Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany.
PLoS One. 2011;6(11):e26865. doi: 10.1371/journal.pone.0026865. Epub 2011 Nov 15.
Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output.
Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a rat model of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics.
Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p<0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9±0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76±0.07 for BIM-28131, 0.68±0.12 for BIM-28125, and 0.48±0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment.
Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound.
在心衰大鼠模型（心肌梗死）中，研究 50nmole/kg/d 和 500nmole/kg/d 的人源 ghrelin 或两种类似物 BIM-28125 和 BIM-28131（也称为 RM-131）与安慰剂相比的效果。动物（SD 大鼠，手术时约 225g）从第 14 天开始接受利尿剂，从第 28 天开始使用渗透泵接受 4 周的化合物治疗。监测体重并进行身体成分分析（NMR 扫描）。通过超声心动图和血流动力学评估心功能。
在心衰大鼠模型（心肌梗死）中，研究 50nmole/kg/d 和 500nmole/kg/d 的人源 ghrelin 或两种类似物 BIM-28125 和 BIM-28131（也称为 RM-131）与安慰剂相比的效果。动物（SD 大鼠，手术时约 225g）从第 14 天开始接受利尿剂，从第 28 天开始使用渗透泵接受 4 周的化合物治疗。监测体重并进行身体成分分析（NMR 扫描）。通过超声心动图和血流动力学评估心功能。
与假手术大鼠相比，MI 动物直到治疗开始时体重增加较少（311g 与 324g，p=0.0129）。与安慰剂和假手术组相比，用 BIM-28131 50nmole/kg/d 或所有化合物 500nmole/kg/d 治疗的动物体重增加更明显（均 p<0.001）。治疗前，所有组的身体成分相似（平均：36g 脂肪，248g 瘦肉）。安慰剂治疗的大鼠没有增加脂肪，但只有瘦肉。活性化合物诱导脂肪和瘦肉的增加，但程度不同。组织获得的脂肪与肌肉的比值，用 BIM-28131 50nmole/kg/d 治疗时为 0.9±0.07，而用 BIM-28131 500nmole/kg/d 治疗时为 0.76±0.07，用 BIM-28125 治疗时为 0.68±0.12，用 ghrelin 治疗时为 0.48±0.05。MuRF-1 和 MAFbx 的表达受到治疗的差异调节。
ghrelin 是治疗心衰性恶病质的一种很有前途的治疗方法，类似物 BIM-28131（RM-131）是最有效的化合物。
