with long-lasting intergenerational effects. In this review, we discuss current clinical and preclinical evidence regarding the role of endocannabinoids in development, function, and immunity of the maternal–fetal interface, focusing on the impact of Cannabis constituents on each of these gestational processes. We also discuss the intrinsic limitations of the available studies and the future perspectives in this challenging research field.

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Tocolytic Effect of Δ9-Tetrahydrocannabinol in Mice Model of Lipopolysaccharide—Induced Preterm Delivery: Role of Nitric Oxide

Abstract: Delta(9)-Tetrahydrocannabinol contributes to the regulation of gestational duration in LPS-induced preterm delivery probably by NO coupling through the CB1 receptor.

Cited by 7 publications

References 31 publications

Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice

Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice

Premature delivery and cannabinoid receptor expression in the placenta after delivery: an observational study.

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

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