Resveratrol mitigates TOCP-induced spinal cord neurotoxicity by suppressing ferroptosis, a process mediated through the p62/Keap1/Nrf2 pathway

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2026-02-01 Epub Date: 2025-12-29 DOI:10.1016/j.taap.2025.117698

Sangping Li, Shule Tan, Xiangsheng Tian, Yiquan Ou, Shujuan Hu, Weichao Zhao, Dingxin Long

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Abstract

This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe²⁺ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.

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白藜芦醇通过抑制p62/Keap1/Nrf2通路介导的铁凋亡来减轻tocp诱导的脊髓神经毒性。

本研究研究了白藜芦醇（Res）对三o-甲酰磷酸（TOCP）诱导的成年母鸡脊髓神经毒性的保护作用，重点研究了其通过p62/Keap1/Nrf2通路对铁死亡的调节作用。白藜芦醇是一种经典的神经保护化合物，具有抗氧化特性和激活Nrf2的能力。将成年母鸡分为对照组、TOCP组、他汀铁素-1 （fer1）组、他汀铁素-1 + TOCP组、白藜芦醇组和白藜芦醇+ TOCP组。脊髓组织采用行为OPIDN评分、组织学（苏木精-伊红和尼氏染色）、生化分析和Western blotting检测p62/Keap1/ nrf2相关蛋白。TOCP暴露诱导了严重的超微结构损伤，包括髓鞘破坏和神经元变性，同时丙二醛（MDA）和Fe2+水平升高，谷胱甘肽（GSH）和超氧化物歧化酶（SOD）活性降低。Western blot分析显示NCOA4、ACSL4、Nrf2、P62和LC3 II表达上调，GPX4、SLC7A11、FTH1和Keap1表达下调。白藜芦醇治疗显著减轻了这些分子、生化和组织病理学改变，减轻了氧化应激和铁的变化。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.