Study of the cytoprotective effect of low molecular weight chitosan on a model of indomethacin gastropathy in rats

Background. Currently, gastropathy (band and punctate erosions) caused by the use of nonsteroidal anti-inflammatory drugs are the most common complications of drug therapy for acute respiratory viral infections and rheumatoid diseases. With prolonged use of nonsteroidal anti-inflammatory drugs and when treated in high doses, erosions of the gastric mucosa very often progress and transform into chronic gastric ulcers, which, in terms of pathophysiological mechanisms, are identical to gastric ulcer disease with the involvement of Helicobacter pylori. Currently, there are no effective means for the prevention of drug-induced gastropathy. Attempts to create nonsteroidal anti-inflammatory drugs that do not cause gastropathy have also been unsuccessful. The authors of the article propose the use of low molecular weight chitosan as a gastroprotective agent.
Objective. To evaluate the effectiveness of low molecular weight chitosan (50 kDa) as a means of preventing damage to the gastric mucosa during the administration of nonsteroidal anti-inflammatory drugs in a model of indomethacin gastropathy in rats.
Materials and Methods. The study was performed on 14 male Wistar rats, 3 months old with an average body weight of 240-250 g. Under light ether anesthesia, the animals were administered an intragastrically indomethacin suspension at a dose of 60 mg per 1 kg of body weight. One hour after the administration of the indomethacin suspension, the animals of the control group were administered intragastrically 2 ml of a 0.9% sodium chloride solution, and the animals of the experimental group were administered 2 ml of a 0.2% aqueous solution of low-molecular chitosan (50 kDa). Twenty-four hours after the administration of the test substances, all rats were euthanized by an overdose of ether anesthesia. The stomachs of the animals of the experimental and control groups were removed, cut along the lesser curvature, washed with saline, and the gastric mucosa was scanned at a resolution of 1200 dpi. The area of erosions in the gastric mucosa (ribbon and punctate) in mm2 and the area of the mucosa in mm2 were calculated in Corel Draw 13.
Results. The studies showed that low-molecular chitosan (50 kDa) has a pronounced cytoprotective effect and significantly reduces the percentage of damage to the gastric mucosa in the indomethacin gastropathy model in rats. The most likely mechanism of the described therapeutic effect of low-molecular chitosan is the activation of gastric mucosal macrophages and the expression of the synthesis of antiinflammatory cytokines by them. Moreover, with intragastric administration of low-molecular chitosan, not only the total area of erosive damage to the stomach decreases, but also a significant (more than fivefold) decrease in the area of ribbon erosions.
Conclusion. Low-molecular chitosan has a distinct gastroprotective effect when administered with indomethacin and can be considered as a promising drug for the prevention of non-steroidal gastropathy. At the same time, low-molecular chitosan may be a very promising additional component in the production of nonsteroidal anti-inflammatory drugs dosage forms with reduced side effects on the gastric mucosa.

1. Tsimmerman Ya. S. Gastroduodenal lesion induced by non-steroidal anti-inflammatory drugs (NSAIDs): NSAID-gastritis or NSAIDgastropathy? Clin. Pharmacol. Ther. 2018; 27 (1): 14-21.

2. Preventive and therapeutic strategies of pharmacocorrection gastropathy induced by nonsteroidal anti-inflammatory drugs. Reviews on Clinical Pharmacology and Drug Therapy. 2017; 15 (4): 14-23. DOI: 10.17816/RCF15414-23.

3. Takeuchi K. Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility. World J Gastroenterol. 2012; 18 (18): 2147-2160. Available from: DOI: 10.3748/wjg.v18.i18.2147.

4. Lamarque D. Physiopathologie des lésions gastroduodénales induites par les anti-inflammatoires non stéroïdiens [Pathogenesis of gastroduodenal lesions induced by non-steroidal antiinflammatory drugs]. Gastroenterol Clin Biol. 2004; 28 Spec No 3: C18-26. French. DOI: 10.1016/s0399-8320(04)95275-x. PMID: 15366671.

5. Lanas A. Cyclo-oxygenase-1/cyclo-oxygenase-2 non selective non-steroidal anti-inflammatory drugs: epidemiology of gastrointestinal events. Dig Liver Dis. 2001; 33 Suppl 2: S29-34. DOI: 10.1016/s1590-8658(01)80156-0. PMID: 11827360.

6. Viktorova I. A., Trukhan D. I., Ivanova D. S. Modern opportunities for treatment and prevention of NSAID-induced enteropathies. Meditsinskii Sovet. 2020; (5):30-40. doi: 10.21518/2079-701X-2020-5-30-40. (In Russ.)

7. Zharikov A. Yu., Lorents S. E., Bobrov I. P., Mazko O. N., Makarova O. G. Search for New Oligopeptide Molecules for Pharmacological Corrections of Nsaids-induced Gastric Ulcer. Biomeditsina. 2019; 15 (3): 90-97. doi:10.33647/2074-5982-15-3-90-97 (In Russ.)

8. Gmurov D. V., Parfenteva M. A., Semenova Y. V., Rubtsov D. A., Osinskii V. A. NSAIDS-associated peptic ulcer of the stomach and duodenum. Technical science. Colloquium-journal. 2020; 11 (63). DOI: 10.24411/2520-6990-2020-11731.

9. Chinese Rheumatism Data Center; Chinese Systemic Lupus Erythematosus Treatment and Research Group. [Recommendation for the prevention and treatment of non-steroidal antiinflammatory drug-induced gastrointestinal ulcers and its complications]. Zhonghua Nei Ke Za Zhi. 2017; 56 (1): 81-85. Chinese. https://doi.org/10.3760/cma.j.issn.0578-1426.2017.01.021. PMID: 28056333.

10. Adefisayo M. A., Akomolafe R. O., Akinsomisoye S. O., Alabi Q. K., Ogundipe O. L., Omole J. G., Olamilosoye K. P. Gastro-protective effect of methanol extract of Vernonia amygdalina (del.) leaf on aspirin-induced gastric ulcer in Wistar rats. Toxicol Rep. 2017; 4: 625-633. DOI: 10.1016/j.toxrep.2017.11.004. PMID: 29657922; PMCID: PMC5897319.

11. Troitsky A. V., et al. Study of the Cytoprotective Effect of Low Molecular Weight Chitosan on a Model of Indomethacin Gastropathy in Rats. Acta Scientific Medical Sciences. 2024; 10 (8): 48-52. DOI: http://actascientific.com/ASMS/pdf/ASMS-08-1923.pdf.