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<p>Multiple sclerosis (MS) is a hypersensitivity reaction with increased inflammation, which leads to demyelination and neuronal degeneration. Currently, there are limited medications to improve the remyelination capacity. This study aimed to evaluate the neuroprotective and remyelinating potential of a novel sulfonamide derivative, KM11 [N-(7-hydroxy-1,3-benzothiazol-2-yl)-4-methylbenzene-1-sulfonamide], in ethidium bromide (EtBr)-induced demyelination models in zebrafish. KM11 was synthesised in the laboratory and tested using an integrated approach. SH-SY5Y cells treated with KM11 (10–200&#xa0;µM) were assessed for morphology, viability (MTT), and apoptosis (AO/PI staining). Furthermore, zebrafish embryos were evaluated for developmental toxicity. Larvae were pre-exposed to EtBr (75&#xa0;µM) through bath immersion and then treated with KM11 (50–100&#xa0;µM). The effects on oxidative stress (DCFDA), apoptosis (AO), and macrophage activation (neutral red) were evaluated. Adult zebrafish received EtBr (75&#xa0;µM) intramuscularly, followed by KM11 administration via oral gavage for 14&#xa0;days, and biochemical, histological, and gene expression analyses were performed. Results showed dose-dependent cytoprotection, with 100&#xa0;µM KM11 limited viability and reducing late apoptosis. Zebrafish embryos exhibited increased malformations at ≥ 150&#xa0;µM, but KM11 reduced EtBr-induced ROS, macrophage activation, and apoptosis. In adult zebrafish, KM11 restored AChE activity, reduced LDH and MPO levels, and downregulated <i>TNF-α</i>, <i>IL-1β</i>, <i>COX-2</i>, <i>NFKB1</i>, and <i>iNOS</i>. KM11 100&#xa0;µM restores the optical tectum structure and promotes remyelination on Luxol Fast Blue staining. These findings demonstrate KM11’s potent antioxidant, anti-inflammatory, and remyelinating activity, supporting its potential as a therapeutic candidate for MS. </p>

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Exploring the Neuroprotective Role of the Sulfonamide Derivative KM11 in Ethidium Bromide-induced Demyelination in Zebrafish Model Through Modulation of Antioxidant and Inflammatory Cytokine Pathways

  • 期刊论文

  • 发表日期：

    2025年12月20日

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  • Karthikeyan Ramamurthy,
  • Magesh Santhanakrishnan,
  • S. Madesh,
  • Prasannakumar Raja,
  • Senthilkumar Palaniappan,
  • Bader O. Almutairi,
  • Mikhlid H. Almutairi,
  • Muhammad Obaid M. Alotaibi,
  • Yahya Madkhali,
  • Manikandan Palanisamy,
  • Kathiravan Muthu Kumaradoss,
  • Jesu Arockiaraj

摘要

Multiple sclerosis (MS) is a hypersensitivity reaction with increased inflammation, which leads to demyelination and neuronal degeneration. Currently, there are limited medications to improve the remyelination capacity. This study aimed to evaluate the neuroprotective and remyelinating potential of a novel sulfonamide derivative, KM11 [N-(7-hydroxy-1,3-benzothiazol-2-yl)-4-methylbenzene-1-sulfonamide], in ethidium bromide (EtBr)-induced demyelination models in zebrafish. KM11 was synthesised in the laboratory and tested using an integrated approach. SH-SY5Y cells treated with KM11 (10–200 µM) were assessed for morphology, viability (MTT), and apoptosis (AO/PI staining). Furthermore, zebrafish embryos were evaluated for developmental toxicity. Larvae were pre-exposed to EtBr (75 µM) through bath immersion and then treated with KM11 (50–100 µM). The effects on oxidative stress (DCFDA), apoptosis (AO), and macrophage activation (neutral red) were evaluated. Adult zebrafish received EtBr (75 µM) intramuscularly, followed by KM11 administration via oral gavage for 14 days, and biochemical, histological, and gene expression analyses were performed. Results showed dose-dependent cytoprotection, with 100 µM KM11 limited viability and reducing late apoptosis. Zebrafish embryos exhibited increased malformations at ≥ 150 µM, but KM11 reduced EtBr-induced ROS, macrophage activation, and apoptosis. In adult zebrafish, KM11 restored AChE activity, reduced LDH and MPO levels, and downregulated TNF-α, IL-1β, COX-2, NFKB1, and iNOS. KM11 100 µM restores the optical tectum structure and promotes remyelination on Luxol Fast Blue staining. These findings demonstrate KM11’s potent antioxidant, anti-inflammatory, and remyelinating activity, supporting its potential as a therapeutic candidate for MS.