Article
Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus

https://doi.org/10.1016/S1472-6483(10)60033-8Get rights and content

Abstract

In women, the association between chronic marijuana smoking and early miscarriage has long been known. Anandamide, a major endocannabinoid, mimics some of the psychotropic, hypnotic and analgesic effects of Δ9-tetrahydrocannabinol, the psychoactive component of marijuana. The uterus contains the highest concentrations of anandamide yet discovered in mammalian tissues and this suggests that it might play a role in reproduction. The production of small amounts of nitric oxide (NO) regulates various physiological events including implantation and myometrial relaxation, but in an inflammatory setting such as sepsis, NO has toxic effects as it is a free radical. The results presented in this study indicate that anandamide modulates NO production induced by lipopolysaccharide (LPS) in an in-vitro murine model. It was shown that LPS-induced NO synthesis and tissue damage were mediated by anandamide, as a cannabinoid receptor type 1 antagonist could block the effect of LPS (P < 0.001). This endotoxin inhibited anandamide uterine degradation (P < 0.05) and increased the expression of one of its synthesizing enzymes (P < 0.05). Contrary to the known anti-inflammatory and protective effects, in this model anandamide seems to act as a pro-inflammatory molecule modulating the production of NO induced by LPS. This pro-inflammatory effect of anandamide may be implicated in pathological reproductive events such as septic abortion.

Section snippets

Ana Franchi received her initial training in chemistry at the School of Sciences, University of Buenos Aires. She first became interested in prostaglandin metabolism in the sex cycle. As a post-doc she began to work in pregnancy and she developed two rodent models of diseases that take place in pregnancy: pre-term labor and septic abortion. She is currently a researcher for the National Research Council and a director of CEFYBO (School of Medicine).

References (33)

  • BC Paria et al.

    Ligand–receptor signaling with endocannabinoids in preimplantation embryo development and implantation

    Chemistry and Physics of Lipids

    (2000)
  • S Preutthipan et al.

    Inhibition of nitric oxide synthesis potentiates apoptosis in the rabbit corpus luteum

    Reproductive BioMedicine Online

    (2004)
  • M Yu et al.

    Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2

    Journal of Biological Chemistry

    (1997)
  • J Aisemberg et al.

    Nitric oxide mediates prostaglandin deleterious effect on lipopolysaccharide-triggered murine fetal resorption

    Proceedings of the National Academy of Sciences of the United States of America

    (2007)
  • K Chwalisz et al.

    Role of nitric oxide in implantation and menstruation

    Human Reproduction

    (2000)
  • K Chwalisz et al.

    Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat

    Human Reproduction

    (1999)
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    Ana Franchi received her initial training in chemistry at the School of Sciences, University of Buenos Aires. She first became interested in prostaglandin metabolism in the sex cycle. As a post-doc she began to work in pregnancy and she developed two rodent models of diseases that take place in pregnancy: pre-term labor and septic abortion. She is currently a researcher for the National Research Council and a director of CEFYBO (School of Medicine).

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