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Troglitazone as a Novel Nrf2 Activator to Attenuate Oxidative Stress and Exert Neuroprotection

Linjie Zhang1, Shuang Wang2, Yanxia Zhang3

  • 1State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.

ACS Chemical Neuroscience
|March 26, 2025
PubMed

Insights

Troglitazone activates the Nrf2 pathway, offering a new therapeutic strategy for neurodegenerative diseases. This diabetes drug shows promise in protecting neurons and improving motor function in preclinical models.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Nuclear factor erythroid 2 related factor 2 (Nrf2) pathway is crucial in combating oxidative stress implicated in neurodegenerative diseases.
  • Activation of antioxidant response elements (AREs) via Nrf2 is a validated therapeutic strategy for neurodegeneration.

Purpose of the Study:

  • To investigate troglitazone, a diabetes medication, as a potential Nrf2 activator for treating neurodegenerative conditions.
  • To elucidate the mechanism of troglitazone's action on the Nrf2 pathway and its therapeutic efficacy.

Main Methods:

  • In vitro studies using PC12 cells exposed to oxidative stress (H2O2, 6-OHDA).
  • In vivo studies utilizing a zebrafish model of neurodegeneration induced by 6-OHDA.
  • Assessment of neuronal damage, motor activity, and neurodevelopmental outcomes.
  • Mass spectrometry imaging to confirm blood-brain barrier penetration.

Main Results:

  • Troglitazone effectively alleviated oxidative stress in neuronal cells.
  • In vivo, troglitazone rescued motor activity and neurodevelopmental deficits in zebrafish.
  • Troglitazone demonstrated the ability to cross the blood-brain barrier in zebrafish models.

Conclusions:

  • Troglitazone acts as a novel Nrf2 activator by binding to Keap1, leading to Nrf2 nuclear translocation and ARE activation.
  • The findings support troglitazone's potential therapeutic value for neurodegenerative diseases.
  • This study provides a basis for repurposing troglitazone for neurological disorders.
Keywords:
6-hydroxydopamineNrf2Parkinson’s diseaseneuroprotectiontroglitazone

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