Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Córdoba, Avenida Menéndez Pidal, 14004 Córdoba, Spain.
Endocrinology. 2010 Apr;151(4):1902-13. doi: 10.1210/en.2009-1259. Epub 2010 Feb 16.
Identification of RF-amide-related peptides (RFRP), as putative mammalian orthologs of the avian gonadotropin-inhibitory hormone, has drawn considerable interest on its potential effects and mechanisms of action in the control of gonadotropin secretion in higher vertebrates. Yet, these analyses have so far relied mostly on indirect approaches, while direct assessment of their physiological roles has been hampered by the lack of suitable antagonists. RF9 was recently reported as a selective and potent antagonist of the receptors for RFRP (RFRPR) and the related neuropeptides, neuropeptide FF (NPFF) and neuropeptide AF (NPFF receptor). We show here that RF9 possesses very strong gonadotropin-releasing activities in vivo. Central administration of RF9 evoked a dose-dependent increase of LH and FSH levels in adult male and female rats. Similarly, male and female mice responded to intracerebroventricular injection of RF9 with robust LH secretory bursts. In rats, administration of RF9 further augmented the gonadotropin-releasing effects of kisspeptin, and its stimulatory effects were detected despite the prevailing suppression of gonadotropin secretion by testosterone or estradiol. In fact, blockade of estrogen receptor-alpha partially attenuated gonadotropin responses to RF9. Finally, systemic administration of RF9 modestly stimulated LH secretion in vivo, although no direct effects in terms of gonadotropin secretion were detected at the pituitary in vitro. Altogether, these data are the first to disclose the potent gonadotropin-releasing activity of RF9, a selective antagonist of RFRP (and NPFF) receptors. Our findings support a putative role of the RFRP/gonadotropin-inhibitory hormone system in the central control of gonadotropin secretion in mammals and have interesting implications concerning the potential therapeutic indications and pharmacological effects of RF9.
RF-amide 相关肽（RFRP）作为禽类促性腺激素抑制激素的哺乳动物同源物，因其在控制高等脊椎动物促性腺激素分泌方面的潜在作用和作用机制而引起了相当大的关注。然而，这些分析迄今为止主要依赖于间接方法，而由于缺乏合适的拮抗剂，直接评估它们的生理作用受到了阻碍。RF9 最近被报道为 RFRP（RFRPR）和相关神经肽，神经肽 FF（NPFF）和神经肽 AF（NPFF 受体）受体的选择性和有效拮抗剂。我们在这里表明，RF9 在体内具有很强的促性腺激素释放活性。RF9 的中枢给药在成年雄性和雌性大鼠中诱发了 LH 和 FSH 水平的剂量依赖性增加。同样，雄性和雌性小鼠对 RF9 的侧脑室注射也表现出强烈的 LH 分泌爆发。在大鼠中，RF9 的给药进一步增强了 kisspeptin 的促性腺激素释放作用，并且尽管睾酮或雌二醇普遍抑制了促性腺激素的分泌，但仍检测到其刺激作用。事实上，雌激素受体-α的阻断部分减弱了 RF9 对促性腺激素的反应。最后，RF9 的全身给药在体内适度刺激了 LH 的分泌，尽管在体外垂体中没有检测到直接的促性腺激素分泌作用。总的来说，这些数据首次揭示了 RF9 的强烈促性腺激素释放活性，RF9 是 RFRP（和 NPFF）受体的选择性拮抗剂。我们的发现支持了 RFRP/促性腺激素抑制激素系统在哺乳动物促性腺激素分泌的中枢控制中的假定作用，并对 RF9 的潜在治疗适应症和药理学效应具有有趣的影响。
