Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway

Jiang, Wei; Geng, Hongzhi; Lv, Xiaoqing; Ma, Jing; Liu, Fuchen; Lin, Pengfei; Yan, Chuanzhu

doi:10.1007/s10557-020-07018-5

Cited by 32 publications

(25 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, studies in rodents consistently reported antioxidant effects of idebenone [ [48] , [49] , [50] ], while only very low nanomolar concentrations in target tissues could be detected for only short periods of time [ 16 , 31 , 51 ]. In addition, idebenone produces fluctuating plasma concentrations due to its short half-life, without significant evidence of drug accumulation in tissues after repeated dosing [ 16 , 31 ].…”

Section: Is Idebenone a Direct Antioxidant?mentioning

confidence: 99%

“…In a model of galactose-induced cataract formation idebenone reduced oxidative damage by increasing total endogenous tissue antioxidant capacity [ 56 ]. This increased antioxidant capacity by idebenone is likely the consequence of an increased expression of a range of endogenous antioxidants such as superoxide dismutase (SOD), catalase, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione (GSH), and glutathione peroxidase (GPx) [ 37 , 45 , 48 , 49 , 57 ], while also downregulating the superoxide-producing enzyme NOX2 [ 58 ]. Interestingly, some of the antioxidant genes reported to be activated by idebenone such as SOD, NQO1 and GPx are controlled by the transcription factor Nrf2.…”

Section: Is Idebenone a Direct Antioxidant?mentioning

confidence: 99%

“…A growing body of evidence suggests that idebenone reduces inflammation in a variety of test systems such as lupus [ 106 ], neuroinflammation [ 58 , 74 ], ulcerative colitis [ 37 ], sepsis [ 107 ], nano-toxicity [ 108 ], atherosclerosis [ 48 ] and drug-induced inflammation [ 109 ]. This effect cannot be explained by antioxidant activity or a normalisation of energy supply alone.…”

Section: New Insightsmentioning

confidence: 99%

See 2 more Smart Citations

Idebenone: When an antioxidant is not an antioxidant

et al. 2021

View full text Add to dashboard Cite

Idebenone is a well described drug that was initially developed against dementia. The current literature widely portrays this molecule as a potent antioxidant and CoQ 10 analogue. While numerous papers seem to support this view, a closer look indicates that the pharmacokinetics of idebenone do not support these claims. A major discrepancy between achievable tissue levels, especially in target tissues such as the brain, and doses required to show the proposed effects, significantly questions our current understanding. This review explains how this has happened and highlights the discrepancies in the current literature. More importantly, based on some recent discoveries, a new framework is presented that can explain the mode of action of this molecule and can align formerly contradictory results. Finally, this new appreciation of the molecular activities of idebenone provides a rational approach to test idebenone in novel indications that might have not been considered previously for this drug.

show abstract

Section: Is Idebenone a Direct Antioxidant?mentioning

confidence: 99%

Section: Is Idebenone a Direct Antioxidant?mentioning

confidence: 99%

Section: New Insightsmentioning

confidence: 99%

See 1 more Smart Citation

Idebenone: When an antioxidant is not an antioxidant

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Coenzyme Q10 reduces RAGE levels in the joint tissue of rats with osteoarthritis [ 22 ], and several studies have found that idebenone inhibits Aβ plaque accumulation in Aβ peptide-infused rats and mice [ 15 , 23 ]. In high-fat-diet-treated human endothelial cells, idebenone pretreatment decreases caspase-3 expression [ 24 ]. The present study is the first to examine the effects of idebenone on Aβ plaque number and RAGE/caspase-3 levels in 5xFAD mice.…”

Section: Discussionmentioning

confidence: 99%

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

Lee

Jeong

Park

et al. 2021

Biology

View full text Add to dashboard Cite

The coenzyme Q10 analogue idebenone is an FDA-approved antioxidant that can cross the blood–brain barrier (BBB). The effects of idebenone on the pathology of Alzheimer’s disease (AD) and the underlying molecular mechanisms have not been comprehensively investigated. Here, we examined the impact of idebenone treatment on AD pathology in 5xFAD mice, a model of AD. Idebenone significantly downregulated Aβ plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the Aβ degradation enzyme NEP and α-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3βY216 levels, thereby inhibiting tau hyperphosphorylation at Thr231 and total tau levels in 5xFAD mice. Taken together, the present study indicates that idebenone modulates amyloidopathy and tauopathy in 5xFAD mice, suggesting therapeutic potential for AD.

show abstract

“…MHF downregulated SOD2 and CAT in the fetal kidney, which compromises the ability of the cell to neutralize superoxide. 32 NOS2 catalyzes the production of nitric oxide (NO). NO or its derivatives RNS inhibit mitochondrial respiration and induce mitochondrial permeability transition.…”

mentioning

confidence: 99%

Maternal High-Fat Diet Programs Renal Peroxisomes and Activates NLRP3 Inflammasome-Mediated Pyroptosis in the Rat Fetus

Zhou¹,

Guan²,

Guo³

et al. 2021

JIR

View full text Add to dashboard Cite

Maternal obesity impairs kidney development and function of the offspring and leads to a greater risk of kidney disease in adulthood. The present study aimed to investigate the link between peroxisomes, oxidative stress (OS), and inflammasomes in the fetal kidney of maternal obesity rats and to explore the potential therapeutic effects of the antioxidant pyrroloquinoline quinone (PQQ). Methods: Maternal obesity rats were developed by administration of a high fat diet plus supplementation with PQQ (40 mg/kg body weight) as a potential therapy. Renal histology was observed by Periodic Acid-Schiff staining. The expression profiles of peroxins, fatty acid β-oxidation enzymes, antioxidants, and the regulators of the unfolded protein response (UPR) pathway and NLRP3 inflammasome were analyzed in the kidneys and tubular epithelial cells (TECs) from near-term fetuses (embryonic day 20). Results: The present work revealed that: 1) a maternal high fat diet (MHF) led to higher blood pressure in adult offspring; 2) MHF led to downregulation of peroxisome markers PEX3 and 14 in fetal kidneys; 3) the antioxidant SOD2 and catalase were decreased, and oxidative stress marker Ephx2 was increased; 4) MHF-induced activation of the UPR pathway; 5) the KEAP1-NRF2 pathway was activated; 6) activation of the NLRP3 inflammasome led to secretion of pro-inflammation factors; 7) in TECs, the changes in PEXs and NLRP3 are similar to tissues, but UPR and NRF2 pathways showed opposite trends; 8) and the antioxidant PQQ alleviated maternal lipotoxicity by decreasing ROS levels and inhibiting activation of ER stress and inflammasome in fetal kidney. Conclusion:A maternal high fat diet decreased the number of peroxisomes, subsequently activated OS and inflammasomes, resulting in pyroptosis and apoptosis in fetal kidney. The antioxidant PQQ served a protective role against the effects of lipotoxicity on kidney programming and, thus, is a potential candidate to prevent maternal obesity-induced renal programming.

show abstract

Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway

Cited by 32 publications

References 55 publications

Idebenone: When an antioxidant is not an antioxidant

Idebenone: When an antioxidant is not an antioxidant

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

Maternal High-Fat Diet Programs Renal Peroxisomes and Activates NLRP3 Inflammasome-Mediated Pyroptosis in the Rat Fetus

Contact Info

Product

Resources

About