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Background <p>Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via <i>in silico</i> and <i>in vivo</i> studies for repurposing against AD.</p> Methodology <p><i>In silico</i> analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5&#xa0;mg/kg and 10&#xa0;mg/Kg, <i>p.o.</i>) for 14&#xa0;days in lipopolysaccharide-induced neuroinflammatory (250&#xa0;µg/Kg, <i>i.p.</i>) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl’s staining.</p> Results <p>Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (<i>p</i> &lt; 0.001), reduced AChE level (<i>p</i> &lt; 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (<i>p</i> &lt; 0.0001), and preserved hippocampal neuronal structure.</p> Conclusion <p>The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.</p> Graphical abstract <p></p> <p>Neuroinflammation mediated repurposing of clemastine for Alzheimer’s disease using <i>in silico</i> (network pharmacology, molecular docking, and dynamics) and <i>in vivo</i> (rat model-based) experimental studies.</p>

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Neuroinflammation mediated repurposing of clemastine for Alzheimer’s disease through network pharmacology, molecular dynamics, and experimental validation studies

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Simran Soni,
  • Sinjini Sarkar,
  • Pratigya Tripathi,
  • Satyamvada Maurya,
  • Ginpreet Kaur,
  • Shafiul Haque

摘要

Background

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via in silico and in vivo studies for repurposing against AD.

Methodology

In silico analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5 mg/kg and 10 mg/Kg, p.o.) for 14 days in lipopolysaccharide-induced neuroinflammatory (250 µg/Kg, i.p.) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl’s staining.

Results

Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (p < 0.001), reduced AChE level (p < 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (p < 0.0001), and preserved hippocampal neuronal structure.

Conclusion

The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.

Graphical abstract

Neuroinflammation mediated repurposing of clemastine for Alzheimer’s disease using in silico (network pharmacology, molecular docking, and dynamics) and in vivo (rat model-based) experimental studies.