Neuroprotective effects of morroniside against Parkinson's Disease via inhibiting oxidative stress and ferroptosis

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease accompanied by the death of dopaminergic neurons and brain nigrostriatal mitochondrial damage in the elderly population. The features of the disease include tremor, rigidity, postural instability, and motor retardation. The pathogenesis of Parkinson’s disease is complex, and abnormal lipid metabolism resulting in ferroptosis due to the excessive accumulation of free radicals from oxidative stress in the substantia nigra of the brain was thought to be one of the factors causing the disease. Morroniside has been reported to have significant neuroprotective effects, although it has not been studied in PD. Therefore, this study focused on determining the neuroprotective effects of morroniside (25, 50, and 100 mg/kg) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg)-induced mice models of PD and explored 1-methyl-4-phenylpyridinium MPP+-induced ferroptosis in PC12 cells. Morroniside restored the impaired motor function in the PD mice models while reducing neuronal injury. The activation of nuclear factor erythroid 2-related factor 2/antioxidant response elements (Nrf2/ARE) by morroniside promoted antioxidation, the content of reducing agent glutathione (GSH) increased, and the level of the lipid metabolite malondialdehyde (MDA) decreased. Notably, morroniside inhibited ferroptosis in substantia nigra of the brain and PC12 cells, reduced iron levels, and upregulated the expression of the iron-regulated proteins glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH-1), and ferroportin (FPN). More importantly, morroniside repaired the mitochondrial damage, restored the mitochondrial respiratory chain, and inhibited the production of reactive oxygen species (ROS). These data indicated that morroniside could activate the Nrf2/ARE signaling pathway to increase the antioxidant capacity, thereby inhibiting abnormal lipid metabolism and protecting dopaminergic neurons from ferroptosis in PD.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis

“…51 The specific inhibitor of Nrf2, ML385, significantly inhibited FTH1 and Fpn1 in PC12 cells treated with MPP + (1-methyl 4-phenyl pyridinium), a classical model of Parkinson's disease. 52 In other words, the modulation of Nrf2 on ferritin and Fpn1 should be synchronous. The disruption of Nrf2 cannot fully explain https://doi.org/10.2147/DDDT.S458013…”

Morroniside Protects C2C12 Myoblasts from Oxidative Damage Caused by ROS-Mediated Mitochondrial Damage and Induction of Endoplasmic Reticulum Stress

“…GSH exists not only in the cytoplasm but also in mitochondria, and protects mitochondria from oxidative stress by scavenging ROS generated during electron transport and oxidative phosphorylation within mitochondria (Jacobs and Riemer, 2023). Recently, Li et al (2023) found that morroniside can reduce ROS production by restoring the mitochondrial respiratory chain in a Parkinson's disease model. Our results using Mito-SOX showed that morroniside effectively attenuated H2O2-induced mitochondrial superoxide production, corresponding to major mtROS (Fujii et al, 2022;Jomova et al, 2023).…”

“…They also reported that the anti-cytotoxic effect of morroniside in response to H2O2 treatment was associated with preservation of SOD activity, inhibition of calcium (Ca 2+ ) accumulation, and blockade of mitochondrial membrane potential (MMP) reduction (Wang et al, 2009). Morroniside also prevented brain injury following focal cerebral ischemia by protecting oxidative stress and apoptosis (Wang et al, 2010), and was proven to have similar efficacy in models of Alzheimer's (Chen et al, 2023) and Parkinson's disease (Li et al, 2023). Recently, we reported that heme oxygenase-1 activation by morroniside plays a crucial role in minimizing oxidative and inflammatory damage in lipopolysaccharide-challenged macrophages (Park et al, 2021).…”

Oxidative stress in hair follicle development and hair growth: Signalling pathways, intervening mechanisms and potential of natural antioxidants

“…Et zucc, attenuates ROS-mediated mitochondrial damage in the treatment of Parkinson's. 123 Its hair growth-promoting effects have long been reported. 120 Therefore, it is reasonable to believe that these natural compounds in the tables can intervene in the hair cycle transition by counteracting OS in the HF, but their specific molecular mechanisms need to be further investigated.…”

“…Then, a recent study found that morroniside, a natural compound from Cornus officinalis sieb. Et zucc , attenuates ROS‐mediated mitochondrial damage in the treatment of Parkinson's 123 . Its hair growth‐promoting effects have long been reported 120 .…”