3. Umbruch 4.4..2005 - Online Pot

74 M. Maccarrone
FAAH and the regulation of spermatogenesis
Despite the knowledge that chronic administration of ∆ 9 -THC to animals
lowers testosterone secretion and reduces the production, motility and viability
of sperm [35], a role for the endocannabinoid system in controlling male
fertility remains to be elucidated. Evidence that AEA regulates human sperm
functions has been recently presented [11], and in vitro studies have demonstrated
that the AEA congener PEA may affect the time course of capacitation
of human spermatozoa, by modulating the properties of their membranes
[36]. In addition, rat testis is able to synthetize AEA [37], and this compound
has been detected in human seminal plasma at approximately 10 nM [26].
More recently, the presence of CB 1 receptors in Leydig cells and their
involvement in testosterone secretion have been demonstrated in mice [38].
Also the function of Sertoli cells has been shown to be altered by ∆ 9 -THC,
though the molecular basis for this alteration has not been established [39].
As Sertoli cells of the mammalian seminiferous epithelium are involved in
the regulation of germ cell development by providing nutrients and hormonal
signals needed for spermatogenesis, we have recently investigated whether
Sertoli cells are able to bind and degrade AEA, and whether this endocannabinoid
might control survival and death of these cells. This is also in
view of the well-documented pro-apoptotic activity of AEA [16]. In the same
context, the effect of follicle-stimulating hormone (FSH) has been checked,
because it dramatically impacts fetal and early neonatal Sertoli cell proliferation,
and is critical in determining the spermatogenic capacity in the adult
mammals [40]. To date this study on Sertoli cells represents the only characterization
of the endocannabinoid system and its role in male reproductive
function [41]. Therefore, the main outcomes will be briefly summarized here
to put in a better perspective their physiological relevance and potential therapeutic
implications.
We found that Sertoli cells have the biochemical machinery to bind and
degrade AEA, and we have characterized this machinery in cells at a range of
ages (4–24 days), largely used as a model for immature mice in endocrinological
studies. Immature Sertoli cells express functional CB 2 receptors on
their surface, and the level of these receptors is constant in ageing cells [41].
Instead, FAAH activity declines age-dependently, due to a lower gene expression,
and also the uptake of AEA through AMT declines in ageing Sertoli cells.
Incidentally, to the best of our knowledge this evidence represents the first
demonstration of the modulation of the endocannabinoid system by ageing. In
addition, we found that AEA uptake by Sertoli AMT, like that of other human
peripheral cells, is significantly increased by NO donors [41], which might be
relevant in vivo because NO plays several roles in regulating male fertility [42,
43]. In particular, NO regulates the contribution of Sertoli cells to fertility and
inflammation-mediated infertility [42–44], and a faster removal of AEA from
the extracellular space, which leads to termination of its biological activity,
might be the rationale for these effects of NO.