Atractylenolide III alleviates isoflurane‐induced injury in rat hippocampal neurons by activating the PI3K/Akt/mTOR pathway

Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.

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Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

Scientific Reports ◽

10.1038/srep22991 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 8

Author(s):

Yuki Matsushita ◽

Yasunari Sakai ◽

Mitsunori Shimmura ◽

Hiroshi Shigeto ◽

Miki Nishio ◽

...

Keyword(s):

Hippocampal Neurons ◽

Focal Cortical Dysplasia ◽

Mossy Fibers ◽

Premature Death ◽

Mtor Pathway ◽

Conditional Knockout ◽

Inhibitory Neurons ◽

Sequencing Data ◽

Functional Roles ◽

Synaptic Markers

Abstract Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.

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Long noncoding RNA Nespas inhibits apoptosis of epileptiform hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway

Experimental Cell Research ◽

10.1016/j.yexcr.2020.112384 ◽

2021 ◽

Vol 398 (1) ◽

pp. 112384

Author(s):

Hongxuan Feng ◽

Qian Gui ◽

Guanhui Wu ◽

Wei Zhu ◽

Xiaofeng Dong ◽

...

Keyword(s):

Long Noncoding Rna ◽

Hippocampal Neurons ◽

Noncoding Rna ◽

Mtor Pathway

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Correction: Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

PLoS Biology ◽

10.1371/journal.pbio.1002625 ◽

2018 ◽

Vol 16 (3) ◽

pp. e1002625

Author(s):

Keyword(s):

Cognitive Deficits ◽

Hippocampal Neurons ◽

Mtor Pathway ◽

Postnatal Exposure

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Schizandrol A protects against Aβ1–42-induced autophagy via activation of PI3K/AKT/mTOR pathway in SH-SY5Y cells and primary hippocampal neurons

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-019-01792-2 ◽

2020 ◽

Vol 393 (9) ◽

pp. 1739-1752 ◽

Cited By ~ 3

Author(s):

Lin Song ◽

Lifen Yao ◽

Limei Zhang ◽

Zhongyuan Piao ◽

Yichan Lu

Keyword(s):

Hippocampal Neurons ◽

Mtor Pathway ◽

Primary Hippocampal Neurons

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Neuroprotective Effects of Oxymatrine on PI3K/Akt/mTOR Pathway After Hypoxic-Ischemic Brain Damage in Neonatal Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.642415 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wei Wei ◽

Min Lu ◽

Xiao-bing Lan ◽

Ning Liu ◽

Wei-ke Su ◽

...

Keyword(s):

Brain Damage ◽

Hippocampal Neurons ◽

Mitochondrial Permeability Transition ◽

Chinese Herb ◽

Specific Inhibitor ◽

Mtor Pathway ◽

Protective Effects ◽

Neuroprotective Effects ◽

Ischemic Brain Damage ◽

Ischemic Brain

Oxymatrine (OMT), a quinolizidine alkaloid extracted from traditional Chinese herb Sophora flavescens Ait, has drawn attention because of its beneficial bioactivities against hypoxic–ischemic brain damage (HIBD). However, the underlying molecular mechanism remains unclear. In this study, we determined the in vivo and in vitro effects of OMT on seven-day old Sprague–Dawley rats with HIBD and in a rat model of primary hippocampal neuron oxygen glucose deprivation reoxygenation (OGD/R). This study was aimed to evaluate whether OMT exerted neuroprotective effects mediated by the (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) PI3K/Akt/mTOR pathway after HIBD. Experimental results showed that the alkaloid significantly improved the early neurofunctional development, brain water content, abnormal pathological changes, and necrosis of neurons after HIBD. Moreover, OMT enhanced the cell viability and stabilized the mitochondrial permeability transition pore in the primary hippocampal neurons after OGD/R. OMT significantly decreased the autophagosome generation, elevated the expression of PI3K, Akt, and mTOR, and simultaneously reversed the mRNA expression of microtubule-associated protein 1-light chain 3 (LC3), Beclin-1, and sequestosomel (P62) induced by hypoxia and ischemia. However, these protective effects against HIBD could be suppressed when rapamycin, a specific inhibitor of mTOR, was included. Hence, the OMT exerted neuroprotective effects against HIBD by attenuating excessive autophagy by mediating the PI3K/Akt/mTOR pathway.

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Sinisan Protects Primary Hippocampal Neurons Against Corticosterone by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.627056 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mingjia Zhang ◽

Yi Zhang ◽

Haitao Sun ◽

Hui Ni ◽

Jialing Sun ◽

...

