Mechanistic Insights and Therapeutic Potential of Quercetin in Neuroprotection: A Comprehensive Review of Pathways and Clinical Perspectives

Quercetin, a bioactive flavonoid abundant in diverse plant species, has been extensively investigated for its neuroprotective properties against neurodegenerative diseases (NDDs), such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review systematically explored the multifaceted therapeutic potential of quercetin, emphasizing the mechanisms of action, pharmacologic efficacy, and translational significance in modern neurotherapeutics. Quercetin demonstrated potent antioxidant effects by scavenging reactive oxygen species and modulating the Nrf2-ARE pathway, thereby mitigating oxidative stress, a hallmark of NDDs associated with mitochondrial dysfunction, protein aggregation, and neuronal apoptosis. Furthermore, the ability of quercetin to regulate the PI3K/Akt pathway promoted mitochondrial biogenesis and preserved neuronal integrity by stabilizing membrane potential. Anti-inflammatory effects were evident vis-a-vis inhibition of the NF-κB and MAPK pathways, suppression of microglial activation, and cytokine release. In addition, quercetin disrupted tau hyperphosphorylation via GSK3β inhibition and attenuated amyloid-beta toxicity, offering cognitive protection. Preclinical studies highlighted the ability of quercetin to modulate excitotoxicity and enhance neuroplasticity, while emerging evidence support synergy of quercetin with existing pharmacologic agents. Genetic variations influencing key pathways, including Nrf2 and PI3K, underscore the necessity for personalized therapeutic approaches. Advances in drug delivery systems, scaffold modelling, and CRISPR-mediated interventions revealed the potential for optimizing the bioavailability and specificity of quercetin. This review bridges critical knowledge gaps by integrating mechanistic insights with clinical perspectives, advocating for translating quercetin-based therapies into precision medicine. By addressing challenges in bioavailability and exploring innovative strategies, this article underscores the promise of quercetin as a cornerstone for neuroprotective interventions in NDDs.