Oral Administration of Silibinin Ameliorates Cognitive Deficits of Parkinson’s Disease Mouse Model by Restoring Mitochondrial Disorders in Hippocampus

Liu, Xiumin; Wang, Chenkang; Liu, Weiwei; Song, Siaoyu; Fu, Jianing; Hayashi, Toshihiko; Mizuno, Kazunori; Fujisaki, Hitomi; Ikejima, Takashi

doi:10.1007/s11064-021-03363-5

Cited by 15 publications

(9 citation statements)

References 54 publications

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“…Exposure of Drosophila to Rot mimics numerous of the features of human PD and is widely used as a model for investigating the pathogenesis of PD ( 31 ). Consistent with the aforementioned study, it was determined that exposure of flies to 515 µM Rot for 7 days before analysis caused a loss of dopaminergic neurons, as measured by staining of Drosophila brains for the marker protein TH ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuroprotective effect of Ginsenoside Re against neurotoxin‑induced Parkinson's disease models via induction of Nrf2

et al. 2022

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The aim of the present study was to examine the neuroprotective effects of a panel of active components of ginseng and to explore their molecular mechanisms of action in two rotenone (Rot)-induced models of Parkinson's disease: An in vitro model using the human neuroblastoma cell line SH-SY5Y and an in vivo model using Drosophila . Ginsenoside Re (Re) was identified as the most potent inhibitor of Rot-induced cytotoxicity in SH-SY5Y cells by Cell Counting kit-8 assay and lactate dehydrogenase release assay. Flow cytometry, Hoechst staining, Rhodamine 123 staining, ATP and cytochrome c release revealed that Re rescue of Rot-induced mitochondrial dysfunction and inhibition of the mitochondrial apoptotic pathway. Western blot analysis demonstrated that Re alleviated Rot-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway, and these effects were abolished by RNA interference-mediated knockdown of Nrf2. Re enhanced phosphorylation of components of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and extracellular regulated protein kinase (ERK) pathways, and pharmacological inhibition of these pathways reduced Re-mediated Nrf2 activation and neuroprotection. In the Drosophila model, Immunofluorescence microscopy, reactive oxygen species (ROS), hydrogen peroxide and knockdown analysis revealed that Re reversed Rot-induced motor deficits and dopaminergic neuron loss while concomitantly alleviating Rot-induced oxidative damage. The findings of the present study suggest that Re protects neurons against Rot-induced mitochondrial dysfunction and oxidative damage, at least in part, by inducing Nrf2/heme oxygenase-1 expression and activation of the dual PI3K/AKT and ERK pathways.

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Section: Resultsmentioning

confidence: 99%

Neuroprotective effect of Ginsenoside Re against neurotoxin‑induced Parkinson's disease models via induction of Nrf2

et al. 2022

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“…Despite a lack of direct measurement of the permeability across the blood–brain barrier, several studies have reported the treatment effects of silibinin on neurological disorders after oral administration. For example, silibinin attenuated the loss of dopamine neurons and hippocampal neuron apoptosis in mice models of Parkinson’s disease [ 47 , 48 ]. Moreover, oral administration of silibinin (200 mg/kg) decreased Aβ deposition and the levels of soluble Aβ1–40/1–42 in the hippocampus by downregulating APP and BACE1 in the brains of APP/PS1 mice [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Silibinin Protects against H2O2-Induced Oxidative Damage in SH-SY5Y Cells by Improving Mitochondrial Function

Tie

et al. 2022

Antioxidants

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Oxidative stress plays a critical role in the pathogenesis of various neurodegenerative diseases. Increasing evidence suggests the association of mitochondrial abnormalities with oxidative stress-related neural damage. Silibinin, a natural flavonol compound isolated from Silybum marianum, exhibits multiple biological activities. The present study investigated the effects of silibinin on H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells. Exposure to H2O2 (750 µM) reduced the viability of SH-SY5Y cells, which was coupled with increased reactive oxygen species (ROS), abnormal cell morphology, and mitochondrial dysfunction. Remarkably, silibinin (1, 5, and 10 µM) treatment attenuated the H2O2-induced cell death. Moreover, silibinin reduced ROS production and the levels of malondialdehyde (MDA), increased the levels of superoxide dismutase (SOD) and glutathione (GSH), and increased mitochondrial membrane potential. Moreover, silibinin normalized the expression of nuclear factor 2-related factor 2 (Nrf2)-related and mitochondria-associated proteins. Taken together, our findings demonstrated that silibinin could attenuate H2O2-induced oxidative stress by regulating Nrf2 signaling and improving mitochondrial function in SH-SY5Y cells. The protective effect against oxidative stress suggests silibinin as a potential candidate for preventing neurodegeneration.

