Protective effects of Gypenoside XVII against cerebral ischemia/reperfusion injury via SIRT1-FOXO3A- and Hif1a-BNIP3-mediated mitochondrial autophagy

Xie, Weijie; Zhu, Ting; Zhang, Shuxia; Sun, Xiaobo

doi:10.1186/s12967-022-03830-9

Cited by 19 publications

(9 citation statements)

References 45 publications

(72 reference statements)

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“…In addition, the dose of GP-17 used to prevent neuronal damage in our in vivo study was 30 mg/kg. Consistent with our study, studies have revealed that the effect of GP-17 occurs at 10-50 mg/kg in vivo [17,65]. Other gypenosides administered at doses of 100-200 mg/kg can attenuate depression-or anxiety-like behavior of the mice [67] and improve memory impairment in rats [68].…”

Section: Discussionsupporting

confidence: 92%

“…Studies in laboratory animals indicate that GP-17 has neuroprotective effects [17,18,65]. However, the mechanisms underlying the neuroprotective effects of GP-17 are still under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Several experimental studies have reported various pharmacological properties to GP-17, including immunoregulatory, anti-inflammatory, neuroprotective, cardioprotective, lipid-lowering, and neuroprotective effects [11][12][13][14][15][16]. Regarding its neuroprotective effect, GP-17 attenuated cerebral infarct volume and alleviated neurological dysfunction in a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model [17]. GP-17 also attenuates Aβ-induced oxidative stress, apoptosis, and autophagic cell death in PC12 cells, prevents the formation of Aβ plaques in the hippocampus and cortex, and improves spatial learning and memory deficits in APP/PS1 mice [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

Lu,

Lin,

Chiu

et al. 2024

Biomolecules

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Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside XVII (GP-17), a gypenoside monomer, on the glutamatergic system. In vitro, in rat cortical nerve terminals (synaptosomes), GP-17 dose-dependently decreased glutamate release with an IC50 value of 16 μM. The removal of extracellular Ca2+ or blockade of N-and P/Q-type Ca2+ channels and protein kinase A (PKA) abolished the inhibitory effect of GP-17 on glutamate release from cortical synaptosomes. GP-17 also significantly reduced the phosphorylation of PKA, SNAP-25, and synapsin I in cortical synaptosomes. In an in vivo rat model of glutamate excitotoxicity induced by kainic acid (KA), GP-17 pretreatment significantly prevented seizures and rescued neuronal cell injury and glutamate elevation in the cortex. GP-17 pretreatment decreased the expression levels of sodium-coupled neutral amino acid transporter 1, glutamate synthesis enzyme glutaminase and vesicular glutamate transporter 1 but increased the expression level of glutamate metabolism enzyme glutamate dehydrogenase in the cortex of KA-treated rats. In addition, the KA-induced alterations in the N-methyl-D-aspartate receptor subunits GluN2A and GluN2B in the cortex were prevented by GP-17 pretreatment. GP-17 also prevented the KA-induced decrease in cerebral blood flow and arginase II expression. These results suggest that (i) GP-17, through the suppression of N- and P/Q-type Ca2+ channels and consequent PKA-mediated SNAP-25 and synapsin I phosphorylation, reduces glutamate exocytosis from cortical synaptosomes; and (ii) GP-17 has a neuroprotective effect on KA-induced glutamate excitotoxicity in rats through regulating synaptic glutamate release and cerebral blood flow.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

Lu,

Lin,

Chiu

et al. 2024

Biomolecules

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“…(Pan et al, 2021). The underlying mechanisms of HIF-1 regulated stroke including apoptotic (Cheng et al, 2014), neurogenesis (Wu et al, 2018), BBB integrity (Liu et al, 2021b) inflammation (Pan et al, 2021), autophagy (Xie et al, 2022;Zhang et al, 2022), and oxidative stress (Peng et al, 2020). However, the effect of HIF-1 was doublesided and may be related to the time and degree of ischemia.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke

Liu

Zhang

et al. 2023

Front. Pharmacol.

