Mild Hypothermia Alleviates Complement C5a-Induced Neuronal Autophagy During Brain Ischemia–Reperfusion Injury After Cardiac Arrest

Wang, Ling; Sun, Yuanyuan; Kong, Fang; Jiang, Yi; An, Meng-Meng; Jin, Beibei; Cao, Da Long; Li, Ruifang; Guan, Xiao-Lan; Liang, Shuangshuang; Abudurexiti, Subi; Gong, Ping

doi:10.1007/s10571-022-01275-8

Cited by 4 publications

(4 citation statements)

References 46 publications

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“…In ischemia and hypoxia, the level of ATP in the brain is reduced because lack of oxygen and nutrition, which in turn inhibiting the expression of mTOR and activating autophagy. Previous studies showed that PI3K/Akt/mTOR signaling is essential to the survival of neurovascular units cerebral ischemia [37]. Our study revealed that the infarct volume as well as the leakage rate of the BBB, was significantly decreased, and the neurological function was significantly improved in CI/R rats after cornin treatment (Table .1 and Fig.…”

Section: Discussionsupporting

confidence: 59%

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

Lan

et al. 2022

BMC Pharmacol Toxicol

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Background Ischemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism. Methods Cornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood–brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells. Results The results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood–brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5–10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells. Conclusions These results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

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Section: Discussionsupporting

confidence: 59%

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

Lan

et al. 2022

BMC Pharmacol Toxicol

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“…This indicates that abnormal OPC autophagy is up-regulated and the Beclin 1/Bcl-2 complex is degraded, thus promoting OPC apoptosis. Multiple studies targeting inflammatory neurological diseases have demonstrated that autophagy mediated by the Akt/mTOR pathway plays an important role in this process [17,19]. Akt directly phosphorylates and activates mTOR.…”

Section: Discussionmentioning

confidence: 99%

“…Akt directly phosphorylates and activates mTOR. As discovered in an in vitro study on cerebral ischemia-reperfusion injury, following cerebral ischemia-reperfusion injury, complement activation produces C5a, which interacts with C5a receptor 1 to inactivate mTOR, leading to autophagy activation through the Akt/mTOR pathway and eventually neuronal apoptosis and brain damage [19]. This finding suggests that the Akt/mTOR pathway is involved in regulating autophagy and apoptosis.…”

Section: Introductionmentioning

confidence: 92%

Akt/mTOR Pathway Agonist SC79 Inhibits Autophagy and Apoptosis of Oligodendrocyte Precursor Cells Associated with Neonatal White Matter Dysplasia

Li,

Zhang,

Huang

et al. 2023

Neurochem Res

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White matter dysplasia (WMD) in preterm infants due to intrauterine inflammation is caused by excessive apoptosis of oligodendrocyte precursor cells (OPCs). In recent years, studies have found that excessive autophagy and apoptosis are highly interconnected and important in infection and inflammatory diseases in general. Therefore, in this study, we aimed to confirm whether regulation of autophagy by using the Akt phosphorylation agonist SC79 can inhibit abnormal apoptosis of OPCs and promote myelin maturation and white matter development in neonatal rats with WMD. We investigated the effect of inflammation on oligodendrocyte development in P0 neonatal rats by intracerebellar injection of LPS, and collected brain tissue at P2 and P5. Immunohistochemical and immunofluorescence staining were used to evaluate white matter damage, while immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling analysis (TUNEL), and western blotting were used to evaluate autophagy and apoptosis. First, we observed that white matter development was arrested and white matter fiber maturation was impaired in LPS-inflicted pups compared with those in the sham-operated group. Second, treatment with SC79 reduced the levels of LC3II, caspase 3, caspase 9, and Bax/Bcl-2 and increased the levels of p62, p-Akt, and p-mTOR in the brain tissue of neonatal rats. Finally, SC79 treatment inhibited OPC apoptosis by increasing the binding of Beclin 1 to Bcl-2, which promoted OPC differentiation and maturation. However, the opposite results were observed after rapamycin administration. Taken together, our results suggest that SC79 can inhibit the abnormal apoptosis of OPCs caused by excessive autophagy through the Akt/mTOR pathway and that SC79 is a potential therapeutic agent for WMD in preterm infants.

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“…[3][4][5] This approach has been shown to improve neuronal survival in the brain and other tissues following ischemiareperfusion, and its neuroprotective properties have been demonstrated to mitigate further damage caused by brain trauma, stroke, and spinal cord injury. 6,7 Mild therapeutic hypothermia also served as a neuroprotective treatment following spinal cord injury, with notable results observed in both preclinical and clinical settings.…”

Section: Introductionmentioning

confidence: 99%

The Protective Role and Mechanism of Mild Therapeutic Hypothermia Protection on Brain Cells

Liang¹,

Ti²,

Li³

et al. 2023

NDT

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Background: Moderate therapeutic hypothermia is protective against several cellular stressors. However, the mechanisms behind this protection are not entirely known. In the current investigation, we investigated that therapeutic hypothermia at 33°C administered following peroxide-induced oxidative stress might protect human oligodendroglioma cells using an in vitro model. Methods and Results: Tert-butyl peroxide treatment for one hour significantly increased cell apoptosis and suppressed cell viability. In the range of 50-1000 M tert-butyl peroxide, this cell death was dose-dependent. MTT assay and cell apoptosis assay were applied to analyze cell viability/death at 24 hours after peroxide-induced stress. Therapeutic hypothermia at 33°C delivered for two hours after peroxide exposure significantly increased cell viability and suppressed cell death. Even 15 minutes after peroxide washout when delayed hypothermia was used, this protection was still apparent. Three FDA-approved antioxidants (Tempol, EUK134, and Edaravone at 100 M) were added immediately after tert-butyl peroxide, followed by hypothermia treatment. These three antioxidants greatly increased cell viability and cell apoptosis. RT-qPCR was applied to determine the effects of hypothermia treatment on the expression of caspase-3 and −8 as well as tumor necrosis factor-alpha (TNF-α). Therapeutic hypothermia significantly downregulated these three factors. Conclusion: Overall, these findings confirmed that hypothermia and antioxidants quenching reactive oxygen species may lower mitochondrial oxidative stress and/or apoptotic pathways. Further investigation are needed to investigate the role of hypothermia in other cell models.

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Mild Hypothermia Alleviates Complement C5a-Induced Neuronal Autophagy During Brain Ischemia–Reperfusion Injury After Cardiac Arrest

Cited by 4 publications

References 46 publications

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

Akt/mTOR Pathway Agonist SC79 Inhibits Autophagy and Apoptosis of Oligodendrocyte Precursor Cells Associated with Neonatal White Matter Dysplasia

The Protective Role and Mechanism of Mild Therapeutic Hypothermia Protection on Brain Cells

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