Dysregulation of mTOR Signaling after Brain Ischemia

Villa-González, Mario; Martín-López, Gerardo; Pérez-Álvarez, María José

doi:10.3390/ijms23052814

Cited by 20 publications

(15 citation statements)

References 192 publications

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“…Simultaneously, Akt phosphorylation was inhibited by artesunate at various doses (Figure 6A,D). As mTORC1 is fully activated when located in the lysosomal membrane, 42 we used immunofluorescence staining to confirm whether artesunate exerted any effect on the subcellular localization of mTORC1. The results indicate that artesunate had no influence on the connection between mTORC1 and the lysosomal marker protein LAMP1 (Figure 7A,B).…”

Section: Resultsmentioning

confidence: 99%

Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1‐polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway

Xie

Liang

Gao

et al. 2023

Basic Clin Pharma Tox

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Intracerebral haemorrhage (ICH) is a catastrophic subtype of stroke with severe morbidity and mortality. However, little progress has been made in the subsequent secondary injury. Artesunate, a water-soluble semi-synthetic derivative of artemisinin, exhibits remarkable pharmacological effects on anti-neuroinflammation. However, the effects of artesunate on ICH remain unknown.In the present study, haemoglobin (Hb) treatment in BV2 cell and collagenase type IV intracerebroventricular injection in Sprague-Dawley rats were used to establish in vitro and in vivo ICH models, respectively. For in vivo, the neurological scores, haematoma volume, brain oedema, inflammatory factors and iron deposition were evaluated. Besides, lipopolysaccharide (LPS) was used in in vitro to polarize BV2 cell to M1 phenotype. Cell viability, cellular reactive oxygen species (ROS), Fe 2+ concentration, and lipid peroxidation levels, ferroptosis-associated proteins and mRNA, morphological of mitochondria were measured in vitro. Additionally, the AMP-activated protein kinase (AMPK)/mammalian/mechanistic target of rapamycin (mTOR) pathway were measured by western blot and immunofluorescence staining. The present in vivo results indicated that artesunate significantly ameliorated neurological deficits, haematoma volume and brain oedema in ICH rats. Besides, artesunate suppressed the M1-microglia relative inflammatory factors and up-regulated iron deposition. For in vitro, artesunate significantly selectively decreased the viability of LPS-stimulated BV2 cell. Furthermore, ROS and lipid peroxidation levels were up-regulated. And the glutathione peroxidase 4 (GPX4) were silenced via the AMPK/mTORC1 axis. Our finding supports that artesunate ameliorates the ICH secondary injury both in vitro and in vivo by inducing ferroptosis in microglia and further inhibiting inflammation mainly through the Guanfeng Xie and Yubing Liang contributed equally to this work.

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Section: Resultsmentioning

confidence: 99%

Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1‐polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway

Xie

Liang

Gao

et al. 2023

Basic Clin Pharma Tox

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“…The restoration of blood flow can mitigate the effects of ischemia only when performed a few hours after onset of the first symptoms. However, despite the beneficial effects of this approach, it is not suitable for all patients and does not reduce subsequent neurodegeneration (Sommer, 2017; Villa-González et al, 2022). In this context, considerable research efforts focus on the search for pharmacological alternatives to improve ischemic damage in these patients and enhance the effects of reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, the less damaged peri-infarct zone is potentially recoverable with an early intervention (Mansfield et al, 2018). The only therapeutical approximation approved in acute phase is reperfusion, however, it does not reduce the consequent neurodegeneration (Villa-González et al, 2022). Therefore, it is necessary to find alternative treatments to reduce ischemic damage and improve the beneficial effects of reperfusion.…”

Section: Introductionmentioning

confidence: 99%

“…mTOR is a ubiquitous serine-threonine protein kinase, highly conserved, formed by two multiprotein complexes: mTORC1 and mTORC2. Both mTOR complexes (mTORCs) coordinate a wide range of anabolic and catabolic responses, so it is considered a pivotal player in the cellular homeostasis (Liu & Sabatini, 2020; Villa-González et al, 2022). Consequently, mTOR signalling dysregulation or dysfunction significantly affect CNS integrity (Karalis & Bateup, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity

Villa-González,

Rubio,

Martín-López

et al. 2024

Preprint

Self Cite

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Ischemic stroke is a sudden and acute disease characterized by neuronal death, glia activation, and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Microglial activation involves functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such microglial activation is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia. Here, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury. Our data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.

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“…Hence, it is concluded that MSC-Exos might affect GLT-1 expression by regulating miR-124. The mTOR pathway, which is regarded as a target of therapy for ischemic stroke, plays a significant role in its pathogenic progression [14]. It has been shown that insulin promotes the downregulated GLT-1 expression induced by Abeta through the mTOR pathway [15].…”

Section: Introductionmentioning

confidence: 99%

Marrow Mesenchymal Stem Cell-Derived Exosomes Upregulate Astrocytic Glutamate Transporter-1 Expression via miR-124/mTOR Pathway against Oxygen-Glucose Deprivation/Reperfusion Injury

Huang,

Fan,

Jiang

et al. 2023

J. Integr. Neurosci.

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Background: Experimental investigations have reported the efficacy of marrow mesenchymal stem cell-derived exosomes (MSC-Exos) for the treatment of ischemic stroke. The therapeutic mechanism, however, is still unknown. The purpose of the study is to show whether MSC-Exos increases astrocytic glutamate transporter-1 (GLT-1) expression in response to ischemic stroke and to investigate further mechanisms. Methods and Results: An in vitro ischemia model (oxygen-glucose deprivation/reperfusion, OGD/R) was used. MSC-Exos was identified by Western blot (WB) and transmission electron microscopy (TEM). To further investigate the mechanism, MSC-Exos, miR-124 inhibitor, and mimics, and a mTOR pathway inhibitor (rapamycin, Rap) were used. The interaction between GLT-1 and miR-124 was analyzed by luciferase reporter assay. The GLT-1 RNA expression and miR-124 was assessed by quantitative real-time polymerase chain reaction (qRTPCR). The protein expressions of GLT-1, S6, and pS6 were detected by WB. Results demonstrated that MSC-Exos successfully inhibited the decrease of GLT-1 and miR-124 expression and the increase of pS6 expression in astrocytes after OGD/R. miR-124 inhibitor suppressed the effect of MSC-Exos on GLT-1 upregulation after OGD/R. Rapamycin notably decreased pS6 expression with significantly higher GLT-1 expression in astrocytes injured by OGD/R. Luciferase activity of the reporter harboring the wild-type or mutant GLT-1 3 ′ UTR was not inhibited by miR-124 mimics. Further results showed that the inhibiting effect of MSC-Exos on pS6 expression and promoting effect of MSC-Exos on GLT-1 expression could be reversed by miR-124 inhibitor after OGD/R; meanwhile, the above conditions could be reversed again by rapamycin. Conclusions: Results show that miR-124 and the mTOR pathway are involved in regulation of MSC-Exos on GLT-1 expression in astrocytes injured by OGD/R. miR-124 does not directly target GLT-1. MSC-Exos upregulates GLT-1 expression via the miR-124/mTOR pathway in astrocytes injured by OGD/R.

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Dysregulation of mTOR Signaling after Brain Ischemia

Cited by 20 publications

References 192 publications

Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1‐polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway

Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1‐polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway

Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity

Marrow Mesenchymal Stem Cell-Derived Exosomes Upregulate Astrocytic Glutamate Transporter-1 Expression via miR-124/mTOR Pathway against Oxygen-Glucose Deprivation/Reperfusion Injury

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