Dataset Information

New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease.

ABSTRACT: 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.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.

SUBMITTER: Karasawa H

PROVIDER: S-EPMC4457321 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease.

Karasawa H H Pietra C C Giuliano C C Garcia-Rubio S S Xu X X Yakabi S S Taché Y Y Wang L L

Neurogastroenterology and motility 20141019 12

<h4>Background</h4>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.<h4>Methods</h4>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/carbido ...[more]

PMID: 25327342

Similar Datasets

Project description:Background & aimsRM-131, a synthetic ghrelin agonist, greatly accelerates gastric emptying of solids in patients with type 2 diabetes and delayed gastric emptying (DGE). We investigated the safety and effects of a single dose of RM-131 on gastric emptying and upper gastrointestinal (GI) symptoms in patients with type 1 diabetes and previously documented DGE.MethodsIn a double-blind cross-over study, 10 patients with type 1 diabetes (age, 45.7 ± 4.4 y; body mass index, 24.1 ± 1.1 kg/m(2)) and previously documented DGE were assigned in random order to receive a single dose of RM-131 (100 μg, subcutaneously) or placebo. Thirty minutes later, they ate a radiolabeled solid-liquid meal containing EggBeaters (ConAgra Foods, Omaha, NE), and then underwent 4 hours of gastric emptying and 6 hours of colonic filling analyses by scintigraphy. Upper GI symptoms were assessed using a daily diary, gastroparesis cardinal symptom index (total GCSI-DD) and a combination of nausea, vomiting, fullness, and pain (NVFP) scores (each rated on a 0-5 scale).ResultsAt screening, participants' mean level of hemoglobin A1c was 9.1% ± 0.5%; their total GCSI-DD score was 1.66 ± 0.38 (median, 1.71), and their total NVFP score was 1.73 ± 0.39 (median, 1.9). The t1/2 of solid gastric emptying was 84.9 ± 31.6 minutes when subjects were given RM-131 and 118.7 ± 26.7 when they were given a placebo. The median difference (Δ)was 33.9 minutes (interquartile range [IQR] -12, -49), or -54.7% (IQR, -21%,-110%). RM-131 decreased gastric retention of solids at 1 hour (P = .005) and 2 hours (P = .019). Numeric differences in t1/2 for gastric emptying of liquids, solid gastric emptying lag time, and colonic filling at 6 hours were not significant. Total GCSI-DD scores were 0.79 on placebo (IQR, 0.75, 2.08) and 0.17 on RM-131 (IQR, 0.00, 0.67; P = .026); NVFP scores were lower on RM-131 (P = .041). There were no significant adverse effects.ConclusionsRM-131 significantly accelerates gastric emptying of solids and reduces upper GI symptoms in patients with type 1 diabetes and documented DGE.

Project description:BackgroundIt remains controversial as to whether delayed gastric emptying in functional dyspepsia is associated with a specific symptom pattern, and it is unknown if gastric emptying in functional dyspepsia is a driver of impaired health related quality of life (HRQOL). We aimed to evaluate the relationship between functional dyspepsia symptoms, gastric emptying, and HRQOL.MethodsUS patients (n=864; mean age 44 years (range 18-82); 74% female) with functional dyspepsia, as defined by Rome II criteria, were enrolled into one of four clinical trials. All patients had a baseline scintigraphic assessment of gastric emptying of an egg substitute meal, and the trials were stratified on this assessment. Delayed gastric emptying was defined as having at least 6.3% residual volume at four hours. A total of 290 (34%) patients had delayed gastric emptying. HRQOL was assessed by the SF 36 and Nepean dyspepsia index (NDI).ResultsPostprandial fullness was independently associated with delayed gastric emptying but the association was weak (odds ratio (OR) 1.98 (95% confidence interval (CI) 1.02, 3.86); p=0.04). No independent association was seen with epigastric pain, early satiety, nausea, or bloating. Mean SF 36 physical composite score (PCS) was 42.3 (95% CI 41.6, 43.0) and the mean SF 36 mental composite score (MCS) was 46.8 (95% CI 46.0, 47.5); both mean scores were significantly lower than age and sex adjusted national norms of 50 (p<.0001). Female sex, increasing age, and higher symptom scores for fullness, epigastric pain, and nausea were each independently associated with decreased PCS scores (all p<0.05). Higher baseline nausea symptom score, lower gastric emptying rates at one hour, and lower body mass index were associated with decreased MCS (all p<0.05). Female sex, epigastric pain, and nausea, but not gastric emptying, were associated with an impaired score on the NDI. However, the magnitude of the significant associations were all small.ConclusionsIn patients with functional dyspepsia selected for a clinical trial programme, gastric emptying did not usefully stratify them symptomatically. Quality of life of patients with functional dyspepsia enrolled in this clinical trial programme was significantly impaired but this was not explained by delayed gastric emptying.

