Everolimus inhibits PI3K/Akt/mTOR and NF-kB/IL-6 signaling and protects seizure-induced brain injury in rats

Huang, Xiangyi; Hu, Qing-peng; Shi, Hongyun; Zheng, Ya-yu; Hu, Rongrong; Guo, Qian

doi:10.1016/j.jchemneu.2021.101960

Cited by 25 publications

(16 citation statements)

References 36 publications

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“…mTOR inhibition also improves anti-inflammation through the regulation of T cells and modulation of immune response by a potent suppression of CD4+ effector T cells, promotion of Tregs, and activation of the innate immune system . Notably, suppression of the PI3K/Akt/mTOR pathway in epileptic rats inhibited microglia activation and neuronal cell apoptosis . These inhibitory effects highlight the role of PI3K/Akt/mTOR in microglial activation and immunomodulation.…”

Section: Resultsmentioning

confidence: 90%

Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy

Senousy

Hanafy

Shehata

et al. 2022

ACS Chem. Neurosci.

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Oxidative stress and mitochondrial dysfunction are among the mechanisms expected to explain the pathogenesis of Huntington's disease. Erythropoietin (EPO) and the Bacillus Calmette−Gueŕin (BCG) vaccine have neuroprotective effects against neurodegenerative diseases; however, the full mechanisms of their action are currently unclear. Here, for the first time, we investigated the neuroprotective effect of BCG vaccination in Huntington-like disease induced by 3-nitropropionic acid (3-NP) and its combination with EPO. Male Wistar rats were randomized into five groups: saline-treated control; 3-NP group (20 mg/kg/day, i.p.) for 7 days; EPO-treated group (5000 IU/kg/day, i.p.) for 14 days after 3-NP administration; live BCG vaccine prophylactic group (5000 cfu/g, i.p.) 10 days prior to 3-NP administration; and live BCG vaccine (5000 cfu/g, i.p.) 10 days before 3-NP administration, followed by EPO treatment (5000 IU/kg/day, i.p.) for 14 days. In a histopathological examination, striatum neurodegeneration was evidenced in the 3-NP injected rats. Administration of 3-NP elevated the levels of p-PI3K, p-Akt, p-mTOR, p-P70S6K, BAX, malondialdehyde, nitric oxide, and cytochrome oxidase while reduced the levels of BCL-2, superoxide dismutase, reduced glutathione, and the autophagy marker microtubule-associated protein light chain 3 in the striatum. EPO and BCG ameliorated the biochemical, histopathological, and behavioral derangements induced by 3-NP, with prominent neuroprotection observed in rats administered the BCG prophylactic combined with EPO treatment. These results highlight the role played by EPO and BCG in the management of 3-NP-induced Huntington-like disease by inhibiting the PI3K/Akt/mTOR/P70S6K pathway and enhancing the autophagy.

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Section: Resultsmentioning

confidence: 90%

Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy

Senousy

Hanafy

Shehata

et al. 2022

ACS Chem. Neurosci.

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“…The results revealed that treatment of RAD001 diminished the expression levels of PI3K, p-AKT, p-mTOR, p-S6K1, and p62, and elevated the LC3-II/LC3-I ratio and amount of acidic autophagic vesicles in CC cells. Consistently, RAD001 impedes the expression levels of PI3K, p-AKT, AKT, mTOR, and p-mTOR in epilepsy rats [ 71 ]. Mounting evidence has unveiled the promotion effect of numerous anti-tumor drugs on apoptosis and autophagy through the suppression of AKT/mTOR signaling [ 72 ].…”

Section: Discussionmentioning

confidence: 92%

Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway

2022

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Cervical cancer (CC) is the 4 th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.

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“…Pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-10, TNF-α, and IFN-γ, are usually released by activated microglia and astrocytes ( O’Neill and Kaltschmidt, 1997 ; Vezzani and Baram, 2007 ) and typically concentrated in low quantities within the brain. Their expression increased after seizures ( Scorza et al, 2018 ), and they can enhance neuronal excitability and form a toxic microenvironment that promotes the progression of epilepsy ( Kovács et al, 2011 ; Huang et al, 2021 ). The imbalance between glutamate and γ-aminobutyric acid (GABA) in the brain after epileptic seizures depends on the action of these cytokines ( Hu et al, 2000 ; Takeuchi et al, 2006 ), and they may cause neuronal death through mitochondrial dysfunction or abnormal ion currents ( Folbergrová and Kunz, 2012 ).…”

Section: Abnormal Expression Of Nuclear Factor Kappa B and Its Target...mentioning

confidence: 99%

The Function of NF-Kappa B During Epilepsy, a Potential Therapeutic Target

Cai

Lin

2022

Front. Neurosci.

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The transcriptional regulator nuclear factor kappa B (NF-κB) modulates cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. The NF-κB pathway plays a major role in the expressing genes related to inflammation, including chemokines, interleukins, and tumor necrosis factor. It also transcribes genes that can promote neuronal survival or apoptosis. Epilepsy is one of the most common brain disorders and it not only causes death worldwide but also affects the day-to-day life of affected individuals. While epilepsy has diverse treatment options, there remain patients who are not sensitive to the existing treatment methods. Recent studies have implicated the critical role of NF-κB in epilepsy. It is upregulated in neurons, glial cells, and endothelial cells, due to neuronal loss, glial cell proliferation, blood-brain barrier dysfunction, and hippocampal sclerosis through the glutamate and γ-aminobutyric acid imbalance, ion concentration changes, and other mechanisms. In this review, we summarize the functional changes caused by the upregulation of NF-κB in the central nervous system during different periods after seizures. This review is the first to deconvolute the complicated functions of NF-κB, and speculate that the regulation of NF-κB can be a safe and effective treatment strategy for epilepsy.

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Everolimus inhibits PI3K/Akt/mTOR and NF-kB/IL-6 signaling and protects seizure-induced brain injury in rats

Cited by 25 publications

References 36 publications

Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy

Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy

Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway

The Function of NF-Kappa B During Epilepsy, a Potential Therapeutic Target

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