Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats.
OBJECTIVE
To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats.


METHODS
Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg, 3 mg/kg or 10 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8 and myeloperoxidase (MPO) in mucosal tissues.


RESULTS
Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin. Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dose-dependent manner. The mucosal concentrations of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-8) and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacin-treated rats. Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin.


CONCLUSIONS
The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.
Zhang
Xin
X
Department of Pharmacology, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan. x.zhang@po.nippon-shinyaku.co.jp
Tajima
Koyuki
K
Kageyama
Kiyoto
K
Kyoi
Takashi
T
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007213:Indomethacin; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000897:Anti-Ulcer Agents; D016207:Cytokines; D053583:Interleukin-1beta; D016209:Interleukin-8; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C041836:irsogladine; D007213:Indomethacin