Gastroprotective effect and mechanism of amtolmetin guacyl in mice.
OBJECTIVE
To investigate the gastroprotective effect and mechanism of amtolmetin guacyl (AMG, MED15) in mice.


METHODS
Male and female Kunming strain mice, weighing 18-22 g, were utilized in the experiment. Normal or ethanol-induced gastric mucosal damage models in mice were successfully established to investigate the gastroprotective effect and mechanism of AMG. In the experiment of gastric mucosal damage after repeated treatment with AMG, the mice were randomly divided into 5 groups: normal group, 3 AMG groups receiving (75, 150 and 300 mg/kg), and tolmetin group receiving 90 mg/kg. The mice were randomly divided into 6 groups as follows: normal group, model group, AMG groups with doses of 75, 150 and 300 mg/kg, respectively, and tolmetin group with a dose of 90 mg/kg in ethanol-induced gastric mucosal damage experiment. The severity of gastric mucosal lesions was scored from 0 to 5. Gastric tissue sections were stained with hematoxylin and eosin (HE) and examined under light microscopy. Also gastric tissue sections were stained with uranyl acetate and lead citrate, and examined under electron microscopy. In addition, nitric oxide (NO) and malondialdehyde (MDA) contents, and nitric oxide synthase (NOS) and superoxide dismutase (SOD) activities in the stomach tissue homogenates were measured by biochemical methods.


RESULTS
Repeated treatment with AMG (75, 150 and 300 mg/kg) for 7 d did not induce any appreciable mucosal damage, and the average score was not significantly different from that of normal mice. In contrast, tolmetin (90 mg/kg) produced significant gastric mucosal lesions compared with the normal group (P<0.01). AMG (75, 150 and 300 mg/kg) significantly reduced the severity of gastric lesions induced by ethanol in a dose-dependent manner as compared with the model group (P<0.05, AMG 75 and 150 mg/kg vs model; P<0.01, AMG 300 mg/kg vs model). Light and electron microscopy revealed that AMG (150 and 300 mg/kg) induced minimal changes in the surface epithelium layer, without vascular congestion or leucocyte adherence. AMG (75,150 and 300 mg/kg) demonstrated dose-dependent gastroprotective effects on mice in our study. AMG (75, 150 and 300 mg/kg) could significantly increase NO content and NOS level in the stomach homogenates of mice compared with the model group (P<0.05, AMG 75 mg/kg and 150 mg/kg groups vs model group; P<0.01, AMG 300 mg/kg vs model group) respectively. Moreover, AMG (150 and 300 mg/kg) not only significantly increased SOD activities but also obviously decreased the MDA content in the stomach homogenates of mice.
Li
Yuan-Hai
YH
School of Pharmacy, Anhui Medical University, Institute of Clinical Pharmacology, Anhui Medical University,Tunxi West Road, Hefei 230032, Anhui Province, China.
Li
Jun
J
Huang
Yan
Y
Lu
Xiong-Wen
XW
Jin
Yong
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D046529:Microscopy, Electron, Transmission; D008871:Microvilli / Q000473:pathology / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002492:Central Nervous System Depressants; D011758:Pyrroles; C065762:ST 679; D009569:Nitric Oxide; D000431:Ethanol; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D005998:Glycine