Cysteamine Attenuate Intestinal Reperfusion Injury Induced by Occlusion of Mesenteric Artery by Enhancing Intracellular Thiol Activities

Abstract

Background Ischemia/reperfusion has been reported to further damage the intestine reperfusion injury (IRI) and cause multiple distal organ dysfunction through oxidative stress, inflammation, and apoptosis. Cysteamine is known to inhibit oxidative stress, inflammatory cytokines and apoptosis. This experiment was designed to evaluate the role of cysteamine against IRI in rats

Methods Thirty-two Wistar rat strains were assigned to four groups: sham, Intestinal-reperfusion injury (IRI), 50 mg/kg and 100 mg/kg cysteamine treatment IRI. A 5 cm segment of terminal ileum was twisted 360° clockwise along the mesentery for 45 minutes to induce ischemia before detorsion. Tissues were preserved for biochemical evaluation and histology 4 hours after detorsion. Activities of GPx, GSH, protein and non-protein thiol, H₂O₂, MDA were evaluated. Serum concentration of nitrite, MPO, ALT, AST TNF-alpha and IL-6 were measured. Caspase 3 and bax were evaluated by immunohistochemistry. Statistical significance was set as p<0.05

Results Significant (p<0.05) increase in H₂O_2, MDA and nitrite but reduction in GPx, GSH, protein thiol and non-protein thiol in the IRI rats was reversed by 50 and 100 mg/kg cysteamine. Serum MPO, TNF-α, IL6, AST and ALT was significantly elevated in IRI while the rats treated with cysteamine showed a significant decrease (p<0.05) in the activities of these inflammatory and hepatic injury markers.

Conclusion Cysteamine mitigate IRI by enhancing intracellular antioxidant defense system, inhibiting inflammatory mediators and intestinal tissue expression of pro-apoptotic protein.

Key words

Detorsion - cytokines - apoptosis - hepatic injury - terminal ileum - mesenteric artery - cysteamine antioxidants

