Abstract: Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions. The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs, which have a range of serious adverse effects. As an alternative, naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions. Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models, in the face of neuroinflammatory insults induced by lipopolysaccharide, through a systematic review and meta-analysis. A search of the preclinical literature was conducted across four databases (PubMed, Web of Science, Scielo, and Google Scholar). Studies were selected based on inclusion and exclusion criteria, assessed for methodological quality using CAMARADES, and risk of bias using the SYRCLE tool, and data were extracted from the studies. The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis. A total of 384 potentially relevant articles were identified, of which 11 studies were included in the analysis. The methodological quality was assessed, resulting in an average score of 5.8/10, and the overall risk of bias analysis revealed a lack of methodological clarity in most studies. Furthermore, through the meta-analysis, it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin 6, interleukin 1β (n = 89; SMD = –2.00; 95% CI: –3.29 to –0.71), and microgliosis (n = 33; SMD = –2.56; 95% CI: –4.07 to –1.10). In terms of underlying mechanisms, quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties, possibly through the nuclear factor erythroid 2-related factor 2 (Nrf2)/ HO-1 pathways, increasing the expression of antioxidant enzymes and reducing reactive species, and modulating the caspase pathway, increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins. Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation. However, despite promising results in animal models, future directions should focus on well-designed clinical studies to assess the safety, bioavailability, and efficacy of quercetin and its derivatives in humans. Additionally, standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.

Key words: α-glycosyl isoquercitrin, alternative therapies, anti-apoptotic, antioxidant, chronic inflammation, cytokines, inflammatory mediators, neuronal damage, quercitrin