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<p>The Kelch-like ECH-associated protein 1 (Keap1)–Nuclear factor E2-related factor 2 (Nrf2) pathway is integral to cellular defense mechanisms against oxidative and xenobiotic stress by neutralizing reactive oxygen species (ROS). An increase in ROS levels is a significant factor in the advancement of neurodegenerative diseases (NDDs). Consequently, the development of effective Keap1 inhibitors that disrupt the Keap1-Nrf2 interactions and subsequently enhance Nrf2’s transcriptional activity may represent promising therapeutic avenues for NDDs. Given that <i>Nardostachys jatamansi</i> (<i>N. jatamansi</i>), a medicinal plant, has shown potential as a treatment for Parkinson’s disease (PD), we sought to assess its influence on the Keap1-Nrf2 pathway. Our research demonstrates that the phytochemicals in the methanol extract of <i>N. jatamansi</i> can activate the Keap1–Nrf2–ARE signalling cascade. Computational analyses, including molecular docking and molecular dynamics simulations with AutoDock Vina and Desmond, respectively, revealed the binding properties of selected <i>N. jatamansi</i> compounds, of which 16 phytocompounds were confirmed in the methanol extract using LC/MS. In vitro assays demonstrated a dose-dependent interaction of the extract with both the BTB and β-propeller domains of Keap1, as well as inhibition of the BTB–Cullin3 interaction. The extract was assessed for its ability to protect N27 dopaminergic neurons from rotenone-induced neurotoxicity by activating the Nrf2-ARE pathway. It demonstrated dose-dependent ARE transactivation, suggesting Nrf2 dissociation from Keap1. Altogether, these observations indicate that phytocompounds derived from <i>N. jatamansi</i> offer significant potential for therapeutic or neuroprotective applications in Parkinson’s disease.</p>

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Neuroprotective Potential of Nardostachys jatamansi Extract via Keap1–Nrf2 Pathway Regulation in Parkinson’s Disease

  • 期刊论文

  • 发表日期：

    2026年7月14日

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  • Gopinatha Krishnappa,
  • Snehal Aouti,
  • Sreekumar Sreedevi,
  • Ashok Sridhar,
  • Kuppamuthu Murugesan,
  • Ramprasad Srinivasan,
  • Shridevi Gothe,
  • Subramanya Kumar,
  • Kuppan Gokulakrishnan,
  • M. M. Srinivas Bharath,
  • Saravanamuthu Thiyagarajan,
  • Balasundaram Padmanabhan

摘要

The Kelch-like ECH-associated protein 1 (Keap1)–Nuclear factor E2-related factor 2 (Nrf2) pathway is integral to cellular defense mechanisms against oxidative and xenobiotic stress by neutralizing reactive oxygen species (ROS). An increase in ROS levels is a significant factor in the advancement of neurodegenerative diseases (NDDs). Consequently, the development of effective Keap1 inhibitors that disrupt the Keap1-Nrf2 interactions and subsequently enhance Nrf2’s transcriptional activity may represent promising therapeutic avenues for NDDs. Given that Nardostachys jatamansi (N. jatamansi), a medicinal plant, has shown potential as a treatment for Parkinson’s disease (PD), we sought to assess its influence on the Keap1-Nrf2 pathway. Our research demonstrates that the phytochemicals in the methanol extract of N. jatamansi can activate the Keap1–Nrf2–ARE signalling cascade. Computational analyses, including molecular docking and molecular dynamics simulations with AutoDock Vina and Desmond, respectively, revealed the binding properties of selected N. jatamansi compounds, of which 16 phytocompounds were confirmed in the methanol extract using LC/MS. In vitro assays demonstrated a dose-dependent interaction of the extract with both the BTB and β-propeller domains of Keap1, as well as inhibition of the BTB–Cullin3 interaction. The extract was assessed for its ability to protect N27 dopaminergic neurons from rotenone-induced neurotoxicity by activating the Nrf2-ARE pathway. It demonstrated dose-dependent ARE transactivation, suggesting Nrf2 dissociation from Keap1. Altogether, these observations indicate that phytocompounds derived from N. jatamansi offer significant potential for therapeutic or neuroprotective applications in Parkinson’s disease.