Protective effects of morin on colistin-induced neurotoxicity in rats via modulation of oxidative, inflammatory, apoptotic, and autophagic alterations

The increasing prevalence of multidrug-resistant Gram-negative bacterial infections, particularly in intensive care units, has led to the widespread use of colistin as a last-resort antibiotic. However, colistin is associated with severe side effects, including neurotoxicity, which manifests as oxidative stress, inflammation, apoptosis, and autophagy in brain tissues. This study aims to investigate the ameliorative effects of morin against colistininduced neurotoxicity in rats. A total of 35 male Sprague Dawley rats were divided into five groups: control, morin alone (100 mg/kg), colistin alone (15 mg/kg/day, administered intraperitoneally for 7 consecutive days), and colistin combined with morin at 50 mg/kg and 100 mg/kg doses. Colistin treatment significantly increased lipid peroxidation (MDA), inflammatory mediators (NF-kappa B, TNF-alpha, nNOS, and IL-1 beta), and pro-apoptotic markers (p53, Bax, caspase-3 and caspase-9) while reducing antioxidant defense system (SOD, CAT, GPx, and GSH) and anti-apoptotic marker (Bcl-2). Colistin also increased the mRNA transcript levels of endoplasmic reticulum stress parameters such as ATF-6, PERK, IRE-1, GRP78, and CHOP. Additionally, it upregulated autophagy-related markers (Beclin-1, LC3A, LC3B, Atg5, and Atg7) and downregulated the PI3K/Akt/mTOR signaling pathway. Morin treatment reversed these effects, reducing oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and autophagy in a dose-dependent manner. Histopathological analysis further confirmed the ameliorative role of morin in mitigating colistin-induced neuronal damage. This study is the first to demonstrate the ameliorative effects of morin against colistin-induced brain toxicity and provides insights into its molecular mechanisms. The findings suggest that morin may serve as a potential therapeutic agent for managing neurotoxicity associated with colistin and other oxidative stress-induced neurodegenerative disorders.

Journal

TISSUE & CELL

Year

2026

Volume

101

ISSN

0040-8166

DOI

10.1016/j.tice.2026.103420

WoS UID

WOS:001713053300001