Akt Phosphorylation and Neuronal Survival after Traumatic Brain Injury in Mice

Noshita, Nobuo; Lewén, Anders; Sugawara, Taku; Chan, Pak H.

doi:10.1006/nbdi.2002.0482

Cited by 131 publications

(98 citation statements)

References 49 publications

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“…Akt activation in the brain following TBI is mainly considered in the context of limiting apoptosis. 26 The current study demonstrates that Akt/mTOR activation may be a beneficial response to concussion (impact and inertial forces) independent of focal injury and acute cell death.…”

Section: Discussionmentioning

confidence: 60%

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Zhu

Park

Golinski

et al. 2014

J Cereb Blood Flow Metab

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Akt (protein kinase B) and mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of cell death and cognitive outcome after cerebral contusion in mice; however, a role for Akt/mTOR in concussive brain injury has not been well characterized. In a mouse closed head injury (CHI) concussion traumatic brain injury (TBI) model, phosphorylation of Akt (p-Akt), mTOR (p-mTOR), and S6RP (p-S6RP) was increased by 24 hours in cortical and hippocampal brain homogenates (Po0.05 versus sham for each), and p-S6RP was robustly induced in IBA-1 þ microglia and glial fibrillary acidic protein-positive (GFAP þ ) astrocytes. Pretreatment with inhibitors of Akt or mTOR individually by the intracerebroventricular route reduced phosphorylation of their respective direct substrates FOXO1 (Po0.05) or S6RP (Po0.05) after CHI, confirming the activity of inhibitors. Rapamycin pretreatment significantly worsened hidden platform (Po0.01) and probe trial (Po0.05) performance in CHI mice. Intracerebroventricular administration of necrostatin-1 (Nec-1) before CHI increased hippocampal Akt and S6RP phosphorylation and improved place learning (probe trials, Po0.001 versus vehicle), whereas co-administration of rapamycin or Akt inhibitor with Nec-1 eliminated improved probe trial performance. These data suggest a beneficial role for Akt/mTOR signaling after concussion TBI independent of cell death that may contribute to improved outcome by Nec-1.

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Section: Discussionmentioning

confidence: 60%

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Zhu

Park

Golinski

et al. 2014

J Cereb Blood Flow Metab

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“…After TBI in mice, increased phosphorylation of PKB at Ser473 in the ipsilateral CA1 hippocampus and cortex was observed, along with increased phosphorylation of BAD and glucose synthetase kinase-3 (Noshita et al, 2002). After mild TBI in immature rats, alteration of phosphorylated PKB enzyme substrates was also reported in the ipsilateral hippocampus (Jenkins et al, 2002).…”

Section: Discussionmentioning

confidence: 95%

Increased Phosphorylation of Protein Kinase B and Related Substrates after Traumatic Brain Injury in Humans and Rats

Zhang

Chen

Ikonomović

et al. 2005

J Cereb Blood Flow Metab

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Activation of protein kinase B (PKB, also known as Akt) by phosphorylation at serine-473 and threonine-308 promotes cell survival in multiple in vitro and in vivo models where neuronal death is seen, including traumatic brain injury (TBI); however, whether PKB is activated in humans after TBI was heretofore unknown. Activated PKB inhibits apoptogenic factors and is involved in the regulation of several transcription factors. Accordingly, we examined phosphorylation of the PKB signaling pathway in humans as well as rats after TBI using phosphospecific antibodies. Increased phosphorylation of PKB and PKB substrates was detected in injured brain from both humans and rats. In humans, increased phosphorylation of the PKB signaling pathway-related proteins Bad and forkhead transcription factor (FKHR) was detected in patients with TBI versus controls. In rats, increased phosphorylation of FKHR, inhibitor of jBa, and cyclic adenosine monophosphate responsive element binding protein (CREB) was detected after TBI versus controls. The deoxyribonucleic acid-binding activity of CREB was also enhanced after TBI in rats. Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats. These data show increased phosphorylation of PKB, PKB substrates, and related proteins after both experimental and clinical TBI, suggesting either activation of the PKB signaling pathway or reduced phosphatase activity in both species.

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“…Two studies demonstrated rapidly decreased Akt levels, 31,32 whereas another showed increased levels of total and phosphorylated Akt. 33 Differences in injury type and tissue sampling may in part explain these varied results.…”

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

confidence: 97%

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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Akt Phosphorylation and Neuronal Survival after Traumatic Brain Injury in Mice

Cited by 131 publications

References 49 publications

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Increased Phosphorylation of Protein Kinase B and Related Substrates after Traumatic Brain Injury in Humans and Rats

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

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