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At present, the preventive effect of ischemic stroke is not ideal, and the preventive drugs are limited. Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of cardiovascular diseases for many years. Phenolic Acids extracted from danshen, which showed multiple biological activities, have been developed as an injection for the treatment of ischemic stroke. However, its preventive effect on ischemic stroke has not been fully reported. The current study aimed to identify the potential active phenolic acids for the prevention of ischemic stroke and explore its mechanism using network pharmacology and experimental analyses. The targets of phenolic acids and ischemic stroke were obtained from public databases. Network pharmacology predicted that 35 kinds of phenolic acids had 201 core targets with ischemic stroke. The core prevention targets of ischemic stroke include IL-6, AKT1, VEGFA, etc. The signaling pathways involved in core targets include AGE-RAGE signaling pathway, HIF-1 signaling pathway, and cAMP signaling pathways, etc. Then, the antiplatelet effect of phenolic acids was screened by in vitro antiplatelet experiment. Our results showed that phenolic acids have a good inhibitory effect on ADP-induced platelet aggregation and salvianolic acid A had a good antiplatelet effect. We further demonstrated that SAA preventive administration reduced neurobehavioral scores, decreased infarct size, and protected tight junction proteins in autologous thrombus stroke model. These studies not only shed light on the potential mechanisms of phenolic acids active components on ischemic stroke, but also provided theoretical and experimental information for the development of new medicines from Danshen for the prevention of ischemic stroke. In addition, our results suggest that SAA has the potential to be a candidate for ischemic stroke prevention drug.

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“…As described previously, Western Blot was conducted (Karda et al 2017 ; Xie et al 2022 ). In brief, proteins (20–40 ug) were subjected to electrophoresis, electroporation, blocking, and incubation with the primary antibodies and the corresponding secondary antibodies (Table S2 ).…”

Section: Methodsmentioning

confidence: 99%

SIRT1 restores mitochondrial structure and function in rats by activating SIRT3 after cerebral ischemia/reperfusion injury

Chen,

Liu,

et al. 2024

Cell Biol Toxicol

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Mitochondrial dysfunction contributes to cerebral ischemia–reperfusion (CI/R) injury, which can be ameliorated by Sirtuin-3 (SIRT3). Under stress conditions, the SIRT3-promoted mitochondrial functional recovery depends on both its activity and expression. However, the approach to enhance SIRT3 activity after CI/R injury remains unelucidated. In this study, Sprague–Dawley (SD) rats were intracranially injected with either adeno-associated viral Sirtuin-1 (AAV-SIRT1) or AAV-sh_SIRT1 before undergoing transient middle cerebral artery occlusion (tMCAO). Primary cortical neurons were cultured and transfected with lentiviral SIRT1 (LV-SIRT1) and LV-sh_SIRT1 respectively before oxygen–glucose deprivation/reoxygenation (OGD/R). Afterwards, rats and neurons were respectively treated with a selective SIRT3 inhibitor, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). The expression, function, and related mechanism of SIRT1 were investigated by Western Blot, flow cytometry, immunofluorescence staining, etc. After CI/R injury, SIRT1 expression decreased in vivo and in vitro. The simulation and immune-analyses reported strong interaction between SIRT1 and SIRT3 in the cerebral mitochondria before and after CI/R. SIRT1 overexpression enhanced SIRT3 activity by increasing the deacetylation of SIRT3, which ameliorated CI/R-induced cerebral infarction, neuronal apoptosis, oxidative stress, neurological and motor dysfunction, and mitochondrial respiratory chain dysfunction, promoted mitochondrial biogenesis, and retained mitochondrial integrity and mitochondrial morphology. Meanwhile, SIRT1 overexpression alleviated OGD/R-induced neuronal death and mitochondrial bioenergetic deficits. These effects were reversed by AAV-sh_SIRT1 and the neuroprotective effects of SIRT1 were partially offset by 3-TYP. These results suggest that SIRT1 restores the structure and function of mitochondria by activating SIRT3, offering neuroprotection against CI/R injury, which signifies a potential approach for the clinical management of cerebral ischemia. Graphical Abstract 1. SIRT1 is downregulated after cerebral ischemia/reperfusion injury. 2. SIRT1 can increase the deacetylation of SIRT3 and enhance the activity of SIRT3 after cerebral ischemia/reperfusion injury. 3. SIRT1 enhances the mitochondrial structure repair and functional recovery by activating SIRT3 after cerebral ischemia/reperfusion injury in rats, thereby promoting neurological function.

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Protective effects of Gypenoside XVII against cerebral ischemia/reperfusion injury via SIRT1-FOXO3A- and Hif1a-BNIP3-mediated mitochondrial autophagy

Cited by 19 publications

References 45 publications

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke

SIRT1 restores mitochondrial structure and function in rats by activating SIRT3 after cerebral ischemia/reperfusion injury

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