Rhein Relieves Oxidative Stress in an Aβ1-42 Oligomer-Burdened Neuron Model by Activating the SIRT1/PGC-1α-Regulated Mitochondrial Biogenesis

Abstract

Neuronal mitochondrial oxidative stress induced by β-amyloid (Aβ) is an early event of Alzheimer’s disease (AD). Emerging evidence has shown that antioxidant therapy represents a promising therapeutic strategy for the treatment of AD. In this study, we investigated the antioxidant activity of rhein against Aβ1-42 oligomer-induced mitochondrial oxidative stress in primary neurons and proposed a potential antioxidant pathway involved. The results suggested that rhein significantly reduced reactive oxygen species (ROS) level, reversed the depletion of mitochondrial membrane potential, and protected neurons from oxidative stress-associated apoptosis. Moreover, further study indicated that rhein activated mitochondrial biogenesis accompanied by increased cytochrome C oxidase (CytOx) and superoxide dismutase (SOD) activities. CytOx on the respiratory chain inhibited the production of ROS from electron leakage and SOD helped to eliminate excess ROS. Finally, western blot analysis confirmed that rhein remarkedly increased the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) together with its upstream deacetylase sirtuin 1 (SIRT1), and activated downstream transcription factor nuclear respiratory factor 1, promoting mitochondrial biogenesis. In conclusion, our results demonstrate that rhein activates mitochondrial biogenesis regulated by the SIRT1/PGC-1α pathway as an antioxidant defense system against Aβ1-42 oligomer-induced oxidative stress. These findings broaden our knowledge of improving mitochondrial biogenesis as an approach for relieving neuronal oxidative stress in AD.

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK–FGF23 signaling

“…The elevated NOX2 and NOX4 protein levels after Ang II stimulation in the CMs and CFs were obviously reversed by rhein. Consistent with these findings, rhein significantly suppressed neuronal oxidative stress in Alzheimer disease [ 40 ], hydrogen peroxide-induced oxidative stress in intestinal epithelial cells [ 41 ], and ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes [ 18 ]. Further research is needed to examine whether rhein has similar effects on ROS derived from the mitochondria or other sources.…”

Rhein Ameliorates Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease by Relieving Oxidative Stress through Activating the SIRT1/PGC-1α Pathway

“…Our previous research has proven that rhein relieves oxidative stress by activating the SIRT1/PGC-1 α -regulated mitochondrial biogenesis in vitro [ 29 ]. Thus, western blot was employed to detect the protein expression of SIRT1, PGC-1 α , and NRF1 in the hippocampal tissues.…”

“…A growing body of evidence demonstrates that neuronal oxidative stress contributes significantly to the pathogenesis and progression of AD, and activating the endogenous antioxidant pathway represents a great promising target to modulate AD pathology [ 46 , 47 ]. Previous research conducted in our group unveils that rhein effectively relieves mitochondrial oxidative stress in primary neurons induced by A β 42 oligomers, and mitochondrial biogenesis regulated by the SIRT1/PGC-1 α pathway is a potential antioxidant pathway involved [ 29 ]. While impressive in vitro antioxidant activity and neuroprotection were obtained, pharmacodynamics evaluation of rhein for AD in vivo still needs to be carried out.…”

“…Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), a type of anthraquinone compound derived from rhubarb, is identified as a potent antioxidant for multiple diseases, such as cerebral ischemic/reperfusion [ 26 ], hyperglycemia [ 27 ], and traumatic brain injury [ 28 ]. By establishing an A β 42 oligomer-burdened neuron model, our previous work has proven that rhein notably mitigated intracellular ROS levels, reversed the depletion of mitochondrial membrane potential in neurons, and protected neurons from mitochondrial oxidative damage-associated apoptosis [ 29 ]. Moreover, activation of the SIRT1/PGC-1 α -regulated mitochondrial biogenesis is an essential mechanism of rhein for mobilizing the mitochondrial antioxidant defense system.…”

Explore the Mechanism of β-Asarone on Improving Cognitive Dysfunction in Rats with Diabetic Encephalopathy

“…During the occurrence of DE, the brain is more susceptible to oxidative stress than other organs. Most of the components of neurons (lipid, protein, and nucleic acid) may be oxidized, thereby promoting the apoptosis of related neurons [ 12 ]. The brain-derived neurotrophic factor (BDNF) is the most prominent neurotrophic factor in the human body, and it plays an important role in neuronal development, survival, and synaptic plasticity [ 13 ].…”