Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity

Peng, Jialing; Wang, Hongxuan; Gong, Zhe; Li, Xiangpen; He, Lei; Shen, Qingyu; Pan, Jianke; Peng, Ying

doi:10.1016/j.molimm.2020.04.013

Cited by 59 publications

(41 citation statements)

References 46 publications

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“…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 recent study supported the hypoxia-dependent activity of idebenone in a neuroinflammatory model. Idebenone, at nanomolar to low micromolar concentrations, was only protective under hypoxia-reperfusion conditions, while under normoxic conditions it was ineffective [ 58 ]. When we confirmed the protective activity of idebenone in a rodent model of acute colitis, increased protection by idebenone was detected in the distal compared to the proximal colon [ 37 ].…”

Section: New Insightsmentioning

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%

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Idebenone: When an antioxidant is not an antioxidant

et al. 2021

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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.

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Section: Is Idebenone a Direct Antioxidant?mentioning

confidence: 99%

Section: New Insightsmentioning

confidence: 99%

Section: New Insightsmentioning

confidence: 99%

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Idebenone: When an antioxidant is not an antioxidant

et al. 2021

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“…Literature data concerning expression of inflammasome proteins and effectors in cells of the NVU in age-associated CNS diseases are summarized in (Table 1). [139] thromboembolic (CCAT) stroke mouse model NLRP1↑, ASC↑, caspase-1↑ [148] MCAO mouse model NLRP1↑, ASC↑, caspase-1↑, caspase-11↑, IL-1β↑ [139] MCAO rat model NLRP3↑, ASC↑ [154] GD or OGD or IR simulation NLRP1↑, NLRP3↑, ASC↑, XIAP↑, caspase-1↑, caspase-11↑, IL-1β↑, IL-18↑ [139] OGD (cultured with microglia) NLRP3↑, caspase-1↑, IL-1β↑, IL-18↑ [170] OGD NLRP6↑ [151] microglia thromboembolic (CCAT) stroke mouse model NLRP1↑, ASC↑, caspase-1↑ [148] photothrombotic stroke mouse model ASC↑ [155] MCAO mouse model NLRP3↑ [163,179] MCAO mouse model NLRC4↑, caspase-1↑ [145] MCAO mouse model IL-1β↑ [145,153] MCAO rat model ASC↑ [154] MCAO rat model NLRP3↑, caspase-1↑ Both in health and disease, in cells that have already been primed by cytokines, DAMPs or hormones [191], inflammasomes can be activated in response to a wide range of host-derived by-products that are accumulated intra-and extracellularly with aging. Inflammasome activation, in return, leads to the release of pro-inflammatory cytokines (IL-1β or IL-18) and pyroptotic cell death, which eventually amplify the inflammation on site (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, it has been demonstrated that oxidative stress-related TXNIP/NLRP3 inflammasome activation is inhibited by curcumin, the main natural polyphenol of Curcuma species, in neuronal cells [160]. As a different approach, idebenone-a synthethic antioxidant and anti-aging compound-has recently been proposed to counteract the NLRP3 inflammasome-activating effects of ROS and mtDNA in neuron and microglia co-culture in response to OGD [170]. Vascular cells may also be damaged by ROS.…”

Section: Neurovascular Inflammaging In Strokementioning

confidence: 99%

Neurovascular Inflammaging in Health and Disease

Mészáros

Molnár

Nógrádi

et al. 2020

Cells

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Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.

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Evaluation of the Neuroprotective Effects of Idebenone in an Experimental Carbon Monoxide Poisoning Model

Karakus,

Bulbul,

Kulaber

et al. 2024

J of Applied Toxicology

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Carbon monoxide (CO) poisoning is among the main causes of poisoning‐related mortality and morbidity, primarily affecting the central nervous system and leading to delayed neurological sequelae. Idebenone exerts antioxidant and neuroprotective effects. In this study, we aimed to evaluate the specific neuroprotective effects of idebenone against CO poisoning. Forty female Wistar Albino rats were used in this study. Except the controls, the other rats inhaled 5000 ppm CO until a change in consciousness was observed. Rats with carboxyhemoglobin concentrations over 20% in blood samples collected from the tail vein were considered successful acute CO poisoning models. The rats were divided into five groups: healthy control (HC; group 1), CO + saline (CO‐S; group 2), CO + 100 mg/kg idebenone (CO‐I100; group 3), CO + 200 mg/kg idebenone (CO‐I200; group 4), and CO + 300 mg/kg idebenone (CO‐I300; group 5). Pre‐determined doses of idebenon were orally administered to the rats at 24‐h intervals for 5 days. The rats were anesthetized and sacrificed 24 h after the last drug dose. Histopathological and biochemical parameters were examined in the blood and hippocampus samples of the rats. Histopathological grading of neurons in the hippocampus revealed that the CO‐S group exhibited the highest number of grade 1, 2, and 3 degenerative cells (all p = 0.001). Apoptotic index was the highest in the CO‐S group and significantly low in the idebenone‐treated groups (p = 0.001). Neuron‐specific enolase and malondialdehyde levels and oxidative stress index were significantly lower in both the hippocampus and serum samples of the idebenone‐treated groups than in those of the CO‐S group (all p values = 0.001). Overall, idebenone inhibited degeneration due to CO‐induced brain damage and exerted neuroprotective effects against oxidative stress in rats.

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Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity

Cited by 59 publications

References 46 publications

Idebenone: When an antioxidant is not an antioxidant

Idebenone: When an antioxidant is not an antioxidant

Neurovascular Inflammaging in Health and Disease

Evaluation of the Neuroprotective Effects of Idebenone in an Experimental Carbon Monoxide Poisoning Model

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