Publikationsverlauf

Eingereicht: 17. September 2022

Angenommen: 28. Oktober 2022

Artikel online veröffentlicht:
27. Dezember 2022

• References

• 1 Edwards M, Sidebotham D, Smith M. et al. Diagnosis and outcome from suspected mesenteric ischaemia following cardiac surgery. Anaesth Intensive Care 2005; 33: 210Y217
• 2 Ozturk H, Terzi EH, Ozgen U. et al. Lithospermic acid and ischemia/reperfusion injury of the rat small intestine prevention. Adv Clin Exp Med 2012; 21: 433-439
• 3 Karaguzel E, Kadihasanoglu M, Kutlu O. Mechanisms of testicular torsion and potential protective agents. Nat Rev Urol 2014; 11: 391-399
• 4 Ozkisacik S, Yazici M, Gursoy H. et al. Does gradual detorsion protect the ovary against ischemia-reperfusion injury in rats?. Pediatr Surg Int 2014; 30: 437-440
• 5 Jian J, Xuan F, Qin F. et al. The antioxidant, anti-inflammatory and antiapoptotic activities of the bauhinia championii flavon are connected with protection against myocardial/ischemia reperfusion injury. Cell Physiol Bio-chem 2016; 38: 1365-1375
• 6 Ozturk H, Buyukbayram H, Ozdemir E. The effects of nitric oxide on the expression of cell adhesion molecules (ICAM-1, UEA-1, and tenascin) in rats with unilateral testicular torsion. J Pediatr Surg 2003; 38: 1621-1627
• 7 Savas C, Ozogul C, Karaoz E. et al. Splenectomy reduces remote organ damage after intestinal ischemia-reperfusion injury. Acta Chir Beg 2003; 103: 315-320
• 8 Hsieh YH, McCartney K, Moore TA. et al. Intestinal ischemia reperfusion injury leads to inflammatory change brain 2011; Vol. 36 pp. 424Y430
• 9 Kozhura VL, Basarab DA, Golubev AM. Reperfusion injury after critical intestinal ischemia and its correction with perfluorochemical emulsion. World J Gastroenterol 2005; 11: 7084-7090
• 10 Gallego-Villar L, Hannibal L, Häberle J. Cysteamine revisited: repair of arginine to cysteine mutations. J Inherit Metab Dis 2017; 40: 555-567
• 11 Guha S, Konkwo C, Lavorato M. Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease. Hum Mol Genet 2019; 28: 1837-1852
• 12 Elmonem MA, Veys KRP, Prencipe G. Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies. Cells. 2022; 11: 190
• 13 Ames EG, Thoene JG. Programmed Cell Death in Cystinosis. Cells 2022; 11: 670
• 14 Moradin N, Torre S, Gauthier S. Cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malaria. Malar J 2016; 15: 260
• 15 Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013; 122: 3892-3898
• 16 Oladele A, Babatunde A, Temidayo O. et al. Cysteamine mitigate Testicular Torsion/Detorsion-Induced reperfusion injury via inhibition of apoptosis, oxidative stress and inflammatory responses in experimental rat model. Andrologia 2021; 2021: e14243
• 17 Afolabi OA, Akhigbe TM, Akhigbe RE. et al. Methanolic Moringa oleifera leaf extract protects against epithelial barrier damage and enteric bacterial translocation in intestinal I/R: Possible role of caspase 3. Front Pharmacol 2022; 13: 989023
• 18 Alabi B, Omobowale T, Badejo J. et al. Protective effects and chemical composition of Corchorus olitorius leaf fractions against isoproterenol-induced myocardial injury through p65NFkB-dependent anti-apoptotic pathway in rats. J Basic Clin Physiol Pharmacol 2020; 31
• 19 Masella R, Di Benedetto R, Vari R. et al. Novel mechanisms of natural antioxidant compounds in biological system: involvement of glutathione and glutathione- related enzyme. J Nutri Biochem 2005; 16: 577-586
• 20 Luciani DS, White SA, Widenmaier SB. et al. Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ßcells. Diabete 2013; 62: 170-182
• 21 Chenguang F, Jusan Y, Engelhardtz F. Temporal pattern of NFκB activation influences apoptotic cell fate in a stimuli-dependent fashion. J CellSci 2002; 115: 4843-4853
• 22 Omobowale TO. Preconditioning with Azadirachta indica ameliorates cardiorenal dysfunction through reduction in oxidative stress and extracellular signal regulated protein kinase signalling. J Ayurveda Integr Med 2016;
• 23 Crinelli R, Zara C, Smietana M. et al. Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine. Nutrients 2019; 11: 1291
• 24 Forman HJ, Zhang H, Rinna A. Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol Asp Med 2009; 30: 1-12
• 25 Wang Y, Yang J, Yi J. Redox sensing by proteins: Oxidative modifications on cysteines and the consequent events. Antioxid Redox Signal 2012; 16: 649-657
• 26 Dinkova-Kostova AT. The Role of Sulfhydryl Reactivity of Small Molecules for the Activation of the KEAP1/NRF2 Pathway and the Heat Shock Response. Scientifica (Cairo) 2012; 2012: 606104
• 27 Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious disease. Frontiers in Immunology 2014; 5: 491-491
• 28 Griffin GK, Newton G, Tarrio ML. et al. IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol 2012; 188: 6287-6299
• 29 Hsieh YH, McCartney K, Moore TA. et al. Intestinal ischemia reperfusion injury leads to inflammatory change brain 2011; Vol. 36 pp. 424Y430
• 30 Wéra O, Lancellotti P, Oury C. The Dual Role of Neutrophils in Inflammatory Bowel Diseases. J Clin Med 2016; 5: 118
• 31 Ulfig A, Leichert LI. The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens. Cell Mol Life Sci 2021; 78: 385-414
• 32 Lin YW, Chen TY, Hung CY. et al. Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress. Int. J. Mol. Med. 2018; 42: 182-192
• 33 Zhou H, Zhu J, Yue S. et al. The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury. Transplantation 2016; 100: 365-372
• 34 Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta Mol Cell Res 2016; 1863: 2977-2992
• 35 Benhar M. Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways. Antioxidants (Basel) 2020; 9: 309
• 36 Allen EM, Mieyal JJ. Protein-thiol oxidation and cell death: regulatory role of glutaredoxins. Antioxid Redox Signal 2012; 17: 1748-1763
• 37 Hartmann RenataMinuzzo, Licks Francielli, Schemitt ElizângelaGonçalves. et al. Effect of glutamine on liver injuries induced by intestinal ischemia-reperfusion in rats. Nutr Hosp 2017; 34: 540-547