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Melanocortin-4 receptor agonists alleviate intestinal dysfunction in secondary intra-abdominal hypertension rat model
Dong Liu1, Hong-Guang Zhang1, Ming-Tao Chang1
1Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
Background:
Intra-abdominal hypertension (IAH) is a potentially life-threatening disease. Melanocortin-4 (MC4) receptor activation exhibits life-saving properties. The aim of the present study was to examine whether treatment with the MC4 receptor agonist RO27-3225 ameliorates intestinal injury in IAH rats.
Methods:
A total of 72 male Sprague-Dawley rats were randomized into six groups. Group 1 was the sham group. Group 2, the sham + RO group, received RO27-3225 (180 μg/kg, intraperitoneally). IAH was induced in group 3, the IAH group, by blood draw (mean arterial pressure = 30 mm Hg for 90 min) followed by shed blood and/or Ringer solution reinfusion. Intra-abdominal pressure was increased to 20 mm Hg by injecting air into the peritoneal cavity. Group 4, the RO group, was administered RO27-3225 at 5 min after blood draw. Groups 5 and 6 were the chlorisondamine (Chl) and HS024 groups, in which the rats were pretreated with the nicotinic acetylcholine receptor antagonist Chl or selective MC4 receptor antagonist (HS024), respectively, at 2 min before RO27-3225 was administered.
Results:
RO27-3225 restored mean arterial pressure, reduced tumor necrosis factor-α, and interleukin-1β messenger RNA expression increased by IAH, alleviated histologic damage, and improved superoxide dismutase activity in the intestine. Compared with the IAH group, the levels of intestinal fatty acid-binding protein, intestinal edema and intestinal permeability were lower in the RO group. Furthermore, the RO27-3225 treatment increased the expression of Rho-associated coiled-coil-containing protein kinase 1 and phosphorylated myosin light chain. Chl and HS024 abrogated the protective effects of RO27-3225.
Conclusions:
These data indicate that the MC4 receptor agonist counteracts the intestinal inflammatory response, ameliorating intestinal injury in experimental secondary IAH by MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. It may represent a promising strategy for the treatment of IAH in the future.
Insights
Melanocortin-4 (MC4) receptor agonist RO27-3225 treats intestinal injury in intra-abdominal hypertension (IAH) rats. This MC4 receptor activation triggers the cholinergic anti-inflammatory pathway, offering a potential treatment for IAH.
Area of Science:
- Gastroenterology
- Pharmacology
- Critical Care Medicine
Background:
- Intra-abdominal hypertension (IAH) is a critical condition with high mortality.
- Melanocortin-4 (MC4) receptor activation has demonstrated life-saving potential.
- Investigating MC4 receptor agonists for IAH-induced intestinal injury is crucial.
Purpose of the Study:
- To evaluate the efficacy of MC4 receptor agonist RO27-3225 in ameliorating intestinal injury in a rat model of IAH.
- To elucidate the mechanism underlying the protective effects of RO27-3225.
Main Methods:
- Seventy-two Sprague-Dawley rats were randomized into sham and IAH groups.
- IAH was induced via blood draw and reinfusion, followed by increased intra-abdominal pressure.
- Rats received RO27-3225, with some pretreated with nicotinic acetylcholine receptor antagonist (chlorisondamine) or MC4 receptor antagonist (HS024).
Main Results:
- RO27-3225 normalized blood pressure, reduced inflammatory markers (TNF-α, IL-1β), and improved histological damage and antioxidant activity.
- Intestinal injury markers, including fatty acid-binding protein, edema, and permeability, were significantly reduced by RO27-3225.
- RO27-3225 increased Rho-kinase 1 and phosphorylated myosin light chain expression; these effects were blocked by antagonists.
Conclusions:
- MC4 receptor agonist RO27-3225 effectively counteracts intestinal inflammation and injury in experimental secondary IAH.
- The protective mechanism involves MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway.
- RO27-3225 shows promise as a future therapeutic strategy for treating IAH.
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