Quercetin as a Hypothesized Involvement of VMAT2 in Neurodegenerative Diseases-Mechanistic Insight and Therapeutic...

Neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease and Huntington's disease are characterized by progressive neuronal loss driven by complex mechanisms such as oxidative stress, neuroinflammation, protein aggregation, neurotransmitter imbalance, and synaptic dysfunction. Among these, Alzheimer's disease remains the most prevalent and challenging disorder, lacking effective disease-modifying therapies. Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has attracted considerable attention due to its potent antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties, along with its ability to cross the blood-brain barrier. This review critically examines the potential role of quercetin in modulating key pathological pathways in neurological disease, with a special focus on its interaction with the vesicular monoamine transporter 2 (VMAT2). Vesicular monoamine transporter 2 plays a crucial role in maintaining monoamine neurotransmitter homeostasis and protecting neurons from oxidative damage caused by cytosolic monoamine degradation. Increasing data indicates that VMAT2-mediated dysfunction represents one of multiple processes that lead to neurotoxicity by altering monoamine synthesis, increasing oxidative damage, and leading to synaptic damage, especially in neuronal pathways. Quercetin, as a potential monoamine oxidase inhibitor and reactive oxygen species scavenger, may indirectly preserve vesicular monoamine transporter 2 function and mitigate downstream neurotoxic events. Overall, the multitargeted actions of quercetin, combined with its potential influence on vesicular monoamine transporter 2-mediated pathways, highlight its promise as a complementary therapeutic candidate for further neurodegenerative disorders. An increasing number of studies demonstrates that quercetin may indirectly regulate VMAT2 function by eliminating reactive oxygen compounds, decreasing neuroinflammation, inhibiting monoamine oxidase activity, improving mitochondrial activity, and maintaining monoaminergic neuronal function, although there remains limited direct evidence connecting quercetin to VMAT2 regulation. The substance quercetin can reduce oxidative neuronal damage and decrease subsequent neurodegenerative events through several connected methods. Although direct experimental verification of the quercetin-VMAT2 connection is still lacking, the data that is now accessible suggests that VMAT2 may be a suitable target for further research. Therefore, the suggested quercetin-VMAT2 connection should be seen as a hypothetical and mechanistic approach.