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<p>Dementia, characterized by cognitive decline and synaptic dysfunction, presents significant therapeutic challenges. This study explores the potential of SKT-36, a novel Dioxopiperidinamide (DOPA) derivative, in reversing scopolamine (SCP)-induced cognitive deficits in an in-vivo zebrafish model. SKT-36 exhibits high neuroprotective potential due to its inherent antioxidant and anti-inflammatory properties. Network pharmacology analysis revealed 637 intersecting targets linking SKT-36 with dementia-associated genes such as STAT3, GSK3B, and HSP90AB1 identified as key hubs. Molecular docking also confirmed highly favorable binding affinity of SKT-36 with <i>Danio rerio</i> of AChE, exhibited a binding energy of -6.58&#xa0;kcal/mol. For <i>in vivo</i> analysis, zebrafish were treated with SKT-36 at 10 µM and 7.5 µM, and the effects were assessed using neurobehavioral, biochemical, and gene expression studies. SKT-36 at 10 µM significantly enhanced locomotor activity, reduced anxiety-like behavior, and improved spatial and recognition memory, as shown by various behavioral tests. Biochemically, SKT-36 reduced oxidative stress markers and restored antioxidant enzyme activities. Also, superior acetylcholinesterase (AChE) inhibitory activity compared to standard treatments was seen suggesting effective cholinergic modulation. Gene expression analysis indicated SKT-36’s anti-inflammatory and neuroprotective effects, normalizing genes related to inflammation and neuronal plasticity. Histological analysis confirmed reduced neuronal damage and amyloid-beta plaque accumulation observed in the optic tectum regions. These findings highlight SKT-36 as a promising therapeutic agent for dementia, offering neuroprotective and cognitive benefits.</p>

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Dioxopiperidinamide Derivative SKT-36 Alleviates scopolamine-induced Cognitive and Neurobehavioral Impairments in an In-vivo Zebrafish Model

  • 期刊论文

  • 发表日期：

    2025年12月30日

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  • Sanjay Gopi,
  • S. Madesh,
  • Karthikeyan Ramamurthy,
  • S. Kaliraj,
  • Bader O. Almutairi,
  • Ki Choon Choi,
  • Ajay Guru,
  • Kathiravan Muthu Kumaradoss,
  • Jesu Arockiaraj

摘要

Dementia, characterized by cognitive decline and synaptic dysfunction, presents significant therapeutic challenges. This study explores the potential of SKT-36, a novel Dioxopiperidinamide (DOPA) derivative, in reversing scopolamine (SCP)-induced cognitive deficits in an in-vivo zebrafish model. SKT-36 exhibits high neuroprotective potential due to its inherent antioxidant and anti-inflammatory properties. Network pharmacology analysis revealed 637 intersecting targets linking SKT-36 with dementia-associated genes such as STAT3, GSK3B, and HSP90AB1 identified as key hubs. Molecular docking also confirmed highly favorable binding affinity of SKT-36 with Danio rerio of AChE, exhibited a binding energy of -6.58 kcal/mol. For in vivo analysis, zebrafish were treated with SKT-36 at 10 µM and 7.5 µM, and the effects were assessed using neurobehavioral, biochemical, and gene expression studies. SKT-36 at 10 µM significantly enhanced locomotor activity, reduced anxiety-like behavior, and improved spatial and recognition memory, as shown by various behavioral tests. Biochemically, SKT-36 reduced oxidative stress markers and restored antioxidant enzyme activities. Also, superior acetylcholinesterase (AChE) inhibitory activity compared to standard treatments was seen suggesting effective cholinergic modulation. Gene expression analysis indicated SKT-36’s anti-inflammatory and neuroprotective effects, normalizing genes related to inflammation and neuronal plasticity. Histological analysis confirmed reduced neuronal damage and amyloid-beta plaque accumulation observed in the optic tectum regions. These findings highlight SKT-36 as a promising therapeutic agent for dementia, offering neuroprotective and cognitive benefits.