December 12, 2003

Cannabis-like substance found to aid fertility

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S.K. Dey, Ph.D.

Cannabis-like substance
found to aid fertility

Fertility in humans and other mammals depends absolutely on synchronous events that make the developing embryo and the mother’s uterus compatible for implantation. Yet the molecular nuances underlying successful embryo implantation are largely unknown.

Now, Vanderbilt researchers have uncovered a regulatory mechanism that appears to be important in the process. Working in mice, the group showed that a naturally occurring substance, called anandamide, regulates function and implantation of the developing embryo, and that elevated levels of the substance impair that development, preventing implantation.

“The finding has high clinical relevance, since elevated levels of anandamide have been shown to induce spontaneous pregnancy loss in women, “ said S.K. Dey, Ph.D., Dorothy Overall Wells Professor of Pediatrics and professor of Cell & Developmental Biology and Pharmacology.

Dey leads the research group who made the discovery, which currently appears online in Proceedings of the National Academy of Sciences, USA.

Signaling by anandamide, a mammalian cannabinoid, synchronizes embryonic development and uterine receptivity for successful implantation. Cannabinoids are molecules like those extracted from the marijuana plant, Cannabis sativa, known to elicit various psychophysiological responses in animals and humans. Cannabinoids occurring naturally in mammals are called endocannabinoids, and anandamide — a name derived from the Sanskrit word anand, meaning “bliss” — is one of the best studied.

Previous findings from Dey’s lab showed that the mouse pre-implantation embryo, or blastocyst, has significant numbers of cannabinoid receptors. Moreover, anandamide is produced in the uterus and is capable of activating those receptors. Levels of uterine anandamide and of blastocyst cannabinoid receptor (CB1) drop, due to turned down gene expression, before implantation. Higher levels of anandamide in the uterus inhibit blastocyst growth.

“Everybody sees this biphasic effect of endocannabinoids — a low dose stimulates, a high dose inhibits — but I think our study is the first to give some indication of how it works,” said Dey, who is also director of the division of Reproductive Biology.

In the current study, the researchers used genetic, pharmacological, and physiological approaches to investigate the action of anandamide on mouse blastocysts. They found that at low concentrations, anandamide activated the extracellular regulated kinase, or ERK, signaling pathway in dormant embryos, a step necessary to ready the embryo for implantation.

In contrast, at a four-fold higher concentration of anandamide, the ERK pathway was not activated. In addition, calcium channel activity was inhibited, as was embryo implantation. A four-fold increase in anandamide would be considered a high level in the mouse, but still physiologically possible, according to Dey.

The findings provide for a potential “cannabinoid sensor” mechanism for influencing crucial steps during early pregnancy, said Dey. The group will continue its exploration of the role of cannabinoids in mouse embryo implantation, and also has plans to begin similar studies in zebrafish, since that system is less expensive and easier to work with from a mechanistic standpoint.

Haibin Wang, Ph.D., a two-time Lalor Foundation postdoctoral fellow, is first author of the study. Other Vanderbilt co-authors include Hiromichi Matsumoto, Yong Guo, Bibhash Paria, and Richard Roberts. The work was supported by the National Institutes of Health.