Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis

Ding, Ke; Wang, Handong; Wu, Yong; Zhang, Li; Xu, Jianguo; Li, Tao; Ding, Yu; Zhu, Lin; He, Jin

doi:10.1016/j.jss.2014.09.026

Cited by 57 publications

(31 citation statements)

References 36 publications

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“…In our present study, we focused on the regulatory role of mTORC1 especially in NSC proliferation after moderate TBI using a CCI model in rodents. We illustrated that mTORC1 activation in NSCs in the hippocampus was delayed to 24–48 h after initial injury compared with 4 h after trauma in mature neurons reported by other studies (Chen et al, 2007; Ding et al, 2015). In addition, inhibition by rapamycin abolished TBI-enhanced NSC proliferation in the hippocampus 48 h after moderate CCI.…”

Section: Discussionsupporting

confidence: 51%

“…After TBI, activation of mTORC1 signaling in the injured cortex and hippocampus has been noticed for a while (Chen et al, 2007; Park et al, 2012); however, the role of mTORC1 activation remains elusive. Initially, mTORC1 was proven to mediate apoptotic neuronal death within hours after TBI, and early inhibition of mTORC1 signaling by rapamycin pretreatment has been shown to alleviate motor deficits and cognitive impairments 3 days after trauma (Park et al, 2012; Ding et al, 2015). Later on, mTORC1 activation in microglia and astrocytes postinjury has further been noticed, thus bringing about the idea that roles of mTORC1 in TBI pathogenesis include inducing neuroinflammation and promoting astrogliosis, which was also reversed by rapamycin administration (Ding et al, 2014; Nikolaeva et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Wang

Seekaew

Gao

et al. 2016

eNeuro

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Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It was previously shown that traumatic brain injury (TBI) stimulated neural stem cell (NSC) proliferation in the adult hippocampus, indicating an innate repair mechanism, but it is unknown how TBI promotes NSC proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice with TBI from controlled cortical impact (CCI). The peak of mTORC1 activation in the hippocampal subgranular zone, where NSCs reside, is 24–48 h after trauma, correlating with the peak of TBI-enhanced NSC proliferation. By use of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, we found that TBI activated mTORC1 in NSCs. With 5-bromo-2′-deoxyuridine labeling, we observed that TBI increased mTORC1 activation in proliferating NSCs. Furthermore, administration of rapamycin abolished TBI-promoted NSC proliferation. Taken together, these data indicate that mTORC1 activation is required for NSC proliferation postinjury, and thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair after TBI.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Wang

Seekaew

Gao

et al. 2016

eNeuro

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“…Glutamate release caused by excitotoxic damage has been previously associated with Akt inhibition and caspase-independent and dependent cell death 48, 52–56 . In our experimental design, we treated cultures with a sublethal concentration of NMDA (20 μM), as previously described 57 , to mimic the secondary phase of trauma, excitotoxic injury.…”

Section: Discussionmentioning

confidence: 99%

Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

Swiatkowski

Nikolaeva

Kumar

et al. 2017

Sci Rep

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Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or GSK3β, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.

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“…The traumatic penumbra is characterized by metabolic changes as a consequence of neural injury progression [51][52][53] culminating in cell death [26,54]. In this scenario of metabolic crisis, astrocytes may exert a neuroprotective action supplying substrates of glycogen metabolism for the survival of ischemic neurons and oligodendroglial cells [49].…”

Section: Mechanisms Of Neural Injury In the Traumatic Penumbramentioning

confidence: 99%

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Regner¹,

Meirelles²,

Simon³

2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of "traumatic penumbra," represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery.

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Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis

Cited by 57 publications

References 36 publications

Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

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