Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke

Fletcher, Lauren; Evans, Teresa M.; Watts, Lora Talley; Jimenez, David F.; Digicaylioglu, Murat

doi:10.1371/journal.pone.0068281

Cited by 52 publications

(35 citation statements)

References 42 publications

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“…Recent studies have demonstrated that the activation of NF-jB and p38MAPK is linked to the pathogenesis of cerebral ischemia Wang et al 2010). Other research reports have shown that mTOR pathway, as a novel neuroprotectants for IS, plays a pivotal role in protecting against stroke (Xiong et al 2014;Fletcher et al 2013). Our findings indicated that the target genes of these differentially expressed miRNAs might participate in the mTOR, MAPK, and ErB signal pathways.…”

Section: Discussionmentioning

confidence: 99%

Identification of Circulating MicroRNAs as Potential Biomarkers for Detecting Acute Ischemic Stroke

et al. 2014

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MicroRNAs (miRNAs) are present in serum and have the potential to serve as disease biomarkers. As such, it is important to explore the clinical value of miRNAs in serum as biomarkers for ischemic stroke (IS) and cast light on the pathogenesis of IS. In this study, we screened differentially expressed serum miRNAs from IS and normal people by miRNA microarray analysis, and validated the expression of candidate miRNAs using quantitative reverse-transcriptase polymerase chain reaction assays. Furthermore, we performed gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses to disclose functional enrichment of genes predicted to be regulated by the differentially expressed miRNAs. Notably, our results revealed that 115 miRNAs were differentially expressed in IS, among which miR-32-3p, miR-106-5p, and miR-532-5p were first found to be associated with IS. In addition, GO and KEGG pathway analyses showed that genes predicted to be regulated by differentially expressed miRNAs were significantly enriched in several related biological process and pathways, including axon guidance, glioma, MAPK signaling, mammalian target of rapamycin signaling, and ErbB-signaling pathway. In conclusion, we identified the changed expression pattern of miRNAs in IS. Serum miR-32-3p, miR-106-5p, miR-1246, and miR-532-5p may serve as potential diagnostic biomarkers for IS. Our results also demonstrate a novel role for miRNAs in the pathogenesis of IS.

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Section: Discussionmentioning

confidence: 99%

Identification of Circulating MicroRNAs as Potential Biomarkers for Detecting Acute Ischemic Stroke

et al. 2014

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“…Both damaged/stressed neurons and reactive astrocytes quickly initiate post-ischemic inflammation, through producing pro-inflammatory mediators and educating microglia (43, 69, 70). Rapamycin protects neurons after stroke (12, 71) and inhibits reactive astrocytes (72, 73), thus probably preventing the onset of acute neuroinflammation. Hence, the neuroinflammation might have been alleviated even before Tregs entered the brain parenchyma.…”

Section: Discussionmentioning

confidence: 99%

“…Recent data show that mTOR signaling plays an important role in the modulation of both innate and adaptive immune responses (9). In experimental stroke, rapamycin administration 1 hour after focal ischemia ameliorated motor impairment in adult rats (10) and in neonatal rats (11) and improves neuron viability in an in vitro model of stroke (12). However, the mechanisms underlying mTOR-mediated neuroprotection in stroke are unclear.…”

Section: Introductionmentioning

confidence: 99%

mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

Xie

Sun

Wang

et al. 2014

The Journal of Immunology

145

113

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Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in post-stroke neuroinflammation is largely unexplored. Here, we injected rapamycin, an mTOR inhibitor, by the intracerebroventricular route 6 hours after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of gamma delta T (γδ T) cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of pro-inflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization towards the M1 type. In addition, we also found that rapamycin significantly enhanced anti-inflammation activity of regulatory T cells (Tregs), which decreased production of pro-inflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the anti-inflammation activity of Tregs to restrain post-stroke neuroinflammation.

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“…In another study, mixed neuronal cultures that were exposed to oxygen-glucose deprivation and hypoxic post-conditioning, rapamycin exacerbated neuronal death and abolished the protective effects of hypoxic post-conditioning 123 . By contrast, inhibition of autophagy has been demonstrated to prevent mTOR activation in cortical neurons and improve cell survival following oxygen-glucose deprivation 124 .…”

Section: Hypoxia-ischaemiamentioning

confidence: 99%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke

Cited by 52 publications

References 42 publications

Identification of Circulating MicroRNAs as Potential Biomarkers for Detecting Acute Ischemic Stroke

Identification of Circulating MicroRNAs as Potential Biomarkers for Detecting Acute Ischemic Stroke

mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

The mTOR signalling cascade: paving new roads to cure neurological disease

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