Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival

被引：123

作者：

Fujitsuka, N. ^{[1
]}

Asakawa, A. ^{[1
]}

Uezono, Y. ^{[2
]}

Minami, K. ^{[2
]}

Yamaguchi, T. ^{[3
]}

Niijima, A. ^{[4
]}

Yada, T. ^{[5
]}

Maejima, Y. ^{[5
]}

Sedbazar, U. ^{[5
]}

Sakai, T. ^{[6
]}

Hattori, T. ^{[7
]}

Kase, Y. ^{[7
]}

Inui, A. ^{[1
]}

机构：

[1] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Psychosomat Internal Med, Kagoshima 8908520, Japan

[2] Natl Canc Ctr, Canc Pathophysiol Div, Tokyo, Japan

[3] Chiba Canc Ctr, Div Gastroenterol, Chiba 2608717, Japan

[4] Niigata Univ, Sch Med, Dept Physiol, Niigata 951, Japan

[5] Jichi Med Univ, Sch Med, Dept Physiol, Shimotsuke, Tochigi, Japan

[6] Saitama Univ, Grad Sch Sci & Engn, Dept Life Sci, Saitama 3388570, Japan

[7] Tsumura Res Labs, Ibaraki, Japan

来源：

TRANSLATIONAL PSYCHIATRY | 2011年 / 1卷

关键词：

anorexia-cachexia; CRF; ghrelin; GHS-R; neuropeptide Y;

D O I：

10.1038/tp.2011.25

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, a-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

引用

页码：e23 / e23

页数：10

共 53 条

[1]

[Anonymous], 2010, P IEEE PES GEN M MIN, DOI DOI 10.1109/PES.2010.5589388

[2] Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin [J].