Effects of Metastin/Kisspeptin Analog, TAK-683, on Luteinizing Hormone Secretion in Peripheral Plasma, and Gonadotropin-Releasing Hormone Secretion in the Pituitary Portal Circulation in Goats
Metastin/Kisspeptin is a potent secretagogue of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion. The present study aims to determine if a metastin/kisspeptin analogue, TAK-683, has a stimulatory effects on LH secretion in peripheral plasma and GnRH release in the pituitary portal circulation in castrated male or ovariectomized female goats. In experiment 1, castrated (n=5) or ovariectomized (n=5) goats were received a bolus intravenous (iv) injection of TAK-683 (3.5 pmol/head - 3.5 nmol/head). A single injection of TAK-683 stimulated LH secretion in a dose-dependent manner in both castrated and ovariectomized goats. The effective dose (3.5 nmol) of TAK-683 was much lower than that (380 nmol) of the metastin/kisspeptin C-terminal active decapeptide, kisspeptin-10 (1), indicating that TAK-683 is a potent analogue to induce LH secretion. In experiment 2, portal blood sampling techniques were applied to monitor change in GnRH release in pituitary portal circulation. A bolus iv injection of TAK-683 (35 nmol/head) strongly stimulated GnRH release in castrated male goats (n=6). The duration of elevated GnRH/LH secretion lasted for more than 4 hours after the injection. This observation provides direct evidence that TAK-683 induces LH secretion by stimulating hypothalamic GnRH release. In experiment 3, a chronic application of TAK-683 was achieved by subcutaneous implantation of an osmotic pump containing TAK-683 solution (50 nmol/kg BW/week) and pulsatile GnRH/LH secretion was examined in castrated male goats (n=5). By contrast to a bolus iv injection of TAK-683, a chronic treatment of this analogue for 5 to 6 days caused severe suppression of GnRH and LH pulses. This “paradoxical effect” on GnRH/LH secretion was achieved by 3 days after the initiation of TAK-683 application. The present findings demonstrate that TAK-683 is a potent secretagogue of GnRH/LH secretion and that continuous exposure to this metastin/kisspeptin analogue attenuates the responsiveness of GnRH neurons, which in turn decreases LH secretion. These series of experiments using a metastin/kisspeptin analogue suggests that endogenous metastin/kisspeptin is a potent stimulator of LH secretion via GnRH release from the hypothalamus and would be critical for the control of reproductive functions in goats as in other mammalian species. (1) Ohkura S et al., J Neuroendocrinol 2009; 21:813 Nothing to Disclose: SO, TT, TK, YW, TO, MK, HO