Project description:BACKGROUND & AIMS:Muscularis propria macrophages lie close to cells that regulate gastrointestinal motor function, including interstitial cells of Cajal (ICC) and myenteric neurons. In animal models of diabetic gastroparesis, development of delayed gastric emptying has been associated with loss of macrophages that express cytoprotective markers and reduced networks of ICC. Mice with long-term diabetes and normal gastric emptying have macrophages that express anti-inflammatory markers and have normal gastric ICC. Mice homozygous for the osteopetrosis spontaneous mutation in the colony-stimulating factor 1 gene (Csf1op/op) do not have macrophages; when they are given streptozotocin to induce diabetes, they do not develop delayed gastric emptying. We investigated whether population of the gastric muscularis propria of diabetic Csf1op/op mice with macrophages is necessary to change gastric emptying, ICC, and myenteric neurons and investigated the macrophage-derived factors that determine whether diabetic mice do or do not develop delayed gastric emptying. METHODS:Wild-type and Csf1op/op mice were given streptozotocin to induce diabetes. Some Csf1op/op mice were given daily intraperitoneal injections of CSF1 for 7 weeks; gastric tissues were collected and cellular distributions were analyzed by immunohistochemistry. CD45+, CD11b+, F4/80+ macrophages were dissociated from gastric muscularis propria, isolated by flow cytometry and analyzed by quantitative real-time polymerase chain reaction. Cultured gastric muscularis propria from Csf1op/op mice was exposed to medium that was conditioned by culture with bone marrow-derived macrophages from wild-type mice. RESULTS:Gastric muscularis propria from Csf1op/op mice given CSF1 contained macrophages; 11 of 15 diabetic mice given CSF1 developed delayed gastric emptying and had damaged ICC. In non-diabetic Csf1op/op mice, administration of CSF1 reduced numbers of gastric myenteric neurons but did not affect the proportion of nitrergic neurons or ICC. In diabetic Csf1op/op mice given CSF1 that developed delayed gastric emptying, the proportion of nitrergic neurons was the same as in non-diabetic wild-type controls. Medium conditioned by macrophages previously exposed to oxidative injury caused damage to ICC in cultured gastric muscularis propria from Csf1op/op mice; neutralizing antibodies against IL6R or TNF prevented this damage to ICC. CD45+, CD11b+, and F4/80+ macrophages isolated from diabetic wild-type mice with delayed gastric emptying expressed higher levels of messenger RNAs encoding inflammatory markers (IL6 and inducible nitric oxide synthase) and lower levels of messenger RNAs encoding markers of anti-inflammatory cells (heme oxygenase 1, arginase 1, and FIZZ1) than macrophages isolated from diabetic mice with normal gastric emptying. CONCLUSIONS:In studies of Csf1op/op and wild-type mice with diabetes, we found delayed gastric emptying to be associated with increased production of inflammatory factors, and reduced production of anti-inflammatory factors, by macrophages, leading to loss of ICC.

Dataset Information

New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease.

Publications

New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure