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  3. The mechanism of alpha-lipoic acid regulating dopaminergic neuronal damage in Parkinson's disease through the Nrf2/HMOX1 pathway

The mechanism of alpha-lipoic acid regulating dopaminergic neuronal damage in Parkinson's disease through the Nrf2/HMOX1 pathway

  • Neurosci Lett. 2025 Aug 5:865:138338. doi: 10.1016/j.neulet.2025.138338.
Jingyu Wang 1,  Jing Hou 2,  Meixuan Du 3,  Xiaoli Hou 4,  Yixia Wang 3,  Hong Cheng 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Affiliated Hospital of Yangzhou University, Yangzhou 225000 Jiangsu, China; Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Institute of Translational Medicine, Yangzhou University, Yangzhou 225000 Jiangsu, China.
  • 2 Department of Clinical Laboratory, The Second People's Hospital of Huaian, Huaian 223000 Jiangsu, China.
  • 3 Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Institute of Translational Medicine, Yangzhou University, Yangzhou 225000 Jiangsu, China.
  • 4 Department of Medical Science, Yangzhou Polytechnic College, Yangzhou 225000 Jiangsu, China.
  • 5 Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Institute of Translational Medicine, Yangzhou University, Yangzhou 225000 Jiangsu, China. Electronic address: HongCheng0219@163.com.
PMID: 40763886 DOI: 10.1016/j.neulet.2025.138338
Abstract

Objective: Parkinson's disease (PD) is a neurodegenerative disorder distinguished by the progressive loss of dopaminergic neurons in the substantia nigra (SN). This study explored the mechanism by which alpha-lipoic acid (ALA) modulates dopaminergic neuronal damage via the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HMOX1) pathway.

Methods: A PD mouse model was established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by ALA and the Nrf2 inhibitor (ML385) treatment. Motor and cognitive functions were evaluated via behavioral tests. Tyrosine hydroxylase- and dopamine transporter-positive cells in SN, and the lipid peroxidation (LPO; DAT+BODIPY581/591 C11+) level in dopaminergic neurons were quantified by immunohistochemistry and immunofluorescence, respectively. Levels of glutathione, malondialdehyde, Fe2+, and Reactive Oxygen Species, and ferroptosis-related proteins, nuclear/cytoplasmic Nrf2, and HMOX1 expression were determined by kits and Western blot.

Results: MPTP reduced total movement distance, average movement speed, and platform crossings while increasing pole-climbing time, resting time, and escape latency of mice, confirming successful PD model establishment. PD mice exhibited elevated LPO, Fe2+, and Ferroptosis in dopaminergic neurons in SN, indicating dopaminergic neuronal Ferroptosis in SN of PD mice. ALA treatment reversed these effects, reducing dopaminergic neuronal Ferroptosis in SN and improving motor and cognitive functions of PD mice. Mechanistically, ALA activated the Nrf2/HMOX1 pathway by promoting Nrf2 nuclear translocation. The Nrf2/HMOX1 pathway inactivation promoted dopaminergic neuronal Ferroptosis in SN and partially reversed ALA's beneficial effects.

Conclusion: ALA regulates HMOX1 expression by facilitating Nrf2 nuclear translocation, thereby reducing Fe2+ accumulation, inhibiting dopaminergic neuronal Ferroptosis in SN, eventually alleviating motor, memory, and cognitive dysfunctions in PD mice.

Keywords

Alpha-lipoic acid; Dopaminergic neurons; Ferroptosis; Heme oxygenase-1; Lipid peroxidation; Nuclear factor erythroid-2-related factor 2; Parkinson’s disease; Substantia nigra.

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