Neuroprotective effects of morroniside from Cornus officinalis sieb. Et zucc 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 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.

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease

“…Conversely, JWA knockdown amplified ferritinophagy, thereby inciting the Fenton reaction and facilitating ferroptosis. Interestingly, we found that both the mRNA levels of FTH / FTL and the protein level of FTH1 were reduced in the MPP + model, which may be attributed the decreased Nrf2 expression as reported previously [ 35 , 36 ]. However, JWA overexpression served to increase the protein level of FTH1, with no corresponding changes to the mRNA levels of FTH / FTL .…”

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson’s Disease

“…SAL’s ability to upregulate this pathway was evident in A53T-α-syn-SH-SY5Y cells, where it alleviated ferroptosis and promoted cell survival. Related, the research suggests that Morningside can activate the Nrf2/ARE signaling pathway to increase antioxidant capacity, thereby inhibiting abnormal lipid metabolism and protecting dopaminergic neurons in PD from ferroptosis [ 29 ]. Additionally, Sun observed a protective effect against 6-OHDA-induced dopaminergic neuronal ferroptosis in zebrafish and SH-SY5Y cell models through the upregulation of the Nrf2 signaling pathway [ 49 ].…”

“…SYXK (Zhe) 2021-0033). We utilized thirty-two 12-week-old male C57BL/6 mice according to the previous studies [ 28 , 29 ] for consistent progression of PD symptoms, each weighing approximately 25 g, procured from SLAC, Shanghai, China (License No. SCXK (Hu) 2017-0005).…”

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.…”

“…They also reported that the anti-cytotoxic effect of morroniside in response to H 2 O 2 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 ).…”