QUERCETIN AS A MULTIFUNCTIONAL METAL CHELATOR: NEUROPROTECTIVE MECHANISMS IN METAL-INDUCED NEURODEGENERATION

Ali Zarbaliyev, Gulnur Arabaci*

Relevance – A key pathogenic factor in neurodegenerative diseases, most notably Alzheimer's disease and Parkinson's disease, is the dyshomeostasis of heavy and transition metal ions, namely iron (Fe), copper (Cu), cadmium (Cd), manganese (Mn), and zinc (Zn). Heavy metals induce mitochondrial dysfunction, oxidative stress, and neuroinflammation, leading to damage to nerve cells. Synthetic chelators have a number of drawbacks: pronounced side effects, toxicity, and restricted permeability through the blood-brain barrier. This highlights the need to identify alternative, safe chelating agents. The objective of this study was to substantiate the potential of quercetin as a neuroprotective agent for future clinical trials by systematizing data on its biochemical mechanisms of heavy metal ion chelation. A literature review was conducted in the PubMed database using the keywords "the role of quercetin as a heavy metal chelator," "flavonoids as antioxidants," "neuroprotection," "heavy metal neurotoxicity," "neurodegeneration," and combinations thereof. Studies from 2017 to 2025 were analyzed, primarily those with quantitative biochemical data on metal-induced neurotoxicity. Results – An analysis of 17 sources revealed that quercetin chelates metals via structural elements, specifically the catechol group of the B-ring and the 3-OH/4-oxo system of the C-ring. It also exerts a neuroprotective effect by inhibiting the Fenton reaction in iron (Fe) dyshomeostasis, normalizing antioxidant status in manganese (Mn) toxicity, restoring cholinergic neurotransmission in cadmium (Cd) accumulation, and by activating the PI3K/Akt and ERK1/2 signaling pathways in copper (Cu)-induced apoptosis. Bioavailability analysis revealed that it is significantly increased upon conjugation with superparamagnetic nanoparticles (QCSPIONs) and in combination with piperine. Practical significance: This work establishes a theoretical basis for the development of new quercetin-containing neuroprotective drugs for heavy metal-induced neurodegenerative diseases. Target Audience: This work is of interest to neurologists, neurobiologists, pharmacologists, pharmacists, and biochemists involved in the study of metal-induced neurodegeneration and the development of alternative chelating agents.