miR-21 improves the neurological outcome after traumatic brain injury in rats

Ge, Xintong; Lei, Ping; Wang, Hai-Chen; Zhang, Anling; Han, Zhaoli; Chen, Xin; Li, Shenghui; Jiang, Rongcai; Kang, Chunsheng; Zhang, Jianning

doi:10.1038/srep06718

Cited by 142 publications

(118 citation statements)

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“…Consistent with this view of Akt as a key neuroprotective mechanism after CNS injury, others have shown that miR-21, which targets the Akt inhibitor PTEN, is neuroprotective after TBI. 42,43 Although the upregulation of miR-711 occurs rapidly after TBI, it persists for several days suggesting that the therapeutic window for intervention may be significant.…”

Section: Mir-711 Activates Neuronal Apoptosis B Sabirzhanov Et Almentioning

confidence: 99%

miR-711 upregulation induces neuronal cell death after traumatic brain injury

et al. 2015

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Traumatic brain injury (TBI) is a leading cause of mortality and disability. MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at post-transcriptional level and may be key modulators of neuronal apoptosis, yet their role in secondary injury after TBI remains largely unexplored. Changes in miRs after controlled cortical impact (CCI) in mice were examined during the first 72 h using miR arrays and qPCR. One selected miR (711) was examined with regard to its regulation and relation to cell death; effects of miR-711 modulation were evaluated after CCI and using in vitro cell death models of primary cortical neurons. Levels of miR-711 were increased in the cortex early after TBI and in vitro models through rapid upregulation of miR-711 transcription (pri-miR-711) rather than catabolism. Increases coincided with downregulation of the pro-survival protein Akt, a predicted target of miR-711, with sequential activation of forkhead box O3 (FoxO3)a/glycogen synthase kinase 3 (GSK3)α/β, pro-apoptotic BH3-only molecules PUMA (Bcl2-binding component 3) and Bim (Bcl2-like 11 (apoptosis facilitator)), and mitochondrial release of cytochrome c and AIF. miR-711 and Akt (mRNA) co-immunoprecipitated with the RNA-induced silencing complex (RISC). A miR-711 hairpin inhibitor attenuated the apoptotic mechanisms and decreased neuronal death in an Aktdependent manner. Conversely, a miR-711 mimic enhanced neuronal apoptosis. Central administration of the miR-711 hairpin inhibitor after TBI increased Akt expression and attenuated apoptotic pathways. Treatment reduced cortical lesion volume, neuronal cell loss in cortex and hippocampus, and long-term neurological dysfunction. miR-711 changes contribute to neuronal cell death after TBI, in part by inhibiting Akt, and may serve as a novel therapeutic target.

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Section: Mir-711 Activates Neuronal Apoptosis B Sabirzhanov Et Almentioning

confidence: 99%

miR-711 upregulation induces neuronal cell death after traumatic brain injury

et al. 2015

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“…We then measured the expression of miR-21-5p in neurons, astrocytes, microglias and brain microvascular endothelial cells (BMVECs) respectively using combined miRNA in-situ hybridization and immunofluorescence. We found that compared to astrocytes and microglias, neurons and BMVECs expressed more miR-21-5p, and their miR-21-5p levels are more sensitive in response to injury [18] . We evaluated the influence of miR-21-5p on the neurological outcome of TBI rats using modified neurological severity score and Morris Water Maze.…”

Section: Research Highlightmentioning

confidence: 74%

“…We evaluated the influence of miR-21-5p on the neurological outcome of TBI rats using modified neurological severity score and Morris Water Maze. We found that the increased miR-21-5p level in brain post-injury was beneficial for improving the neurological prognosis of TBI [18] . Then, we observed the impact of miR-21-5p on cellular apoptosis in rats and in-vitro cultured neurons to investigate the mechanism of its protective effect in TBI.…”

