Fernandez-Solari Javier, Prestifilippo Juan P, Bornstein Stefan R, McCann Samuel M, Rettori Valeria
Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Cientificas y Técnicas, Buenos Aires, Argentina.
Ann N Y Acad Sci. 2006 Nov;1088:238-50. doi: 10.1196/annals.1366.008.
It is known that Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of marijuana, can suppress reproductive function. Also, we reported previously that the endocannabinoid, anandamide (AEA), inhibited gonadotropin-releasing hormone (LHRH) release from medial basal hypothalamus (MBH) of male rats incubated in vitro as well as reduced plasma LH levels after i.c.v. AEA injections into the cerebral lateral ventricle. On the other hand, it is known that during endotoxemia the hypothalamic gonadotropin axis is inhibited. Therefore, the aim of the present study was to determine whether the effect of TNF-alpha, a proinflammatory cytokine induced by lipopolysaccharide (LPS) that inhibits LHRH release, is mediated by the activation of the endocannabinoid system. The intraperitoneal injection of LPS (5 mg/kg) as well as the i.c.v. injection of tumor necrosis factor-alpha (TNF-alpha) (100 ng/rat) increased significantly the AEA synthesis measured ex vivo in MBHs removed 3 h after the treatments. To examine the possibility that TNF-alpha also acted by increasing the synthesis of AEA that was released and activated the CB1-r followed by inhibition of LHRH release, we measured the effect of TNF-alpha on the AEA synthase activity in MBHs incubated in vitro. As expected, we found that TNF-alpha (2.9 x 10(-9) M) increased the AEA synthesis. Second, we showed that TNF-alpha reduced significantly the forskolin-stimulated LHRH release and that the CB1-r antagonist AM251 (10(-5) M) blocked that inhibition, supporting the hypothesis that TNF-alpha inhibits LHRH release, acting at least in part by activating the endocannabinoid system. Therefore, our data demonstrate a key role for the endocannabinoid system in the response of the reproductive system to inflammatory signals.
众所周知，大麻的主要活性成分Δ⁹-四氢大麻酚（THC）可抑制生殖功能。此外，我们之前报道过，内源性大麻素花生四烯乙醇胺（AEA）可抑制体外培养的雄性大鼠内侧基底下丘脑（MBH）释放促性腺激素释放激素（LHRH），并且在向脑侧脑室注射AEA后可降低血浆促黄体生成素（LH）水平。另一方面，已知在内毒素血症期间，下丘脑促性腺激素轴会受到抑制。因此，本研究的目的是确定由脂多糖（LPS）诱导的促炎细胞因子肿瘤坏死因子-α（TNF-α）抑制LHRH释放的作用是否通过内源性大麻素系统的激活介导。腹腔注射LPS（5 mg/kg）以及脑室内注射肿瘤坏死因子-α（TNF-α）（100 ng/只大鼠）显著增加了处理后3小时取出的MBH中离体测量的AEA合成。为了检验TNF-α是否也通过增加释放并激活CB1受体的AEA合成，随后抑制LHRH释放来发挥作用，我们测量了TNF-α对体外培养的MBH中AEA合酶活性的影响。正如预期的那样，我们发现TNF-α（2.9×10⁻⁹ M）增加了AEA合成。其次，我们表明TNF-α显著降低了福斯可林刺激的LHRH释放，并且CB1受体拮抗剂AM251（10⁻⁵ M）可阻断这种抑制作用，支持了TNF-α抑制LHRH释放至少部分是通过激活内源性大麻素系统发挥作用的假设。因此，我们的数据证明了内源性大麻素系统在生殖系统对炎症信号反应中的关键作用。
