Time-dependent protective and harmful effects of quercetin on 6-OHDA-induced toxicity in neuronal SH-SY5Y cells

Numerous reports have described the effects of quercetin in models of neurodegenerative diseases, or cancer, resulting in a very complex and sometimes paradoxical picture. Understanding how quercetin causes either protection or cell death in the same model is both tempting and essential. We used the 6-OHDA-induced toxicity model in SH-SY5Y cells, applying graded concentrations of quercetin for a variable time period and following cell viability with MTT-assay and LDH-release as well as caspase-3-like activity. We detected a time-dependent action of quercetin and distinguished an early protective effect from a late toxic one. In addition, we revealed a narrower therapeutic dose-range of quercetin than previously reported in the literature, demonstrating that the toxic effects of quercetin occurred at a concentration only 2-fold higher than the one that produced the greatest protection. We also demonstrated, to our knowledge for the first time, that quercetin itself directly inhibits caspase-3-like activity in a dose-dependent manner. Finally, single doses of quercetin failed to protect against 6-OHDA toxicity in a unilateral rat model of Parkinson's disease. In conclusion, our data may offer an explanation for the dualistic effect of quercetin reported in the literature. In fact, in most studies suggesting quercetin protection against oxidative stressors, the experimental setting failed to include prolonged exposure, and therefore the toxic effects may have been missed. This study supports previous in vivo studies that cast doubt on the efficacy of quercetin against neurodegenerative diseases due to its delayed toxicity.