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“…Silibinin, the main bioactive flavonolignan in silymarin, possesses hepatoprotective, anti‐cancer, antioxidative and neuroprotective properties (Bijak, 2017). In PD management, silibinin can protect neurons and improve motor deficits by addressing mitochondrial dysfunction and dynamics (via the upregulation of mitochondrial succinate dehydrogenase, complex IV and complex V activities, the elevation of MFN1 expression, and reduction of Drp1 levels), enhancing mitochondrial membrane potential and mitophagy (through increased expression of PINK1, parkin, and LC3‐II/LC3‐I), mitigating mitochondrial oxidative stress (via elevated SOD and GSH expression and reduced ROS and MDA levels), exerting anti‐inflammatory effects (manifested as downregulation of NLRP3, caspase 1, IL‐1β, and TNF‐α levels), and suppressing mitochondrial apoptosis (by reducing caspase‐3, −8, and −9 activities and inhibiting the NF‐κB pathway) (Geed et al, 2014; Lee et al, 2015; Liu, Liu, et al, 2021; Liu, Wang, et al, 2021). However, silibinin's limited water solubility and absorption efficiency result in low bioavailability and can be potentially overcome by incorporating solubilizing agents into standard silymarin pharmaceutical formulations, using a synthetic mixture of silibinin, phosphatidylcholine and vitamin E, creating bile salts mixed micelles, developing self‐microemulsifying drug delivery systems, formulating specific nanoemulsions and nanosuspensions, and applying the solution‐enhanced dispersion using supercritical fluids (Bijak, 2017).…”

Section: Therapeutic Effects Of Natural Compounds On Pd By Modulating...mentioning

confidence: 99%

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Liang,

Ma,

Zhong

et al. 2024

Phytotherapy Research

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Mitochondrial damage is associated with the development of Parkinson's disease (PD), indicating that mitochondrial‐targeted treatments could hold promise as disease‐modifying approaches for PD. Notably, natural compounds have demonstrated the ability to modulate mitochondrial‐related processes. In this review article, we discussed the possible neuroprotective mechanisms of natural compounds against PD in modulating mitophagy and mitochondrial function. A comprehensive literature search on natural compounds related to the treatment of PD by regulating mitophagy and mitochondrial function was conducted from PubMed, Web of Science and Chinese National Knowledge Infrastructure databases from their inception until April 2023. We summarize recent advancements in mitophagy's molecular mechanisms, including upstream and downstream processes, and its relationship with PD‐related genes or proteins. Importantly, we highlight how natural compounds can therapeutically regulate various mitochondrial processes through multiple targets and pathways to alleviate oxidative stress, neuroinflammation, Lewy's body aggregation and apoptosis, which are key contributors to PD pathogenesis. Unlike the single‐target strategy of modern medicine, natural compounds provide neuroprotection against PD by modulating various mitochondrial‐related processes, including ameliorating mitophagy by targeting the PINK1/parkin pathway, the NIX/BNIP3 pathway, and autophagosome formation (i.e., LC3 and p62). Given the prevalence of mitochondrial damage in various neurodegenerative diseases, exploring the exact mechanism of natural compounds on mitophagy and mitochondrial dysfunction could shed light on the development of highly effective disease‐modifying or adjuvant therapies targeting PD and other neurodegenerative disorders.

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Oral Administration of Silibinin Ameliorates Cognitive Deficits of Parkinson’s Disease Mouse Model by Restoring Mitochondrial Disorders in Hippocampus

Cited by 15 publications

References 54 publications

Neuroprotective effect of Ginsenoside Re against neurotoxin‑induced Parkinson's disease models via induction of Nrf2

Neuroprotective effect of Ginsenoside Re against neurotoxin‑induced Parkinson's disease models via induction of Nrf2

Silibinin Protects against H2O2-Induced Oxidative Damage in SH-SY5Y Cells by Improving Mitochondrial Function

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

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