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<p>This study aimed to evaluate the neuroprotective effect of piperlongumine (PL), a natural alkaloid, on cisplatin-induced peripheral neuropathy (CIPN) in a mouse model, and to elucidate the possible underlying mechanisms involved in its action. In our study, ADMET of PL was done using pkCSM-predicted pharmacokinetic and toxicity properties like molecular weight, saturation, polarity, and solubility. Network pharmacology determined the primary targets and pathways connected to PL's anti-neuropathic actions. Molecular docking and dynamics simulations were performed to explore PL's binding affinity and stability with inflammation targets. CIPN was induced in mice using the standard chemotherapeutic agent cisplatin. PL was administered post-induction, and behavioral assessments were conducted to evaluate neuropathic pain (hot plate, tail flick, and cold allodynia tests). Histological analysis of the sciatic nerve and inflammatory cytokine levels was measured using blood serum. The ADMET study via pkCSM shows that PL molecules have good solubility, low toxicity, and follow Lipinski’s rule, making them promising for CIPN. Network pharmacology revealed that PL modulates key targets involved in the neuroinflammation pathway, such as MAPK1, the IL-17 pathway, and neuronal damage. Docking and MD simulations confirmed strong and stable interactions between PL and target proteins. In animal experiments, PL significantly alleviated thermal hyperalgesia and cold allodynia, downregulated TNF-α, IL-1β, and MAPK1. Histopathological analysis showed preserved axonal integrity and reduced inflammatory infiltration. By integrating network pharmacology with molecular dynamics and experimental validation, this study is the first to elucidate the specific molecular mechanism of piperlongumine (PL) in a mouse model of cisplatin-induced neuropathy. We identified and then confirmed that PL's neuroprotective effects are driven by its direct interaction with key inflammatory targets, primarily MAPK1 and IL-1β, leading to the suppression of the neuroinflammatory cascade.</p> Graphical Abstract <p></p>

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Mechanistic insights into piperlongumine’s neuroprotective role against cisplatin-induced neuropathy: a network pharmacology, molecular dynamics, and experimental approach

  • 期刊论文

  • 发表日期：

    2025年10月9日

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  • Riya Jana,
  • Sourav Ghosh,
  • Monosiz Rahaman,
  • Biswajit Basu,
  • Bhupendra Prajapati

摘要

This study aimed to evaluate the neuroprotective effect of piperlongumine (PL), a natural alkaloid, on cisplatin-induced peripheral neuropathy (CIPN) in a mouse model, and to elucidate the possible underlying mechanisms involved in its action. In our study, ADMET of PL was done using pkCSM-predicted pharmacokinetic and toxicity properties like molecular weight, saturation, polarity, and solubility. Network pharmacology determined the primary targets and pathways connected to PL's anti-neuropathic actions. Molecular docking and dynamics simulations were performed to explore PL's binding affinity and stability with inflammation targets. CIPN was induced in mice using the standard chemotherapeutic agent cisplatin. PL was administered post-induction, and behavioral assessments were conducted to evaluate neuropathic pain (hot plate, tail flick, and cold allodynia tests). Histological analysis of the sciatic nerve and inflammatory cytokine levels was measured using blood serum. The ADMET study via pkCSM shows that PL molecules have good solubility, low toxicity, and follow Lipinski’s rule, making them promising for CIPN. Network pharmacology revealed that PL modulates key targets involved in the neuroinflammation pathway, such as MAPK1, the IL-17 pathway, and neuronal damage. Docking and MD simulations confirmed strong and stable interactions between PL and target proteins. In animal experiments, PL significantly alleviated thermal hyperalgesia and cold allodynia, downregulated TNF-α, IL-1β, and MAPK1. Histopathological analysis showed preserved axonal integrity and reduced inflammatory infiltration. By integrating network pharmacology with molecular dynamics and experimental validation, this study is the first to elucidate the specific molecular mechanism of piperlongumine (PL) in a mouse model of cisplatin-induced neuropathy. We identified and then confirmed that PL's neuroprotective effects are driven by its direct interaction with key inflammatory targets, primarily MAPK1 and IL-1β, leading to the suppression of the neuroinflammatory cascade.

Graphical Abstract