Oxidative Stress and Neurodegeneration in Parkinson's Disease Models

Parkinson’s disease is characterised by progressive loss of dopaminergic neurons in the substantia nigra, the accumulation of misfolded proteins such as α-synuclein, and the emergence of motor and non-motor symptoms. A central driver of neuronal death in experimental models is oxidative stress, arising when reactive oxygen species overwhelm endogenous antioxidant defences. Mitochondrial dysfunction, in particular inhibition of complex I, elevates free radical production, impairs ATP synthesis and triggers lipid peroxidation, protein oxidation and DNA damage. In tandem, glial activation and neuroinflammation exacerbate neuronal vulnerability. Animal and cellular systems employing toxins such as rotenone or genetic perturbations recapitulate key pathological features, from nigrostriatal degeneration to behavioural deficits. Recent advances have refined these models to mirror the delayed onset and progressive nature of human disease, enabling the dissection of protective pathways—particularly those governed by the Nrf2 antioxidant response, autophagic clearance mechanisms and nutrient-sensing kinases such as mTOR. Together, these insights underscore the interplay between mitochondrial health, redox balance and protein homeostasis in driving neurodegeneration and open routes to disease-modifying interventions.

Research from Nature Portfolio

Recent studies have demonstrated that sulforaphane, a dietary isothiocyanate, confers robust neuroprotection in an in vivo rotenone model by engaging multiple convergent pathways. Treatment with sulforaphane attenuates motor impairments and preserves dopaminergic neuron integrity by activating the Nrf2-dependent transcription of downstream antioxidant enzymes such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase. Concurrently, sulforaphane restores normal autophagic flux, reversing rotenone-induced suppression of LC3-II and mTOR-mediated signalling. This multifaceted intervention reduces reactive oxygen species, limits lipid peroxidation and blocks cytochrome c-mediated apoptosis, illustrating the therapeutic potential of targeting redox and proteostasis pathways.

Oxidative Stress and Neurodegeneration in Parkinson's Disease Models publication trend

The graph below shows the total number of articles in oxidative stress and neurodegeneration in parkinson's disease models across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative stress: An imbalance between the generation of reactive oxygen species and the capacity of antioxidant systems to neutralise them.

Dopaminergic neurons: Neurones that synthesise and release dopamine, predominantly in the substantia nigra and ventral tegmental area.

Rotenone: A lipophilic mitochondrial complex I inhibitor widely used to induce Parkinsonian features in experimental models.

Nrf2 pathway: A transcriptional regulatory network that senses oxidative stress and upregulates cytoprotective and antioxidant genes.

Autophagy: A conserved cellular degradation process that recycles damaged organelles and misfolded proteins via lysosomal pathways.

References

1. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2 and autophagy pathways. Scientific Reports (2016).
2. Rotenone exposure causes features of Parkinson`s disease pathology linked with muscle atrophy in developing zebrafish embryo. Journal of Hazardous Materials (2024).
3. Transient exposure to rotenone causes degeneration and progressive parkinsonian motor deficits, neuroinflammation, and synucleinopathy. npj Parkinson's Disease (2023).
4. Neuroprotective Efficacy of a Nanomicellar Complex of Carnosine and Lipoic Acid in a Rat Model of Rotenone-Induced Parkinson’s Disease. Antioxidants (2023).