Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury

Tsai, Tai-Hsin; Lin, Szu-Huai; Wu, Chieh‐Hsin; Tsai, Yi-Cheng; Yang, Sheau-Fang; Lin, Chih-Lung

doi:10.1371/journal.pone.0240122

Cited by 24 publications

(13 citation statements)

References 47 publications

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“…Western blotting (WB) analysis was performed as previously described ( Tsai et al, 2020 ). The extracted brain tissue was homogenized in tissue protein extraction reagent with protease inhibitor cocktail (CWBIO, China) and incubated on ice for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

Gong

Shen

et al. 2021

Front. Mol. Neurosci.

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Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl– cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1β, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.

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Section: Methodsmentioning

confidence: 99%

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

Gong

Shen

et al. 2021

Front. Mol. Neurosci.

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“…The procedures for treatment of the animals used in this study are approved by the Kaohsiung Medical University Animal Care and Use Committee (IACUC approval No: 100201). The experimental procedures are based on the previous article ( Lin et al, 2003 ; Tsai et al, 2020 ). Ninety-six male Sprague-Dawley rats (330 to 370 g), were purchased from BioLASCO Taiwan Co., Ltd.…”

Section: Methodsmentioning

confidence: 99%

“…This study adopted a single-hemorrhage rodent model of SAH. The rod model of SAH was described by Lin et al in a previous journal ( Lin et al, 2003 ; Tsai et al, 2020 ). Niety-six rats were randomly and evenly divided into four groups: a control group (no SAH, with sham surgery) ( n = 24), a SAH only group ( n = 24), a SAH + NC-mimic group ( n = 24), and a SAH + miR-195-5p group ( n = 24).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic effect of and mechanisms underlying the effect of miR-195-5p on subarachnoid hemorrhage-induced vasospasm and brain injury in rats

Tsai

Chang

Lin

et al. 2021

PeerJ

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Objectives There is much evidence suggesting that inflammation contributes majorly to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and brain injury. miRNAs have been found to modulate inflammation in several neurological disorders. This study investigated the effect of miR-195-5p on SAH-induced vasospasm and early brain injury in experimental rats. Methods Ninety-six Sprague-Dawley male rats were randomly and evenly divided into a control group (no SAH, sham surgery), a SAH only group, a SAH + NC-mimic group, and a SAH + miR-195-5p group. SAH was induced using a single injection of blood into the cisterna magna. Suspensions containing NC-mimic and miR-195-5p were intravenously injected into rat tail 30 mins after SAH was induced. We determined degree of vasospasm by averaging areas of cross-sections the basilar artery 24h after SAH. We measured basilar artery endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B), phosphorylated NF-κ B (p-NF-κ B), inhibitor of NF-κ B (Iκ Bα) and phosphorylated-Iκ Bα (p-Iκ Bα). Cell death assay was used to quantify the DNA fragmentation, an indicator of apoptotic cell death, in the cortex, hippocampus, and dentate gyrus. Tumor necrosis factor alpha (TNF-α) levels were measured using sample protein obtained from the cerebral cortex, hippocampus and dentate gyrus. Results Prior to fixation by perfusion, there were no significant physiological differences among the control and treatment groups. SAH successfully induced vasospasm and early brain injury. MiR-195-5p attenuated vasospasam-induced changes in morphology, reversed SAH-induced elevation of iNOS, p-NF-κ B, NF-κ B, and p-Iκ Bα and reversed SAH-induced suppression of eNOS in the basilar artery. Cell death assay revealed that MiR-195-5p significantly decreased SAH-induced DNA fragmentation (apoptosis) and restored TNF-α level in the dentate gyrus. Conclusion In conclusion, MiRNA-195-5p attenuated SAH-induced vasospasm by up-regulating eNOS, down-regulating iNOS and inhibiting the NF-κ B signaling pathway. It also protected neurons by decreasing SAH-induced apoptosis-related cytokine TNF-α expression in the dentate gyrus. Further study is needed to elucidate the detail mechanism underlying miR-195-5p effect on SAH-induced vasospasm and cerebral injury. We believe that MiR-195-5p can potentially be used to manage SAH-induced cerebral vasospasm and brain injury.

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“…RTA-408 protected against propofol-induced memory impairment assessed with the MWM and increased activation of Nrf2 and the inhibition of NF-κB p65 nuclear translocation [103]. Other studies have shown that RTA-408 increases Nrf2 and decreases NF-κB [104][105][106][107][108]. RTA-408 is a promising therapeutic for mitochondrial myopathy and immune disorders such as multiple sclerosis (MS) and Alzheimer's disease.…”

Section: The Role Of Nrf2 In Memorymentioning

confidence: 99%

Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

Davies

Adlimoghaddam

Albensi

2021

Cells

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD.

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Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury

Cited by 24 publications

References 47 publications

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

Therapeutic effect of and mechanisms underlying the effect of miR-195-5p on subarachnoid hemorrhage-induced vasospasm and brain injury in rats

Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

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