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Protective Effect of Dizocilpine (MK-801) On TNBS-Induced Experimental Colitis in Mice
Ehsan Motaghi1, Valiollah Hajhashemi1, Parvin Mahzouni2
1Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Abstract:
Ulcerative colitis is chronic and recurrent disease of the gastrointestinal tract with uncertain etiology and incomplete treatment options. N-methyl-d-aspartate (NMDA) receptor suppression has shown anti-inflammatory effects in-vitro and in-vivo. The aim of present study was to evaluate the role of dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist, on TNBS (trinitrobenzene sulfonic acid)-induced murine model of colitis. Dizocilpine (0.1, 1 and 5 mg/kg) was given to mice intraperitoneally from 24 h before induction of colitis and daily thereafter for 4 days. Dexamethasone (1 mg/kg) was used as the reference drug. Colitis was induced by intracolonic administration of TNBS/Ethanol (50/50 v/v, 40mg/kg). Animals were sacrificed 5 days after colitis induction and distal colons were examined macroscopically and microscopically. The colonic tissue level of pro-inflammatory cytokines including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed by ELISA. Myeloperoxidase (MPO) level was also measured in colon. Dizocilpine, particularly with intermediate dose of 1mg/kg significantly improved animal's weight loss as well as macroscopic and microscopic signs of colitis, reduced colonic levels of IL-1β, IL-6, TNF-α and MPO activity. Hence, dizocilpine has significant protective effects in TNBS-induced colitis and NMDA suppression may be a new and effective therapeutic strategy in ulcerative colitis via decreasing in pro-inflammatory cytokine production.
Insights
Dizocilpine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, significantly reduced inflammation in a mouse model of ulcerative colitis. NMDA receptor suppression shows promise as a novel therapeutic strategy for inflammatory bowel disease.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Ulcerative colitis is a chronic gastrointestinal disease with limited treatment options.
- N-methyl-d-aspartate (NMDA) receptor suppression demonstrates anti-inflammatory properties.
- The efficacy of NMDA receptor antagonists in inflammatory bowel disease requires further investigation.
Purpose of the Study:
- To evaluate the therapeutic potential of dizocilpine (MK-801), an NMDA receptor antagonist, in a murine model of ulcerative colitis.
- To assess the impact of dizocilpine on inflammatory markers and tissue damage in colitis.
Main Methods:
- Trinitrobenzene sulfonic acid (TNBS)-induced colitis was established in mice.
- Dizocilpine (0.1, 1, and 5 mg/kg) or dexamethasone (1 mg/kg) was administered intraperitoneally.
- Colonic tissues were analyzed macroscopically and microscopically for inflammation.
- Levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) were measured.
Main Results:
- Dizocilpine administration significantly improved weight loss and reduced macroscopic and microscopic colitis scores.
- The intermediate dose of dizocilpine (1 mg/kg) demonstrated the most significant protective effects.
- Dizocilpine treatment markedly decreased colonic levels of IL-1β, IL-6, TNF-α, and MPO activity.
Conclusions:
- Dizocilpine exhibits significant protective effects in a TNBS-induced colitis model.
- NMDA receptor suppression represents a potential novel therapeutic strategy for ulcerative colitis.
- Reducing pro-inflammatory cytokine production is a key mechanism underlying dizocilpine's efficacy.
