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Published on: November 18, 2022
Flavanonol taxifolin attenuates proteasome inhibition-induced apoptosis in differentiated PC12 cells by suppressing
Yoon Jeong Nam1, Da Hee Lee, Yong Kyoo Shin
1Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
Abstract:
The proteasomal dysfunction and mitochondrial impairment has been implicated in neuronal degeneration. Taxifolin has antioxidant and anti-inflammatory effects. However, the effect of taxifolin on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of taxifolin on the proteasome inhibition-induced apoptosis in neuronal cell injury using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases(-8, -9 and -3), an increase in the tumor suppressor p53 levels and cleavage of PARP-1. The addition of taxifolin attenuated the proteasome inhibitor-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, depletion and oxidation of GSH, formations of malondialdehyde and carbonyls, and cell death. The results show that taxifolin may attenuate the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of taxifolin appears to be attributed to its inhibitory effect on the formation of reactive oxygen species, and depletion and oxidation of GSH.
Insights
Taxifolin protects neuronal cells from death caused by proteasome inhibition. It reduces oxidative stress and preserves mitochondrial function, offering a potential therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Proteasomal dysfunction and mitochondrial impairment are linked to neuronal degeneration.
- Taxifolin exhibits known antioxidant and anti-inflammatory properties.
- The impact of taxifolin on proteasome inhibition-induced neuronal cell death remains uninvestigated.
Purpose of the Study:
- To investigate the protective effects of taxifolin against proteasome inhibitor-induced apoptosis in differentiated PC12 neuronal cells.
- To elucidate the mechanisms underlying taxifolin's potential neuroprotective actions.
Main Methods:
- Differentiated PC12 cells were treated with proteasome inhibitors (MG132, MG115) with or without taxifolin.
- Apoptosis-related protein levels (Bid, Bcl-2, survivin, Bax, p53, PARP-1), mitochondrial transmembrane potential, cytochrome c release, caspase activation, reactive oxygen species (ROS), and glutathione (GSH) status were assessed.
- Malondialdehyde and carbonyl levels were measured to evaluate oxidative damage.
Main Results:
- Proteasome inhibitors induced apoptosis by altering apoptotic protein expression, disrupting mitochondrial potential, releasing cytochrome c, activating caspases, and increasing p53 and cleaved PARP-1.
- Taxifolin treatment attenuated these apoptotic changes.
- Taxifolin reduced ROS formation, prevented GSH depletion and oxidation, and decreased markers of oxidative damage (malondialdehyde, carbonyls).
Conclusions:
- Taxifolin mitigates proteasome inhibitor-induced apoptosis in PC12 cells.
- The protective effect is mediated by suppressing the mitochondrial pathway and caspase-8/Bid-dependent pathways.
- Taxifolin's neuroprotection is attributed to its antioxidant capacity, including ROS inhibition and preservation of GSH.
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