Alterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury

Chen, Shaoyi; Atkins, Coleen M.; Liu, Chunli L; Alonso, Ofelia F.; Dietrich, W. Dalton; Hu, Bingren

doi:10.1038/sj.jcbfm.9600393

Cited by 84 publications

(92 citation statements)

References 42 publications

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“…Phosphorylation of S6RP was previously described exclusively in neurons after TBI in rats, and was hypothesized to increase neuronal translational capacity (Chen et al, 2007). We also found neuronal expression of p-S6RP before and after CCI.…”

Section: Discussionmentioning

confidence: 60%

Combination Therapy Targeting Akt and Mammalian Target of Rapamycin Improves Functional Outcome after Controlled Cortical Impact in Mice

Park

Zhang

Qiu

et al. 2011

J Cereb Blood Flow Metab

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Akt and mammalian target of rapamycin (mTOR) are both activated after traumatic brain injury (TBI), however complex interplay between the two hampers deciphering their functional implications in vivo. We examined the effects of single and combination inhibitors of Akt/mTOR in a mouse controlled cortical impact (CCI) model. Following CCI, phospho-Akt-473 (p-Akt) and -S6 ribosomal protein (p-S6RP), a downstream substrate of mTOR, were increased in cortical and hippocampal brain homogenates (P<0.05 versus sham). At 24 hours, p-S6RP was detected in neurons and was robustly induced in microglia and astrocytes in injured hippocampus. In vivo activity of Akt and mTOR inhibitors administered separately was confirmed by reduced expression of p-GSK3β (P<0.01) or p-S6RP (P<0.05), respectively, after CCI. Importantly, administration of Akt and mTOR inhibitors together (but not of either alone) improved postinjury motor (P=0.02) and cognitive deficits (hidden platform trials, P=0.001; probe trials, P<0.05), decreased propidium iodide-positive cells in CA1 and CA3 (P<0.005), and unexpectedly increased p-GSK3β in hippocampus. Although the roles of Akt and mTOR in the pathogenesis of TBI remain to be fully elucidated, dual inhibition of Akt and mTOR may have therapeutic potential for TBI.

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Section: Discussionmentioning

confidence: 60%

Combination Therapy Targeting Akt and Mammalian Target of Rapamycin Improves Functional Outcome after Controlled Cortical Impact in Mice

Park

Zhang

Qiu

et al. 2011

J Cereb Blood Flow Metab

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“…13 In two other CHI models, Akt phosphorylation was induced in the hippocampus between 1 and 24 hours in mice, 16 but only transiently at 1 hour after diffuse brain injury in rats, 27 whereas mTOR activation was reported from 30 minutes to 24 hours after fluid percussion in rats. 28 Thus, activation of Akt and mTOR is a generalized feature of TBI, 29 but their exact temporal course is model-specific.…”

Section: Discussionmentioning

confidence: 99%

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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“…6 The focus of the present study is on the PI3K/Akt/mTOR pathway, which other groups have shown to be strongly induced in vivo post-TBI. 7,8 The PI3K/Akt/mTOR signaling pathway is a major player in the control of cell size, dendrite and axon outgrowth during brain development, and repair. 9,10 Growth factors and hormones typically stimulate this pathway through the activation of receptor tyrosine kinases, leading to the activation of the PI3K and downstream Akt, which in turn regulates the activity of many signaling molecules, including mTOR.…”

mentioning

confidence: 99%

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

Nikolaeva

Crowell

Valenziano

et al. 2016

Journal of Neurotrauma

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The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway mediates many aspects of cell growth and regeneration and is upregulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signaling event for recovery of brain function is presently unclear. We analyzed the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI) and identified an early neuronal peak of activity that occurs within a few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin 1 h after CCI and showed that this acute treatment significantly diminishes the extent of neuronal death, astrogliosis, and cognitive impairment 1-3 days after injury. Our findings suggest that the early neuronal peak of mTORC1 activity after TBI is deleterious to brain function, and that acute, early intervention with mTORC1 inhibitors after injury may represent an effective form of treatment to improve recovery in human patients.

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Alterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury

Cited by 84 publications

References 42 publications

Combination Therapy Targeting Akt and Mammalian Target of Rapamycin Improves Functional Outcome after Controlled Cortical Impact in Mice

Combination Therapy Targeting Akt and Mammalian Target of Rapamycin Improves Functional Outcome after Controlled Cortical Impact in Mice

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

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

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