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Purpose <p>Ulcerative colitis is a chronic inflammatory disorder of the gastrointestinal tract often accompanied by extraintestinal complications, including neurobehavioral disturbances. This study aimed to evaluate the therapeutic potential of phenytoin in a rat model of acetic acid–induced colitis, with a focus on its anti-inflammatory effects and associated depression-like behavioral disturbances.</p> Methods <p>Forty male Wistar rats were randomly assigned to five groups (<i>n</i> = 8): Control, Acetic Acid (A.A), Phenytoin 30&#xa0;mg/kg (intraperitoneal) (Phe 30), A.A + Phe 30, and A.A + Phe 60. Colitis was induced using 3% acetic acid. Macroscopic and histological evaluations of the colon were performed. Hippocampal NF-κB expression, inflammatory cytokines (TNF-α, IL-6), and regulatory mediators associated with neuroinflammatory modulation (Sirt1, PGC1-α, NRF2, HO-1) were quantified. Behavioral performance was assessed using the tail suspension and forced swim tests, and locomotor activity was evaluated by the open field test.</p> Results <p>Phenytoin treatment was associated with attenuation of colitis severity, reduction of the colon weight-to-length ratio, and improvement of histopathological alterations. It was accompanied by decreased NF-κB, TNF-α, and IL-6 expression in the colon and hippocampus, as well as increased hippocampal Sirt1, PGC1-α, NRF2, and HO-1 levels. Behavioral testing showed reduced immobility time with no effect on locomotor activity.</p> Conclusion <p>Phenytoin administration was associated with attenuation of acetic acid–induced colitis and concurrent changes in hippocampal inflammatory markers, together with improved depression-like behavioral outcomes in rats. These observations suggest a potential modulatory effect of phenytoin on gut–brain axis–related neuroinflammation, which merits further investigation.</p>

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Phenytoin Attenuates Acetic Acid–induced Colitis and Neurobehavioral Disturbances via NF-κB Suppression and Sirt1/NRF2 Pathway Activation

  • 期刊论文

  • 发表日期：

    2026年2月27日

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  • Hani Alenaser,
  • Kaveh Rahimi,
  • Zohreh Ghotbeddin,
  • Annahita Rezaie

摘要

Purpose

Ulcerative colitis is a chronic inflammatory disorder of the gastrointestinal tract often accompanied by extraintestinal complications, including neurobehavioral disturbances. This study aimed to evaluate the therapeutic potential of phenytoin in a rat model of acetic acid–induced colitis, with a focus on its anti-inflammatory effects and associated depression-like behavioral disturbances.

Methods

Forty male Wistar rats were randomly assigned to five groups (n = 8): Control, Acetic Acid (A.A), Phenytoin 30 mg/kg (intraperitoneal) (Phe 30), A.A + Phe 30, and A.A + Phe 60. Colitis was induced using 3% acetic acid. Macroscopic and histological evaluations of the colon were performed. Hippocampal NF-κB expression, inflammatory cytokines (TNF-α, IL-6), and regulatory mediators associated with neuroinflammatory modulation (Sirt1, PGC1-α, NRF2, HO-1) were quantified. Behavioral performance was assessed using the tail suspension and forced swim tests, and locomotor activity was evaluated by the open field test.

Results

Phenytoin treatment was associated with attenuation of colitis severity, reduction of the colon weight-to-length ratio, and improvement of histopathological alterations. It was accompanied by decreased NF-κB, TNF-α, and IL-6 expression in the colon and hippocampus, as well as increased hippocampal Sirt1, PGC1-α, NRF2, and HO-1 levels. Behavioral testing showed reduced immobility time with no effect on locomotor activity.

Conclusion

Phenytoin administration was associated with attenuation of acetic acid–induced colitis and concurrent changes in hippocampal inflammatory markers, together with improved depression-like behavioral outcomes in rats. These observations suggest a potential modulatory effect of phenytoin on gut–brain axis–related neuroinflammation, which merits further investigation.