Effect of orally active growth hormone secretagogue, MK-677, on somatic growth in rats

Abstract

Growth hormone secretagogues (GHSs) have been considered as alternative for the treatment of diseases related to growth hormone (GH) deficiency because of their ability to release GH in the body. As GH is a large peptide molecule, it must be injected into subcutaneous tissue or muscle to get it into the blood. However, some types of GHS can effectively stimulate GH release by administration through various routes such as intravenously, subcutaneously, intraperitoneally, and orally. The effects of MK-677, an orally active non-peptide mimic of GHS, on somatic growth were studied in rats. To confirm the GH stimulatory effect of MK-677, the concentration of serum GH was measured at regular intervals after oral administration of 0, 2, or 4 mg MK-677/kg. To investigate the growth-promoting effect of MK-677, body weight and body length were measured after oral administration of 4mg MK-677/kg for 6 weeks. Blood samples were collected from the tail vein every 2 weeks for insulin-like growth factor-I determination. After decapitation, tibia length and epiphyseal plate width were measured, and the pituitary gland and hypothalamus were collected and frozen for analysis of GH, GH releasing hormone, GHS receptor, somatostatin, and somatostatin receptor mRNA by real-time polymerase chain reaction. Oral administration of MK-677 at 4 mg/kg significantly increased peak GH concentrations by 1.8-fold, compared to baseline levels. However, oral administration of MK-677 at 4 mg/kg for 6 weeks did not increase the body length, body weight, width of tibia growth plate, and serum level of insulin-like growth factor-I. At 6 weeks after treatment, the GH response to oral administration of MK-677 was abolished. Pituitary GH mRNA and hypothalamic GHRH mRNA levels did not differ between the control and 6-week treatment groups. Treatment with MK-677 did not alter pituitary and hypothalamic GHSR mRNA expression. Somatostatin mRNA expression in the hypothalamus was markedly increased in the treatment group compare to in controls. In addition, somatostatin receptor-2 mRNA expression in the pituitary gland was decreased in the treatment group compare to the controls. Although oral administration of MK-677 stimulated GH secretion, prolonged administration for 6 weeks attenuated the GH stimulatory effect of MK-677 and did not promote growth, which may be related to increased expression of somatostatin in the hypothalamus. Further studies are needed to overcome the desensitization of growth hormone-releasing peptide after the prolonged clinical treatment of growth disorders.

성장호르몬 분비촉진제 (growth hormone secretagogues,GHS)는 성장호르몬 분비를 자극하는 효과를 보이므로 성장장애 치료를 위한 대안으로 여겨진다. 성장호르몬은 크기가 큰 펩티드 분자이기에 이는 피하주사 혹은 근육주사로 투여 해야 한다. 하지만 성장호르몬 분비촉진제(growth hormone secretagogues,GHS)는 피하주사, 근육주사, 복강주사 혹은 경구투여로 성장호르몬분비를 촉진 시킬 수 있다. 성장호르몬 분비촉진제 MK-677 의 신체성장 효과를 흰쥐를 통하여 조사하였다. 성장호르몬 분비촉진제, MK-677 4 mg/kg를 경구로 투여하였을 때 성장호르몬 분비가 최대 1.5배 증가하는 것을 확인하였다. 그러나 6주 동안 흰쥐에 4mg/kg의 MK-677와 위약을 경구 투여하였을 때 신장, 체중, 정강이뼈 길이 모두 큰 차이가 없었으며,인슐린양 성장인자-I (insulin-like growth factor I, IGF-I)의 농도에도 차이가 없었다. 6주 동안 MK-677을 투여한 후에는 MK-677의 성장호르몬 분비 자극 효과가 소실되었다. MK-677을 6주 동안 투여한 후에는 뇌하수체의 성장호르몬 mRNA, 시상하부의 성장호르몬방출호르몬 mRNA와 뇌하수체와 시상하부의 성장호르몬 분비촉진제 수용체 mRNA 발현에는 영향을 주지 않았으나, 시상하부의 소마토스타틴 mRNA 발현이 증가되었다.성장호르몬 분비촉진제가 성장장애의 치료에 이용되기 위해서는 장기간 투여 시 나타나는 소미토스타틴 발현의 증가를 조절하는 방안에 대한 연구가 필요하리라 사료된다.