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

Zhu, Xiaoxia; Park, Juyeon; Golinski, Julianne; Qiu, Jianhua; Khuman, Jugta; Lee, Christopher C.H.; Lo, Eng H.; Degterev, Alexei; Whalen, Michael J.

doi:10.1038/jcbfm.2014.113

Cited by 37 publications

(35 citation statements)

References 39 publications

(84 reference statements)

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“…12 In another, a single dose of rapamycin given just before the injury failed to improve cognitive performance as assessed by the Morris water maze using a CCI model, and worsened cognitive performance in a closed-head injury model. 8,24 Our findings are consistent with previous studies that demonstrate beneficial effects of mTORC1 signaling inhibition. Interestingly, in these studies as in ours, rapamycin treatment was initiated in the 1 to 4 h window after injury.…”

Section: Discussionsupporting

confidence: 83%

“…In one study, treatment was initiated 1 h post-TBI, but continued daily for several weeks, conferring not only protection from neuronal degeneration, but also preventing the development of post-traumatic epilepsy. 24 Together with our studies that demonstrated the beneficial effects of rapamycin on behavioral performance, this work suggests that mTORC1 inhibition may be a viable strategy to ameliorate several aspects of functional recovery after TBI.…”

Section: Discussionmentioning

confidence: 98%

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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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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 98%

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

Nikolaeva

Crowell

Valenziano

et al. 2016

Journal of Neurotrauma

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“…Recent studies have demonstrated that mTOR signaling is involved in the regulation of immune reactions in many neurologic diseases, including brain trauma and AD (55,56). Inhibition of mTOR signaling reduces the deleterious actions of microglia and promotes anti-inflammatory M2 polarization (57,58).…”

Section: Discussionmentioning

confidence: 99%

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

et al. 2017

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Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neuronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR-124-3p increased most apparently in the miRNAs. We found that miR-124-3p promoted the anti-inflamed M2 polarization in microglia, and microglial exosomal miR-124-3p inhibited neuronal inflammation in scratch-injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR-124-3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR-124-3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR-124-3p by pathway analysis. We proved that it was directly targeted by miR-124-3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR-124-3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR-124-3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreased expression on RhoA and neurodegenerative proteins [Ab-peptide and p-Tau]. It also improved the neurologic outcome and inhibited neuroinflammation in mice with rTBI. Taken together, increased miR-124-3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR-124-3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR-124-3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.-Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J. 32, 512-528 (2018). www.fasebj.org

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“…In necroptosis, inhibition of Akt/mTORC1 pathway inhibits ROS production and cell death (167). Akt and mTORC1 activation have been noted in a number of traumatic brain injury (TBI) models (65,215,327). However, TBI models are heterogeneous.…”

Section: F Other Neurodegenerative Diseasesmentioning

confidence: 97%

mTOR in Brain Physiology and Pathologies

Bockaert

Marin

2015

Physiological Reviews

275

204

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TOR (target of rapamycin) and its mammalian ortholog mTOR have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin extracted from a bacterium of the Easter Island (Rapa Nui) soil. mTOR is a serine/threonine kinase found in two functionally distinct complexes, mTORC1 and mTORC2, which are differentially regulated by a great number of nutrients such as glucose and amino acids, energy (oxygen and ATP/AMP content), growth factors, hormones, and neurotransmitters. mTOR controls many basic cellular functions such as protein synthesis, energy metabolism, cell size, lipid metabolism, autophagy, mitochondria, and lysosome biogenesis. In addition, mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development, synaptic plasticity, memory storage, and cognition. Thus it is not surprising that deregulation of mTOR signaling is associated with many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy, cognitive impairment, and brain tumors, whereas stimulation of mTORC1 (direct or indirect) can be beneficial for other pathologies such as depression or axonal growth and regeneration.

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

Cited by 37 publications

References 39 publications

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

mTOR in Brain Physiology and Pathologies

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