Nrf2-Mediated Neuroprotection in Parkinson's Disease Models

Parkinson’s disease is characterised by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein, underpinned by oxidative stress, mitochondrial dysfunction and neuroinflammation. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) has emerged as a master regulator of the endogenous antioxidant defence, orchestrating the expression of genes harbouring the antioxidant response element (ARE) such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 and glutamate-cysteine ligase. In preclinical models, genetic enhancement of Nrf2 or pharmacological compounds that disrupt the Nrf2–Keap1 interaction deliver robust protection to dopaminergic neurones, attenuate microglial activation and preserve mitochondrial integrity. Beyond redox balance, Nrf2 signalling intersects with mitochondrial quality control pathways and anti-inflammatory cascades, thereby offering a multi-modal approach to halt neurodegeneration. The field aims to translate these findings into disease-modifying therapies by optimising blood–brain barrier penetration, selectivity and sustained Nrf2 activation without eliciting off-target effects.

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Nrf2-Mediated Neuroprotection in Parkinson's Disease Models publication trend

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Technical terms

Nuclear factor erythroid 2–related factor 2 (Nrf2): a transcription factor that, upon release from its inhibitor Keap1, translocates to the nucleus to initiate antioxidant gene expression. Antioxidant response element (ARE): DNA sequence in the promoter region of cytoprotective genes recognised by Nrf2. Oxidative stress: a state in which the generation of reactive oxygen species exceeds the capacity of cellular antioxidant defences. Dopaminergic neurons: nerve cells that synthesise and release dopamine; their degeneration is central to Parkinson’s disease. Neuroinflammation: activation of glial cells (microglia and astrocytes) and associated release of pro-inflammatory mediators within the central nervous system.

References

1. Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease. npj Parkinson's Disease (2023).
2. Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson’s disease. Biomedicine & Pharmacotherapy (2023).
3. Chinese medicine PaBing-II protects human iPSC-derived dopaminergic neurons from oxidative stress. Frontiers in Immunology (2024).
4. Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease. Frontiers in Pharmacology (2021).
5. The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson′s Disease. Parkinson's Disease (2011).
6. Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson’s disease. Disease Models & Mechanisms (2011).