Synergistic protective activity of sodium hydrosulfide and L-arginine against cisplatin-induced nephrotoxicity, even during nitric oxide synthase inhibition

Faria Khurshid; Javeid Iqbal; Fiaz-Ud-Din Ahmad; Sana Javaid; Almas Kanwal; Abdul Malik; Suhail Akhtar; Marvi Imam Bux; Zainab Ahmad; Nikhat J Siddiqui; Robert D E Sewell

doi:10.1016/j.jpet.2025.103618

Synergistic protective activity of sodium hydrosulfide and L-arginine against cisplatin-induced nephrotoxicity, even during nitric oxide synthase inhibition

J Pharmacol Exp Ther. 2025 May 27;392(7):103618. doi: 10.1016/j.jpet.2025.103618. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, University of Balochistan, Quetta, Pakistan. Electronic address: faria.pharm@um.uob.edu.pk.
² Department of Pharmacology, Faculty of Pharmacy, University of Balochistan, Quetta, Pakistan.
³ Department of Pharmacology, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan.
⁴ Department of Pharmacy, The Women University, Multan, Pakistan.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Balochistan, Quetta, Pakistan.
⁶ Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁷ Department of Biochemistry, A.T. Still University of Health Sciences, Kirksville, Missouri.
⁸ Department of Internal Surgical Nursing, College of Nursing, King Saud University, Riyadh, Saudi Arabia.
⁹ Department of Pharmacy, CECOS University, Peshawar, Pakistan; Department of Pharmacy, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.

PMID: 40602357
DOI: 10.1016/j.jpet.2025.103618

Abstract

Cisplatin is a chemotherapeutic drug that induces nephrotoxicity through inflammation and oxidative stress. Hydrogen sulfide (H₂S) and nitric oxide (NO) are gaseous signaling molecules with cytoprotective potential in renal damage. The current study evaluated the nephroprotective potential of sodium hydrosulfide (NaHS), an H₂S donor, and L-arginine, a NO precursor, against cisplatin-induced nephrotoxicity, even under NO synthase inhibition. Wistar rats were treated with cisplatin (5 mg/kg) to induce nephrotoxicity while administered with L-N^G-nitro-L-arginine methyl (L-NAME), NaHS, and L-arginine either alone or in combination for 28 days. Renal function was assessed by monitoring various parameters, including body weight and urinary flow. Moreover, H₂S, NO, creatinine level and clearance, blood urea nitrogen (BUN), electrolyte levels, and oxidative stress were monitored in body fluids. The findings revealed that L-NAME exacerbated cisplatin-induced nephrotoxicity, which was evident from reduced weights (P < .0001) and elevated urine output (P < .01), H₂S (P < .0001), NO (P < .0001), creatinine (P < .01), and BUN (P < .0001) levels, along with reduced sodium and potassium (P < .0001) and elevated oxidative stress markers (P < .001) in plasma compared with healthy rats. The treatment with NaHS and L-arginine markedly protected against L-NAME + cisplatin-induced nephrotoxicity as the parameters were reinstated, including urine output (P < .01), H₂S (P < .01), NO (P < .0001), creatinine (P < .05), and BUN (P < .01) levels compared with L-NAME + cisplatin rats. Moreover, coadministration of NaHS + L-arginine restored the sodium (P < .0001) and potassium (P < .01) levels in plasma and mitigated oxidative stress (P < .05). The results suggested that H₂S and NO mitigated L-NAME + cisplatin-induced nephrotoxicity by ameliorating the L-NAME + cisplatin-induced oxidative stress. SIGNIFICANCE STATEMENT: The therapeutic validation of the mentioned agents would be beneficial in the treatment of renal dysfunction.

Keywords: Cisplatin-induced nephrotoxicity; L-NAME; L-arginine; Nitric oxide; Oxidative stress.