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<p>Epilepsy is a chronic neurological disorder that causes disturbances in the electrical activity, leading to neuronal excitability and damage, resulting in a global burden. In the present situation, the treatment of epilepsy focuses on the development of biomarkers and new antiepileptic drug candidates for enhanced diagnosis and treatment. This study aims to determine the potential therapeutic efficacy of salicylhydroxamic acid (SHA) as an antiepileptic candidate through in silico genomic profiling, molecular docking, pharmacokinetic analysis, and in vivo studies using a pentylenetetrazole (PTZ)-induced zebrafish model. Genomic analysis of the GEO database helped to explore the differentially expressed genes and pathways interlinked to the epilepsy. Molegro Molecular Viewer, Avogadro, and AutoDock tools were used to perform the docking studies to predict the binding affinity between the target receptors and hydroxamic acid derivatives. The pharmacokinetic and toxicity profile of SHA was estimated using the SwissADME tool. In vivo analysis was performed using PTZ-induced adult zebrafish treated with low, medium, and high doses of SHA. Seizure behavior was recorded using a 3-stage scale. The histopathological examination of the hippocampal region was carried out to assess the neuroprotective action. The expression of c-FOS/HDAC-related genes was quantified using RT-PCR. Genomic analysis established the pathways linked to the neurotransmitter regulation, histone deacetylase (HDAC) pathways, and inflammatory pathways, corroborating therapeutic implications. Molecular docking studies highlighted that SHA yielded greater binding affinity to the associated targets, surmounting the standard phenytoin and other hydroxamic derivatives. Pharmacokinetic parameters were assessed using the SwissADME tool, which proved good drug-likeness, blood-brain barrier permeability, and minimal toxicity risks. The in vivo analysis resulted in SHA producing a dose-dependent response in seizure suppression, increasing latency, reducing convulsive duration, and improving recovery, with chronic (14-day) administration showing improved stabilization. The histopathological analysis of the hippocampal region revealed a reduction in neuronal degeneration, decreased gliosis, and preserved tissue architecture in SHA-treated groups relative to PTZ controls. RT-PCR analysis showed that SHA treatment significantly reduced the expression of c-FOS and HDAC-associated genes, which supports its molecular neuroprotective effects. This multidimensional approach signifies that SHA imposes anticonvulsant and neuroprotective activity, altering HDAC signaling, neuronal excitability, and seizure-associated gene expression, potentially making it a novel therapeutic candidate for treating epilepsy.</p>

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Antiepileptic potential of salicylhydroxamic acid: genomic, molecular docking, and functional evaluations in pentylenetetrazole-induced adult zebrafish

  • 期刊论文

  • 发表日期：

    2026年7月4日

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  • V. Devi Chaaru Dheeraja,
  • G. Aayushi,
  • J. Praveen Neniwal,
  • M. Arjun Gokulan,
  • Tamilanban Thamaraikani,
  • V. Chitra,
  • J. Narayanan,
  • Suresh V. Chinni,
  • Subash C. B. Gopinath

摘要

Epilepsy is a chronic neurological disorder that causes disturbances in the electrical activity, leading to neuronal excitability and damage, resulting in a global burden. In the present situation, the treatment of epilepsy focuses on the development of biomarkers and new antiepileptic drug candidates for enhanced diagnosis and treatment. This study aims to determine the potential therapeutic efficacy of salicylhydroxamic acid (SHA) as an antiepileptic candidate through in silico genomic profiling, molecular docking, pharmacokinetic analysis, and in vivo studies using a pentylenetetrazole (PTZ)-induced zebrafish model. Genomic analysis of the GEO database helped to explore the differentially expressed genes and pathways interlinked to the epilepsy. Molegro Molecular Viewer, Avogadro, and AutoDock tools were used to perform the docking studies to predict the binding affinity between the target receptors and hydroxamic acid derivatives. The pharmacokinetic and toxicity profile of SHA was estimated using the SwissADME tool. In vivo analysis was performed using PTZ-induced adult zebrafish treated with low, medium, and high doses of SHA. Seizure behavior was recorded using a 3-stage scale. The histopathological examination of the hippocampal region was carried out to assess the neuroprotective action. The expression of c-FOS/HDAC-related genes was quantified using RT-PCR. Genomic analysis established the pathways linked to the neurotransmitter regulation, histone deacetylase (HDAC) pathways, and inflammatory pathways, corroborating therapeutic implications. Molecular docking studies highlighted that SHA yielded greater binding affinity to the associated targets, surmounting the standard phenytoin and other hydroxamic derivatives. Pharmacokinetic parameters were assessed using the SwissADME tool, which proved good drug-likeness, blood-brain barrier permeability, and minimal toxicity risks. The in vivo analysis resulted in SHA producing a dose-dependent response in seizure suppression, increasing latency, reducing convulsive duration, and improving recovery, with chronic (14-day) administration showing improved stabilization. The histopathological analysis of the hippocampal region revealed a reduction in neuronal degeneration, decreased gliosis, and preserved tissue architecture in SHA-treated groups relative to PTZ controls. RT-PCR analysis showed that SHA treatment significantly reduced the expression of c-FOS and HDAC-associated genes, which supports its molecular neuroprotective effects. This multidimensional approach signifies that SHA imposes anticonvulsant and neuroprotective activity, altering HDAC signaling, neuronal excitability, and seizure-associated gene expression, potentially making it a novel therapeutic candidate for treating epilepsy.