Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abdelhamid A.M.; Youssef M.E.; Cavalu S.; Mostafa-Hedeab G.; Youssef A.; Elazab S.T.; Ibrahim S.; Allam S.; Elgharabawy R.M.; El-Ahwany E.; Amin N.A.; Shata A.; Mohammed O.A.; Ibrahim Abdeldaiem M.S.; Alhowail A.; El-Saber Batiha G.; El-Mahmoudy E.A.; Attia M.; Allam A.; Zaater M.Y.; Osman M.M.; Nader M.; Taha A.; Makarem N.A.; Saber S.

Journal: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

Publication Date: 8 June 2022

Volume / Issue: Volume 13

Article No.: 887233

ISSN: 16639812

DOI: 10.3389/fphar.2022.887233

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Cavalu S., Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania; Mostafa-Hedeab G., Pharmacology Department and Health Research Unit, Medical College, Jouf University, Sakakah, Saudi Arabia, Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt; Youssef A., Medical Pharmacology Department, Faculty of Medicine, Cairo University, Giza, Egypt; Elazab S.T., Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; Ibrahim S., Department of Pharmacy Practice, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt; Allam S., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt; Elgharabawy R.M., Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Haematology, Theodor Bilharz Research Institute, Giza, Egypt; Shata A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Mohammed O.A., Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt, Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha, Saudi Arabia; Ibrahim Abdeldaiem M.S., Clinical Pharmacy Department, School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town, Malaysia, Pharmacy Practice Department, Faculty of Pharmacy, Sinai University, Ismailia, Egypt; Alhowail A., Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia; El-Saber Batiha G., Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt; El-Mahmoudy E.A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Attia M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Allam A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Zaater M.Y., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Osman M.M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Nader M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Taha A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Makarem N.A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC. Copyright © 2022 Abdelhamid, Youssef, Cavalu, Mostafa-Hedeab, Youssef, Elazab, Ibrahim, Allam, Elgharabawy, El-Ahwany, Amin, Shata, Mohammed, Ibrahim Abdeldaiem, Alhowail, El-Saber Batiha, El-Mahmoudy, Attia, Allam, Zaater, Osman, Nader, Taha, Makarem and Saber.

Keywords

acetic acid; carbocisteine; colitis; NFκB; Nrf2/HO-1; repositioning; catalase; heme oxygenase 1; immunoglobulin enhancer binding protein; interleukin 10; interleukin 6; myeloperoxidase; protein Bax; protein bcl 2; transcription factor Nrf2; tumor necrosis factor; adult; animal cell; animal experiment; animal model; animal tissue; antiapoptotic activity; antiinflammatory activity; antioxidant activity; Article; coloprotective activity; controlled study; disease activity; down regulation; drug activity; drug repositioning; drug response; enzyme activity; enzyme inhibition; histopathology; inflammation; leukocyte activation; male; neutrophil chemotaxis; nonhuman; oxidative stress; protein expression; rat; ulcerative colitis; upregulation

Citation Information

Scopus Citations: 39

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