Estradiol attenuates the focal cerebral ischemic injury through mTOR/p70S6 kinase signaling pathway

Koh, Phil-Ok; Cho, Jae‐Hyeon; Won, Chung-Kil; Hj, Lee; Sung, Jin-Hee; Kim, Myeong-Ok

doi:10.1016/j.neulet.2008.02.061

Cited by 46 publications

(41 citation statements)

References 27 publications

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“…The fact that E 2 increased phospho-S6K and phospho-4E-BP1 levels is consistent with a recent cell culture study showing that E 2 increases hippocampal dendritic mRNA translation and phosphorylation of S6K and 4E-BP1 (Sarkar et al 2010). This finding is also supported by data that chronic E 2 attenuates ischemia-induced reductions of mTOR and S6K levels in the cerebral cortex of female rats (Koh et al 2008), and reports that the related sex steroid hormones progesterone and testosterone can, . This effect was blocked by all three inhibitors (P , 0.05 relative to E 2 alone).…”

Section: Discussionsupporting

confidence: 68%

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

et al. 2013

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The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17b-estradiol (E 2 ) is dependent on mTOR signaling in the dorsal hippocampus, and whether E 2 -induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E 2 was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E 2 infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E 2 increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E 2 to enhance object recognition memory consolidation and that E 2 -induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.The potent estrogen 17b-estradiol (E 2 ) is a critical regulator of hippocampal synaptic morphology. In rodents and nonhuman primates, E 2 increases hippocampal levels of synaptic proteins, including the presynaptic proteins synaptophysin and syntaxin, and the postsynaptic proteins spinophilin and PSD-95 (Brake et al.

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Section: Discussionsupporting

confidence: 68%

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

et al. 2013

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“…Administration of estradiol to adult female ovariectomied rats prior to focal cerebral ischemia significantly reduces infarct volumes and decreases apoptosis in the cerebral cortex and concurrently prevents ischemia induced-decrease in the expression of phosphorylated mTOR and p70S6K. 39) Depletion of S6K1 enhances oxygen glucose deprivation (OGD), an in vitro model of ischemia, induced injury in astrocytes. In contrast, repletion of S6K1 expression by adenoviral infection reduces cell injury.…”

Section: Discussionmentioning

confidence: 99%

Effects of <i>Salidroside</i> on Cobalt Chloride-Induced Hypoxia Damage and mTOR Signaling Repression in PC12 Cells

Zhong

Lin

et al. 2014

Biological & Pharmaceutical Bulletin

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Salidroside (SA), a phenylpropanoid glycoside isolated from Rhodiola rosea L., has been documented to exert a broad spectrum of pharmacological properties, including protective effects against neuronal death induced by various stresses. To provide further insights into the neuroprotective functions of SA, this study examined whether SA can attenuate cobalt chloride (CoCl 2 )-induced hypoxia damage and mammalian target of rapamycin (mTOR) signaling repression in PC12 differentiated cells. Differentiated PC12 cells were exposed to CoCl 2 for 12 h to mimic hypoxic/ischemic conditions and treated with SA at the same time, followed by electron microscopy and analysis of cell viability, intracellular reactive oxygen species ( Key words salidroside; ischemic; mammalian target of rapamycin (mTOR); hypoxia; cobalt chloride; PC12 cell Focal cerebral ischemia or stroke is characterized by obstruction of blood flow to the brain, resulting in deficient supply of oxygen, glucose, serum, and nutrient that are indispensable for the energy generation. Since central nervous system is most susceptible to hypoxia conditions, the continuous oxygen and energy deprivation results in cognitive disturbances and decreased motor control, leading to fainting, long term loss of consciousness, coma, seizures, cessation of brain stem reflexes, and brain death. Ischemic stroke is currently a leading cause of disability and mortality in the aged population, due to limited medication and therapy, and new therapeutic strategies for this devastating disease are urgently needed.Recently, the role of mammalian target of rapamycin (mTOR) signaling in neurodegenerative and cerebrovascular diseases has attracted great attention.

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“…Interestingly, a gene list enrichment analysis that identifies gene sets associated with common functions or pathways revealed that additional pathways linked to neuroprotection are up-regulated in mRNA samples from L-NR4A2-transduced neurons (SI Appendix, Table S2). Notably, mTOR (38), adrenergic (39), insulin receptor (40), and VEGF signaling pathways (41) have been linked to neuroprotection and are significantly enriched in NR4A2-expressing neurons. Thus, we speculate that NR4A promotes neuroprotection as a result of a combined effect by mutiple genes rather than any individual NR4A target gene.…”

Section: Discussionmentioning

confidence: 99%

NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection

Volakakis

Kadkhodaei²,

Joodmardi³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

115

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Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1α independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.excitotoxicity | kainic acid | oxidative stress N europathological conditions including stroke, Alzheimer's disease, and Parkinson's disease are associated with excitotoxic and oxidative stress. Transcriptional increases of neuroprotective genes, including antiapoptotic factors and scavengers of reactive oxygen species (ROS), are an important strategy for neuroprotection. Thus, understanding how neuroprotective gene programs are controlled at the transcriptional level is of considerable importance and may contribute to the identification of therapeutic strategies of disorders associated with neurodegeneration. cAMP response element binding protein (CREB) is a transcription factor that is activated in response to stressful stimuli such as hypoxia, oxidative stress, excitotoxicity, and ischemia (1). Evidence from loss-of-function and other types of experiments shows that CREB plays an important role in neuronal survival (2-5) and neuroprotection (6). It is also well established that CREB is required for acquisition of ischemic tolerance, an endogenous neuroprotective mechanism whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia (7,8).Despite the well-documented neuroprotective effect of CREB, only little is known of how CREB mediates this activity and only few directly regulated neuroprotective target genes have been identified (9-13). In addition to target genes that are directly neuroprotective, CREB-induced transcription factors or cofactors may also contribute to neuron survival by regulating downstream gene batteries controlled by elevated cAMP levels in a transcription factor cascade initiated by activated CREB. Indeed, CREB induces the expression of peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α), an important regulator of ROS-detoxifying enzyme gene expression (14). However, how CREB mediates neuroprotective gene cascades via the induction of additional transcriptional regulators remains unexplored.The NR4A orphan nuclear receptor (NR...

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Estradiol attenuates the focal cerebral ischemic injury through mTOR/p70S6 kinase signaling pathway

Cited by 46 publications

References 27 publications

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

Effects of <i>Salidroside</i> on Cobalt Chloride-Induced Hypoxia Damage and mTOR Signaling Repression in PC12 Cells

NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection

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