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Objective <p><i>Strychnos nuxvomica</i> L. <i>(S. nuxvomica)</i> is a well-known poisonous medicinal plant that is listed under Schedule E (1) of Drugs and Cosmetics Act, with strict regulations on its use due&#xa0;to its toxicity. Despite its inherent toxicity, it has been widely utilized in traditional medicine after <i>Shodhana</i>, a detoxification process which reduces toxicity and retains therapeutic potency. However, its toxicity profiling post <i>Shodhana</i> remains unexplored. This study aims to generate toxicological profile of <i>Strychnos nuxvomica</i> through 28-day repeated-dose toxicity study, evaluate the effects of <i>Shodhana</i>, and predict its toxicity mechanisms using computational tools.</p> Methods <p>Seeds were detoxified using <i>Shodhana</i>, then extracted via cold maceration, with their composition analyzed by LCMS. Acute (OECD 423) and 28-day repeated-dose toxicity (OECD 407) studies were conducted and parameters evaluated as per guidelines. Computational analysis of identified targets and toxicity pathways were conducted using molecular docking and dynamics to predict the underlying molecular mechanisms.</p> Results <p>In 28-day repeated-dose toxicity tests, Ashodhita <i>S. nuxvomica</i> 15&#xa0;mg/kg led to significant adverse effects, including altered body weight, feed consumption, organ weights, hematological, biochemical parameters, and clinical signs. Histology report confirmed the neurotoxicity and hepatotoxicity in Ashodhita <i>S. nuxvomica</i> 15&#xa0;mg/kg. In contrast, the Shodhita <i>S. nuxvomica</i> extract exhibited abnormalities only in hematology and biochemistry. In silico analysis revealed that strychnine and brucine contribute to toxicity by modulating NFKB1, influencing key pathways such as TNF, neurotrophin, cAMP, PI3K-AKT, and IL-17 signaling.</p> Conclusion <p>A comprehensive analysis of clinical signs, body weight, feed consumption, FOB tests, clinical pathology, and histology suggests that the NOAEL is lower than the tested doses of Shodhita <i>S. nuxvomica</i> (SSNV) and Ashodhita <i>S. nuxvomica</i> (ASNV). NFKB1 and NTRK3 were identified as key mediators of toxicity, disrupting NF-κB and neurotrophin pathways, potentially explaining the observed effects.</p>

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Mechanistic insights into the toxicity of Strychnos nuxvomica L. seeds: Shodhana detoxification, 28-day repeated-dose toxicity and computational studies

  • 期刊论文

  • 发表日期：

    2025年6月1日

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  • Shamanand P. Mallapur,
  • Banappa S. Unger,
  • Mruthyunjay B. Patil,
  • Akshay Shamnewadi,
  • Vishal S. Patil,
  • Veerkumar P. Japti

摘要

Objective

Strychnos nuxvomica L. (S. nuxvomica) is a well-known poisonous medicinal plant that is listed under Schedule E (1) of Drugs and Cosmetics Act, with strict regulations on its use due to its toxicity. Despite its inherent toxicity, it has been widely utilized in traditional medicine after Shodhana, a detoxification process which reduces toxicity and retains therapeutic potency. However, its toxicity profiling post Shodhana remains unexplored. This study aims to generate toxicological profile of Strychnos nuxvomica through 28-day repeated-dose toxicity study, evaluate the effects of Shodhana, and predict its toxicity mechanisms using computational tools.

Methods

Seeds were detoxified using Shodhana, then extracted via cold maceration, with their composition analyzed by LCMS. Acute (OECD 423) and 28-day repeated-dose toxicity (OECD 407) studies were conducted and parameters evaluated as per guidelines. Computational analysis of identified targets and toxicity pathways were conducted using molecular docking and dynamics to predict the underlying molecular mechanisms.

Results

In 28-day repeated-dose toxicity tests, Ashodhita S. nuxvomica 15 mg/kg led to significant adverse effects, including altered body weight, feed consumption, organ weights, hematological, biochemical parameters, and clinical signs. Histology report confirmed the neurotoxicity and hepatotoxicity in Ashodhita S. nuxvomica 15 mg/kg. In contrast, the Shodhita S. nuxvomica extract exhibited abnormalities only in hematology and biochemistry. In silico analysis revealed that strychnine and brucine contribute to toxicity by modulating NFKB1, influencing key pathways such as TNF, neurotrophin, cAMP, PI3K-AKT, and IL-17 signaling.

Conclusion

A comprehensive analysis of clinical signs, body weight, feed consumption, FOB tests, clinical pathology, and histology suggests that the NOAEL is lower than the tested doses of Shodhita S. nuxvomica (SSNV) and Ashodhita S. nuxvomica (ASNV). NFKB1 and NTRK3 were identified as key mediators of toxicity, disrupting NF-κB and neurotrophin pathways, potentially explaining the observed effects.