Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson’s Disease by Inhibiting Ferroptosis

Abstract

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.

Exploring the effectiveness of Chinese herbal medicine as an "iron blade" to get rid of a "hidden murderer" hypertension

“…By controlling the Nrf2-mediated ferroptosis pathway, quercetin also lessens the symptoms of seizures by kainate [49]. Numerous studies have also demonstrated that quercetin, a ferroptosis inhibitor, provides a new therapeutic strategy for ferroptosis-related diseases [50,51]. In addition to the encouraging outcomes of the molecular docking tests, earlier research has shown the importance of this molecular docking investigation.…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Lin et al demonstrated that the substantia nigra of MPTP-induced Parkinson’s disease (PD) mice showed ferroptosis-related biochemical features, with high levels of MDA and low levels of superoxide dismutase (SOD) and GSH, indicating that ferroptosis was involved in the development of PD . Importantly, quercetin could up-regulate the expression of the downstream genes SLC7A11 and GPX4 by activating NRF2, thereby inhibiting lipid peroxidation in dopaminergic neurons . Icariside II, a flavonol glycoside derived from Epimedium koreanum , could suppress the expression of GPX4 via up-regulating miR-324-3p and thus promoted ferroptosis in renal cell carcinoma cells, indicating that icariside II might be used as an adjuvant therapy for renal cancer .…”

“…In-depth studies found that this compound alleviated the morphological changes and lipid peroxidation through activating the Sirtuin 1 (SIRT1)/NRF2/SLC7A11/GPX4 pathway, thus exerting neuroprotective effects. Lin et al demonstrated that the substantia nigra of MPTP-induced Parkinson’s disease (PD) mice showed ferroptosis-related biochemical features, with high levels of MDA and low levels of superoxide dismutase (SOD) and GSH, indicating that ferroptosis was involved in the development of PD . Importantly, quercetin could up-regulate the expression of the downstream genes SLC7A11 and GPX4 by activating NRF2, thereby inhibiting lipid peroxidation in dopaminergic neurons .…”

“…103 Importantly, quercetin could up-regulate the expression of the downstream genes SLC7A11 and GPX4 by activating NRF2, thereby inhibiting lipid peroxidation in dopaminergic neurons. 103 Icariside II, a flavonol glycoside derived from Epimedium koreanum, could suppress the expression of GPX4 via up-regulating miR-324-3p and thus promoted ferroptosis in renal cell carcinoma cells, indicating that icariside II might be used as an adjuvant therapy for renal cancer. 104 Of note, several flavonols, including kaempferol, icariin, and rhamnazin, also regulated cell sensitivity to ferroptosis by targeting GPX4.…”

Quercetin’s Effects on Glutamate Cytotoxicity

“…Quercetin has been shown to prevent the activation of the neuron’s ferroptosis pathway by chelating reduced iron and increasing the expression of the glutathione peroxidase [ 90 ]. The subsequent increase of Nrf2 expression in neurons by quercetin can upregulate the expression of glutathione peroxidase 4 and SLCA11 enzymes that prevent the production of lipid radicals that are the product of iron toxicity [ 91 ].…”