Parkinson’s disease (PD) is a chronic neurodegenerative condition affecting more than 1% of people over 65 years old. It is characterized by the preferential degeneration of nigrostriatal dopaminergic neurons, which is responsible for the motor symptoms of PD patients. The pathogenesis of this multifactorial disorder is still elusive, hampering the discovery of therapeutic strategies able to suppress the disease’s progression. While redox alterations, mitochondrial dysfunctions, and neuroinflammation are clearly involved in PD pathology, how these processes lead to the preferential degeneration of dopaminergic neurons is still an unanswered question. In this context, the presence of dopamine itself within this neuronal population could represent a crucial determinant. In the present review, an attempt is made to link the aforementioned pathways to the oxidation chemistry of dopamine, leading to the formation of free radical species, reactive quinones and toxic metabolites, and sustaining a pathological vicious cycle.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the preferential loss of dopaminergic neurons and by the accumulation of intracellular inclusions mainly composed of α-synuclein (α-Syn). While the etiopathogenesis of the disorder is still elusive, recent experimental evidence supports the involvement of ferroptosis, an iron-dependent cell death pathway, in the pathogenesis of PD. In the present work, using different ferroptosis inducers and inhibitors, we evaluated, in vivo, the involvement of iron in the α-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of α-Syn within dopaminergic neurons, we demonstrated that the over-expression of α-Syn promotes the accumulation of protein aggregates, which is accompanied by dopaminergic neurodegeneration, locomotor impairment, and lifespan reduction. These pathological phenotypes were further exacerbated by reduced intracellular levels of glutathione or increased concentrations of iron. Coherently, both the use of an iron chelator and the presence of the antioxidant compound N-acetylcysteine exerted protective effects. Overall, our results support the involvement of ferroptosis in the α-Syn-mediated toxicity.

Oxidative burden plays a central role in Alzheimer’s disease (AD) pathology, fostering protein aggregation, inflammation, mitochondrial impairment, and cellular dysfunction that collectively lead to neuronal injury. The role of exosomes in propagating the pathology of neurodegenerative diseases including AD is now well established. However, recent studies have also shown that exosomes are crucial responders to oxidative stress in different tissues. Thus, this offers new insights and mechanistic links within the complex pathogenesis of AD through the involvement of oxidative stress and exosomes. Several studies have indicated that exosomes, acting as intracellular communicators, disseminate oxidatively modified contents from one cell to another, propagating the pathology of AD. Another emerging aspect is the exosome-mediated inhibition of ferroptosis in multiple tissues under different conditions which may have a role in neurodegenerative diseases as well. Apart from their involvement in the pathogenesis of AD, exosomes enter the bloodstream serving as novel noninvasive biomarkers for AD; some of the exosome contents also reflect the cerebral oxidative stress in this disease condition. This review highlights the intricate interplay between oxidative stress and exosome dynamics and underscores the potential of exosomes as a novel tool in AD diagnosis.

Rotenone, the inhibitor of mitochondrial complex I, is widely used to develop the experimental models of Parkinson’s disease, but the mechanism of neurotoxicity of rotenone is still not clearly established. In the current study we showed that rotenone mediated mitochondrial dysfunctions and cell death in SH-SY5Y cells (human neuroblastoma cell line) over an incubation period of 48 h are triggered by the accumulation of α-synuclein, and silencing of α-synuclein protein expression by specific siRNA abolished the cytotoxic effects of rotenone. Based on the current and earlier published data, the deleterious action of α-synuclein in SH-SY5Y cells has been ascribed to the activation of mitochondrial permeability transition pore (mPTP). In rotenone induced rat model of Parkinson’s disease, nigral dopaminergic neuronal death and altered functions of isolated midbrain mitochondria such as mitochondrial membrane depolarization, decreased ATP synthesis, increased ROS production and inhibition of complex I-III were observed which could be prevented markedly (except complex I-III inhibition) by cyclosporine A which is a well-known blocker of mPTP. The nigral accumulation of α-synuclein after rotenone treatment of rats, however, was not noticeably prevented by cyclosporine A. Additionally, cyclosporine A prevented neuroinflammation in the midbrain region of rotenone treated rats. These results have implications in the pathogenesis and also highlight the therapeutic potential of cyclosporine A for Parkinson’s disease.