Keyword(s):

Protein Expression ◽

Mrna Expression ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Mtor Pathway ◽

Therapeutic Effects ◽

Protein Ratio ◽

Expression Levels ◽

Primary Hippocampal Neurons ◽

Mrna Expression Levels

Objective: Corticosterone causes significant neurotoxicity in primary hippocampal neurons which is associated with depression. Dysfunctional autophagy is implicated in cognitive impairment and depressive-like behavior. The traditional Chinese medicine Sinisan (SNS) is highly effective in clinical treatment of depression. However, the molecular mechanisms underlying therapeutic effects of SNS are unknown.Purpose: The aim of this study was to elucidate the protective effect of SNS and the underlying mechanisms against corticosterone-induced neuronal damage.Study Design: The effects of serum derived from rats containing SNS (or untreated controls) on the expression of autophagy-related molecules in primary rat hippocampal neurons exposed to different concentrations of corticosterone for different intervals were explored.Methods: CCK-8 assay, LDH assay were used to analyze cell viability and LDH activity. Western blot, qRT-PCR, and immunofluorescence assays were used to determine protein and mRNA expression levels of molecules such as LC3, p62, Beclin1, ULK1, PI3K, p-PI3K, Akt p-Akt, mTOR, p-mTOR, p70S6, p-p70S6, 4ebp1 and p-4ebp1.Results: Corticosterone induced a dose- and time-dependent reduction in cellular viability. Moreover, corticosterone (100–400 μM) treatment for 24 h increased LC3-II/LC3-I protein ratio, increased Beclin1 and ULK1 protein expression levels, and decreased p62, PI3K, p-PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein expression levels. Notably, SNS-containing serum reversed corticosterone-induced reduction of neuronal viability, and increased p62, PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein and mRNA expression levels. In addition, SNS-containing serum decreased LC3-II/LC3-I protein ratio, and downregulated Beclin1, and ULK1 protein and mRNA expression in primary hippocampal neurons.Conclusion: SNS protects primary hippocampal neurons against corticosterone-induced neurotoxicity by preventing excessive autophagy through activation of PI3K/AKT/mTOR pathway.

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Fangjing decoction relieves febrile seizures-induced hippocampal neuron apoptosis in rats via regulating the Akt/mTOR pathway

Bioscience Reports ◽

10.1042/bsr20181206 ◽

2018 ◽

Vol 38 (5) ◽

Author(s):

Xian-ke Xu ◽

Sun-yao Wang ◽

Ying Chen ◽

Lu Zhan ◽

Zheng-yang Shao ◽

...

Keyword(s):

Hippocampal Neurons ◽

Hippocampal Neuron ◽

Febrile Seizures ◽

Mtor Pathway ◽

Mtor Signaling ◽

Rat Hippocampus ◽

Control Group ◽

Protective Effects ◽

Bax Protein ◽

Neuron Apoptosis

Background: Fangjing decoction is a Traditional Chinese Medicine that exhibits anticonvulsive effects in treating febrile seizures (FS). Its action mechanism and the regulation on Akt/mammalian target of rapamycin (mTOR) pathway were revealed in the present study. Methods: FS model was established in Sprague–Dawley rats with or without Fangjing decoction treatment. On day 5, following initiation of drug treatment, seizures were monitored. Hippocampal neuron apoptosis was assessed using terminal dUTP nick end-labeling method. The levels of Bax, protein kinase B (Akt), phospho-Akt (p-Akt), mTOR, and p-mTOR proteins were analyzed using Western blotting. The content of hippocampal γ-aminobutyric acid (GABA) was measured by using ELISA assay. Results: Compared with the control group (n=8), Fangjing decoction effectively shortened escape latency and duration of FS and decreased the frequency of FS in rats (n=8). Concomitantly, the apoptosis of hippocampal neurons, as well as Bax protein levels were also decreased in FS rats which were treated with Fangjing decoction. In addition, the Akt/mTOR signaling was found to be activated in rat hippocampus following FS, as evidenced by increased p-Akt and p-mTOR, while Fangjing decoction could inhibit the activation of Akt/mTOR signaling. Furthermore, the low GABA content in rat hippocampus following FS was significantly elevated by Fangjing decoction treatment. More importantly, SC79, a specific activator for Akt, apparently attenuated the protective effects of Fangjing decoction on FS rats. Conclusion: These results suggest that Fangjing decoction protects the hippocampal neurons from apoptosis by inactivating Akt/mTOR pathway, which may contribute to mitigating FS-induced brain injury.

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