To what extent may aminochrome increase the vulnerability of dopaminergic neurons in the context of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that progresses over time and is characterized by preferential reduction of dopaminergic neurons in the substantia nigra. Although the precise mechanisms leading to cell death in neurodegenerative disorders, such as PD, are not fully understood, it is widely accepted that increased oxidative stress may be a prevalent factor contributing to the deterioration of the nigrostriatal dopaminergic fibers in such conditions. Aminochrome, generated from dopamine (DA) metabolism, plays an important role in multiple pathogenic mechanisms associated with PD. Its capacity to induce a gradual reduction in dopaminergic neurons is due to its endogenous neurotoxicity. The formation of aminochrome results in the production of various reactive oxygen species (ROS), including pro-inflammatory factors, superoxide, nitric oxide, and hydroxyl radicals. This, in turn, causes loss of dopaminergic neurons, reducing DA uptake, and reduced numbers and shortened dendrites. Notably, o-quinones, which are more cytotoxic, arise from the oxidation of DA and possess a higher capacity to impede cellular defense mechanisms, thereby resulting in the death of neuronal cells. Aminochrome potentially contributes to the pathophysiology of PD by forming adducts with various proteins. All of the aforementioned effects suggest that aminochrome may play a crucial role in the pathophysiology of PD. Thus, aminochrome may serve as a more relevant preclinical model for PD, facilitating a better understanding of its pathophysiological processes and identification of novel therapeutic strategies aimed at preventing or slowing disease progression.