Karasawa H, Pietra C, Giuliano C, Garcia-Rubio S, Xu X, Yakabi S, Taché Y, Wang L
Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Neurogastroenterol Motil. 2014 Dec;26(12):1771-82. doi: 10.1111/nmo.12459. Epub 2014 Oct 19.
Constipation and L-dopa-induced gastric dysmotility are common gastrointestinal (GI) symptoms in Parkinson's disease (PD). We investigated the novel ghrelin agonist, HM01 influence on GI motor dysfunctions in 6-hydroxydopamine (6-OHDA) rats.
HM01 pharmacological profiles were determined in vitro and in vivo in rats. We assessed changes in fecal output and water content, and gastric emptying (GE) in 6-OHDA rats treated with orogastric (og) HM01 and L-dopa/carbidopa (LD/CD, 20/2 mg/kg). Fos immunoreactivity (ir) cells in specific brain and lumbosacral spinal cord were quantified.
HM01 displayed a high binding affinity to ghrelin receptor (Ki: 1.42 ± 0.36 nM), 4.3 ± 1.0 h half-life and high brain/plasma ratio. 6-OHDA rats had reduced daily fecal output (22%) and water intake (23%) compared to controls. HM01 (3 and 10 mg/kg) similarly reversed the decreased 4-h fecal weight and water content in 6-OHDA rats. Basal GE was not modified in 6-OHDA rats, however, LD/CD (once or daily for 8 days) delayed GE in 6-OHDA and control rats that was prevented by HM01 (3 mg/kg acute or daily before LD/CD). HM01 increased Fos-ir cell number in the area postrema, arcuate nucleus, nucleus tractus solitarius, and lumbosacral intermediolateral column of 6-OHDA rats where 6-OHDA had a lowering effect compared to controls.
CONCLUSIONS & INFERENCES: 6-OHDA rats display constipation- and adipsia-like features of PD and L-dopa-inhibited GE. The new orally active ghrelin agonist, HM01 crosses the blood-brain barrier and alleviates these alterations suggesting a potential benefit for PD with GI disorders.
便秘和左旋多巴诱导的胃动力障碍是帕金森病（PD）常见的胃肠道症状。我们研究了新型胃饥饿素激动剂HM01对6-羟基多巴胺（6-OHDA）大鼠胃肠道运动功能障碍的影响。
在大鼠体内外确定HM01的药理学特性。我们评估了经口胃内给予HM01和左旋多巴/卡比多巴（LD/CD，20/2mg/kg）的6-OHDA大鼠的粪便排出量、含水量和胃排空（GE）的变化。对特定脑区和腰骶脊髓中的Fos免疫反应性（ir）细胞进行定量。
HM01对胃饥饿素受体表现出高结合亲和力（Ki：1.42±0.36nM），半衰期为4.3±1.0小时，脑/血浆比率高。与对照组相比，6-OHDA大鼠的每日粪便排出量减少（22%），饮水量减少（23%）。HM01（3mg/kg和10mg/kg）同样逆转了6-OHDA大鼠4小时粪便重量和含水量的降低。6-OHDA大鼠的基础胃排空未改变，然而，LD/CD（单次或连续8天每日给药）使6-OHDA大鼠和对照大鼠的胃排空延迟，而HM01（3mg/kg急性给药或在LD/CD给药前每日给药）可预防这种延迟。与对照组相比，HM01增加了6-OHDA大鼠最后区、弓状核、孤束核和腰骶中间外侧柱中Fos-ir细胞的数量，而6-OHDA在此处有降低作用。
6-OHDA大鼠表现出PD的便秘和厌食样特征以及左旋多巴抑制的胃排空。新型口服活性胃饥饿素激动剂HM01可穿过血脑屏障并减轻这些改变，提示其对伴有胃肠道疾病的PD具有潜在益处。