Section: Research Highlightmentioning

confidence: 80%

“…Specifically, we employed the fluid percussion injury rat model, and detected the expression level of miR-21-5p in the traumatic focci using qRT-PCR. We found that the miR-21-5p level was increased from 6 h to 72 h post-injury, and it can be further up-regulated or down-regulated by intracerebroventricularly injection of miR-21-5p agomir or antagomir [18] . We then measured the expression of miR-21-5p in neurons, astrocytes, microglias and brain microvascular endothelial cells (BMVECs) respectively using combined miRNA in-situ hybridization and immunofluorescence.…”

Section: Research Highlightmentioning

confidence: 81%

“…We have proved that neurons-expressed miR-21-5p exerted an anti-apoptosis effect in brain after TBI, thereby promoting the restoration of injured BBB and improving the neurological prognosis of TBI [15,[17][18][19] . Specifically, we employed the fluid percussion injury rat model, and detected the expression level of miR-21-5p in the traumatic focci using qRT-PCR.…”

Section: Research Highlightmentioning

confidence: 92%

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miR-21, a potential therapeutic target of alleviating blood-brain barrier damage after traumatic brain injury

Lei

Zhang

2015

RNA Dis

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Traumatic brain injury (TBI)is a disease with high morbidity and leads to high rate of disability and mortality. The blood-brain barrier (BBB) damage is an important pathological change in brain after TBI, which impacts the development and prognosis of the disease. In our previous research, we have reported that miR-21-5p in neurons can exert an anti-apoptosis effect, and promote the restoration of injured BBB after TBI. Up-regulation of miR-21-5p level in brain can amplify the above functions of miR-21-5p, thus alleviate BBB damage and improve the neurological prognosis of TBI. miR-21-3p, which is generated from pre-miR-21 at the same time with miR-21-5p, has been reported to play significant roles in regulating cellular apoptosis, immuno-inflammatory responses and the expression of angiogenic factors in various diseases. We made a summary of previous research on miR-21-3p and inferred that miR-21-3p could exert an important impact on BBB damage after TBI. Taken together, miR-21 is a vital miRNA that impacts the restoration of injured BBB, thus it could be a potential therapeutic target for interventions in TBI.

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Traumatic brain injury increases levels of miR‐21 in extracellular vesicles: implications for neuroinflammation

et al. 2016

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Traumatic brain injury (TBI) is an important health concern and effective treatment strategies remain elusive. Understanding the complex multicellular response to TBI may provide new avenues for intervention. In the context of TBI, cell–cell communication is critical. One relatively unexplored form of cell–cell communication in TBI is extracellular vesicles (EVs). These membrane‐bound vesicles can carry many different types of cargo between cells. Recently, miRNA in EVs have been shown to mediate neuroinflammation and neuronal injury. To explore the role of EV‐associated miRNA in TBI, we isolated EVs from the brain of injured mice and controls, purified RNA from brain EVs, and performed miRNA sequencing. We found that the expression of miR‐212 decreased, while miR‐21, miR‐146, miR‐7a, and miR‐7b were significantly increased with injury, with miR‐21 showing the largest change between conditions. The expression of miR‐21 in the brain was primarily localized to neurons near the lesion site. Interestingly, adjacent to these miR‐21‐expressing neurons were activated microglia. The concurrent increase in miR‐21 in EVs with the elevation of miR‐21 in neurons, suggests that miR‐21 is secreted from neurons as potential EV cargo. Thus, this study reveals a new potential mechanism of cell–cell communication not previously described in TBI.

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miR-21 improves the neurological outcome after traumatic brain injury in rats

Cited by 142 publications

References 50 publications

miR-711 upregulation induces neuronal cell death after traumatic brain injury

miR-711 upregulation induces neuronal cell death after traumatic brain injury

miR-21, a potential therapeutic target of alleviating blood-brain barrier damage after traumatic brain injury

Traumatic brain injury increases levels of miR‐21 in extracellular vesicles: implications for neuroinflammation

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