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

Amir Mohamed Abdelhamid; Mahmoud E Youssef; Simona Cavalu; Gomaa Mostafa-Hedeab; Amal Youssef; Sara T Elazab; Samar Ibrahim; Shady Allam; Rehab Mohamed Elgharabawy; Eman El-Ahwany; Noha A Amin; Ahmed Shata; Osama A Mohammed; Mahmoud Said Ibrahim Abdeldaiem; Ahmed Alhowail; Gaber El-Saber Batiha; Engy A El-Mahmoudy; Maram Attia; Alaa Allam; Mona Y Zaater; Mona M Osman; Manar Nader; Aya Taha; Nada Abul Makarem; Sameh Saber

doi:10.3389/fphar.2022.887233

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

Front Pharmacol. 2022 Jun 8:13:887233. doi: 10.3389/fphar.2022.887233. eCollection 2022.

Authors

Amir Mohamed Abdelhamid¹, Mahmoud E Youssef¹, Simona Cavalu², Gomaa Mostafa-Hedeab^{3

4}, Amal Youssef⁵, Sara T Elazab⁶, Samar Ibrahim⁷, Shady Allam⁸, Rehab Mohamed Elgharabawy⁹, Eman El-Ahwany¹⁰, Noha A Amin¹¹, Ahmed Shata^{12

13}, Osama A Mohammed^{14

15}, Mahmoud Said Ibrahim Abdeldaiem^{16

17}, Ahmed Alhowail¹⁸, Gaber El-Saber Batiha¹⁹, Engy A El-Mahmoudy²⁰, Maram Attia²⁰, Alaa Allam²⁰, Mona Y Zaater²⁰, Mona M Osman²⁰, Manar Nader²⁰, Aya Taha²⁰, Nada Abul Makarem²⁰, Sameh Saber¹

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
² Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania.
³ Pharmacology Department and Health Research Unit, Medical College, Jouf University, Sakakah, Saudi Arabia.
⁴ Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt.
⁵ Medical Pharmacology Department, Faculty of Medicine, Cairo University, Giza, Egypt.
⁶ Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
⁷ Department of Pharmacy Practice, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
⁸ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.
⁹ Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
¹⁰ Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt.
¹¹ Department of Haematology, Theodor Bilharz Research Institute, Giza, Egypt.
¹² Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
¹³ Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
¹⁴ Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
¹⁵ Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha, Saudi Arabia.
¹⁶ Clinical Pharmacy Department, School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town, Malaysia.
¹⁷ Pharmacy Practice Department, Faculty of Pharmacy, Sinai University, Ismailia, Egypt.
¹⁸ Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia.
¹⁹ Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
²⁰ Department of Biochemistry, 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.

Keywords: NFκB; Nrf2/HO-1; acetic acid; carbocisteine; colitis; repositioning.

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.