T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin‐1‐Like Protein Pathway

Dai, Jiaxing; Xu, Shuai; Okada, Takeshi; Liu, Yu; Zuo, Gang; Tang, Jiping; Zhang, Junyi; Shi, Huaizhang

doi:10.1155/2021/8849131

Cited by 14 publications

(4 citation statements)

References 48 publications

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“…In the present study, activation of the RARα promoted M1-to-M2 phenotypic polarization of microglia in an in vitro model of SAH. Apoptosis, as an important regulatory mechanism of cell death, is involved in the pathological processes underlying many diseases ( 46 , 47 ). Activation of the RARα with Am80 significantly suppressed neuronal apoptosis after SAH; this was consistent with previous research ( 14 ) and suggests that the activation of RARα attenuates the neurotoxic effects of activated microglia by suppressing the production of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

Tian

Liu

et al. 2022

Front. Immunol.

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Background and PurposeSubarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high rates of mortality. In the early stages of SAH, neuroinflammation is one of the important mechanisms leading to brain injury after SAH. In various central nervous system diseases, activation of RARα receptor has been proven to demonstrate neuroprotective effects. This study aimed to investigate the anti-inflammatory effects of RARα receptor activation after SAH.MethodsInternal carotid artery puncture method used to established SAH model in Sprague-Dawley rats. The RARα specific agonist Am80 was injected intraperitoneally 1 hour after SAH. AGN196996 (specific RARα inhibitor), Msr1 siRNA and LY294002 (PI3K-Akt inhibitor) were administered via the lateral ventricle before SAH. Evaluation SAH grade, neurological function score, blood-brain barrier permeability. BV2 cells and SH-SY5Y cells were co-cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. RT-PCR, Western blotting, and immunofluorescence staining were used to investigate pathway-related proteins, microglia activation and inflammatory response. Results: The expression of RARα, Mafb, and Msr1 increased in rat brain tissue after SAH. Activation of the RARα receptor with Am80 improved neurological deficits and attenuated brain edema, blood brain barrier permeability. Am80 increased the expression of Mafb and Msr1, and reduced neuroinflammation by enhancing the phosphorylation of Akt and by inhibiting the phosphorylation of NF-κB. AGN196996, Msr1 siRNA, and LY294002 reversed the therapeutic effects of Am80 by reducing the expression of Msr1 and the phosphorylation of Akt. In vitro model of SAH, Am80 promoted M1-to-M2 phenotypic polarization in microglia and suppressed the nuclear transcription of NF-κB.ConclusionActivation of the RARα receptor attenuated neuroinflammation by promoting M1-to-M2 phenotypic polarization in microglia and regulating the Mafb/Msr1/PI3K-Akt/NF-κB pathway. RARα might serve as a potential target for SAH therapy.

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Section: Discussionmentioning

confidence: 99%

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

Tian

Liu

et al. 2022

Front. Immunol.

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“…Accumulating evidence has revealed that oxidative damage and inflammatory response play critical roles in the pathogenesis of SAH [ 25 – 29 ]. Diminishing oxidative damage and inflammatory response could significantly improve neurological outcome after SAH [ 30 – 33 ].…”

Section: Discussionmentioning

confidence: 99%

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway

Lin

Yao²,

Lai

et al. 2022

Oxidative Medicine and Cellular Longevity

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Subarachnoid hemorrhage (SAH) is an acute cerebral vascular disease featured by oxidative insults and neuroinflammation. Cycloastragenol (CAG), the major active component of Astragalus radix, has a wide range of biological functions. However, the potential beneficial effects and the underlying molecular mechanisms of CAG on SAH remain obscure. In the current study, the cerebroprotective effects and mechanism of CAG on SAH were evaluated both in vivo and in vitro. Our results indicated that CAG significantly suppressed SAH-triggered oxidative insults, inflammatory mediators production, microglia activation, and the neutrophil infiltration in the brain. In addition, CAG improved neurological function and ameliorated neuronal apoptosis and degeneration after SAH. In vitro results also revealed the therapeutic effects of CAG on neurons and microglia co-culture system. Mechanistically, CAG treatment upregulated sirtuin 1 (SIRT1) expression, inhibited the levels of FoxO1, nuclear factor-kappa B, and p53 acetylation, and suppressed the subsequent oxidative, inflammatory, and apoptotic pathways. In contrast, inhibiting SIRT1 by pretreatment with Ex527 abrogated the protective actions of CAG both in vivo and in vitro models of SAH. Collectively, our findings indicated that CAG could be a promising and effective drug candidate for SAH.

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“…Modified Garcia score and the beam balance score were used to assess the short-term neurological function 24 h after SAH. The modified Garcia score was divided into six categories as follows: Voluntary movement, voluntary limb movement, forepaw extension, climbing ability, somatosensory responses and tentacle response, each of which was scored individually and summed to give a total score ranging from 3–18 ( 25 ). Higher scores were considered to indicate better neurological function.…”

Section: Methodsmentioning

confidence: 99%

ASK1 inhibitor NQDI‑1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

et al. 2023

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oxidative stress and neuroapoptosis are key pathological processes after subarachnoid hemorrhage (Sa H ). T he present st udy eva luated t he anti-oxidation and anti-apoptotic neuroprotective effects of the apoptosis signal-regulating kinase 1 (aSK1) inhibitor ethyl-2,7-dioxo-2,7-dihydro-3H-naphtho(1,2,3-de) quinoline1-carboxylate (nQdi-1) in early brain injury (eBi) following SaH in a rat model. a total of 191 rats were used and the SAH model was induced using monofilament perforation. Western blotting was subsequently used to detect the endogenous expression levels of proteins. Immunofluorescence was then used to confirm the nerve cellular localization of aSK1. Short-term neurological function was assessed using the modified Garcia scores and the beam balance test 24 h after SaH, whereas long-term neurological function was assessed using the rotarod test and the Morris water maze test. apoptosis of neurons was assessed by Tunel staining and oxidative stress was assessed by dihydroethidium staining 24 h after SaH. The protein expression levels of phosphorylated (p-)aSK1 and aSK1 rose following SaH. nQdi-1 was intracerebroventricularly injected 1 h after SaH and demonstrated significant improvements in both short and long-term neurological function and significantly reduced oxidative stress and neuronal apoptosis. injection of nQdi-1 caused a significant decrease in protein expression levels of p-ASK1, p-p38, p-JNK, 4 hydroxynonenal, and Bax and significantly increased the protein expression levels of heme oxygenase 1 and Bcl-2. The use of the p38 inhibitor BMS-582949 or the JNK inhibitor SP600125 led to significant decreases in the protein expression levels of p-p38 or p-JnK, respectively, and a significant reduction in oxidative stress and neuronal apoptosis; however, these inhibitors did not demonstrate an effect on p-aSK1 or aSK1 protein expression levels. in conclusion, treatment with nQdi-1 improved neurological function and decreased oxidative stress and neuronal apoptosis in eBi following SaH in rats, possibly via inhibition of aSK1 phosphorylation and the aSK1/p38 and JnK signaling pathway. nQdi-1 may be considered a potential agent for the treatment of patients with SaH.

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T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin‐1‐Like Protein Pathway

Cited by 14 publications

References 48 publications

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway

ASK1 inhibitor NQDI‑1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

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