Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson’s disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.
Background: Inflammasome-induced neuroinflammation is a key contributor to the pathology of Parkinson's disease (PD). NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation has been implicated in PD in postmortem human PD brains, indicating it as a potential target for PD treatment. Melatonin, a multitasking molecule, has been found to have anti-inflammatory activities, mediated by silence information regulator 1 (SIRT1). However, whether and how melatonin is involved in inflammasome-induced neuroinflammation in PD pathogenesis remains unclear. Methods: We investigated the potential anti-inflammatory effects of melatonin in vitro and in vivo, using 1-methyl-4-phenylpyridinium (MPP + )-simulated BV2 and primary microglia cell models, and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine PD model, with or without melatonin treatment. Rotarod, grip strength, and open-field tests were performed to measure the effects of melatonin on MPTP-induced motor disorders. Degeneration of dopaminergic neurons was evaluated by immunofluorescence. Changes in microglia were examined by immunofluorescence and Western blotting, and the expression levels of the involved signaling molecules were assessed by Western blotting and enzymelinked immunosorbent assay (ELISA). Intracellular reactive oxygen species (ROS) was detected using fluorescent probes via flow cytometry. Results: We found that melatonin significantly alleviated motor dysfunction and prevented MPTP-induced neurotoxicity in dopaminergic neurons. Additionally, melatonin reduced MPTP-induced microglial activation and suppressed NLRP3 inflammasome activity, and also inhibited IL-1β secretion. Moreover, in MPP + -primed BV2 cells, melatonin markedly restored the downregulation of SIRT1 and attenuated the activation of the NLRP3 inflammasome. This was reversed by SIRT1 inhibitor treatment.
Conclusion:In conclusion, our data demonstrated that melatonin attenuates neuroinflammation by negatively regulating NLRP3 inflammasome activation via a SIRT1-dependent pathway in MPTP-induced PD models. These findings provide novel insights into the mechanism underlying the anti-inflammatory effects of melatonin in PD.
Background: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. Objective: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). Methods: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. Results: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (β = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid β burden (β = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). Conclusions: APOE ε4 may be associated with rapid motor progression in PD.
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