mTOR is involved in stroke-induced seizures and the anti-seizure effect of mild hypothermia

Yang, Guoshuai; Zhou, Xiaoyan; An, Xue-Fang; Liu, Xuan-Jun; Zhang, Yanjun; Yu, Dan

doi:10.3892/mmr.2018.8629

Cited by 4 publications

(6 citation statements)

References 31 publications

(45 reference statements)

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“…the decreased phosphorylation of p70S6K and RPS6) with CDH, the only known treatment that prevents lamellar structural failure experimentally and in clinical cases, further supports a role for this signalling in lamellar failure. A recent report demonstrating that therapeutic hypothermia in brain injury is effective via mTOR inhibition further supports the likelihood that CDH is effective in laminitis by blocking mTOR‐related signalling . Thus, the current data and research literature support a possible role of mTORC1/RPS6 signalling in lamellar failure in sepsis‐related laminitis.…”

Section: Discussionsupporting

confidence: 59%

Influence of digital hypothermia on lamellar events related to IL‐6/gp130 signalling in equine sepsis‐related laminitis

Dern

Burns

Watts

et al. 2019

Equine Veterinary Journal

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Summary Background Interleukin‐6 (IL‐6) is consistently increased in the digital lamellae in different studies of sepsis‐related laminitis (SRL). IL‐6 signalling through the gp130 receptor activates similar signalling (i.e. mTORC1‐related signalling) previously reported to be activated in models of endocrinopathic laminitis. Objectives To assess the activation state of signalling proteins downstream of IL‐6/gp130 receptor complex activation in an experimental model of SRL. Study design Randomised experimental study. Methods Lamellar phospho‐(P) protein concentrations downstream of the IL‐6/gp130 receptors were assessed in the oligofructose (OF) model of SRL. Fifteen Standardbred horses were administered water (CON, n = 8) or oligofructose (OF, n = 7) via a nasogastric tube. At 12 h post‐OF/water administration, one randomly assigned forelimb was exposed to continuous digital hypothermia (CDH) by placement in ice water (ICE, maintained at <7°C); the other forelimb was maintained at ambient temperature (AMB). Lamellar tissue samples were collected after 24 h of CDH from both ICE and AMB forelimbs and immediately snap‐frozen. Lamellar proteins of interest were assessed by immunoblotting and immunofluorescence. Results Immunoblotting revealed increase (P<0.05) in the phosphorylation states of Akt (Ser 473), RPS6 (Ser235/236), RPS6 (Ser240/244), STAT3 (Ser727) and STAT3 (Tyr705) in lamellar tissue from OF‐treated animals (AMB OF vs. AMB CON limbs); CDH resulted in decreased (P<0.05) lamellar concentrations of phosphorylated Akt, p70S6K, RPS6 (235/236), RPS6 (240/244) and STAT3 (S727) in OF‐treated animals (AMB OF vs. ICE OF). Immunofluorescence showed that activated/phosphorylated forms of RPS6 and STAT3 were primarily localised to lamellar epithelial cells. Main limitations The nature, sequence and timing of sub‐cellular events in this experimental model may differ from those that accompany naturally occurring sepsis. Conclusions There were increased lamellar concentrations of activated signalling proteins downstream of the IL‐6/Gp130 receptor complex in OF‐treated horses; CDH inhibited this activation for the majority of the proteins assessed. These results demonstrate similar lamellar signalling (e.g. mTORC1‐related signalling) and, therefore, possible therapeutic targets occurring in sepsis‐related laminitis as previously reported in models of endocrinopathic laminitis.

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Section: Discussionsupporting

confidence: 59%

Influence of digital hypothermia on lamellar events related to IL‐6/gp130 signalling in equine sepsis‐related laminitis

Dern

Burns

Watts

et al. 2019

Equine Veterinary Journal

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“…The results indicated that the expression of PI3K, Akt, mTOR were significantly higher than that of the Control group, suggesting that PI3K/Akt signaling pathway is involved in the epilepsy pathological process. The reasons are considered as follows: ①Excessive activation of mTOR can lead to gene expression of cerebral cortical malformation and the epileptic phenotype [24]; ②PI3K/Akt/mTOR signaling pathway participates in cell synthesis and proliferation and promotes the synthesis of microglia [25], thereby aggravating the immune inflammatory response and increasing inflammatory cell exudation.③PI3K/Akt/mTOR signal activates hypoxia-inducible factors and regulates the glucose transporter (GLUT), resulting in excessive activation of neurons [26]. Contrary to the postulated role of the PI3K/Akt/mTOR pathway in epilepsy pathology, there have been reports that this signaling cascade confers protective effects due to reducing neuronal apoptosis and ischemic brain injury [27].…”

Section: Discussionmentioning

confidence: 99%

A study on the protective mechanism of mTOR inhibitor Everolimus on brain injury after epilepsy

Huang¹,

Hu²,

Zheng³

et al. 2020

Preprint

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Background: Epilepsy is a common acute and severe disease in infants and children. Recurrent seizures or status epilepticus can cause irreversible brain damage. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, it may also lead to abnormal neuronal signal transduction under pathological conditions, including that of epilepsy. Everolimus (Eve) is an mammalian target of repamycin (mTOR) inhibitor that may affect neuronal excitability and have a therapeutic effect on epilepsy. Therefore, this study aimed to investigate the protective effect of Everolimus on post-epileptic brain injury and the regulation mechanism of the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway. Intraperitoneal administration of kanic acid (KA) 15mg/kg was used to induce epilepsy in the developing rat and Everolimus (1, 2, 5mg/kg) was injected intraperitoneally 2 hours before KA injection. Cerebral cortex tissue was sampled at 24 hours post-epilepsy.Results: The protein and mRNA levels of PI3K、AKt、mTOR、NF-kB and IL-6 as well as microglia activation significantly increased after KA-induced epilepsy, however these effects were inhibited by Everolimus treatment. Furthermore, pretreatment with Everolimus decreased seizure scores and increased seizure latency. This study demonstrates that mTOR inhibitor.Conclusions: Everolimus can decrease the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway, reduce microglia activation, and attenuate seizure susceptibility and intensity, thus having a protective effect on post-epileptic brain damage.

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“…Convulsive seizures occur along with an increased expression of phospho-mTOR and GLUT-1 in the cerebral cortex and hippocampus, as evidenced by immunohistochemistry and western blot analyses. Mild hypothermia and/or rapamycin treatment alleviates GCI-induced seizures by reducing the number of epileptic attacks, seizure severity scores, and seizure discharges [137]. This goes along with a reduction of phosphor-mTOR and its downstream effector p70S6 in neurons.…”

Section: Ischemic/hemorragic Stroke and Brain Traumamentioning

confidence: 94%

“…Stroke is also implicated in the etiology of seizures development. In rat models of global cerebral ischemia (GCI), during the first and the second days following GCI, convulsive seizures frequently occur, which are accompanied by seizure discharge shown by the EEG [137]. Convulsive seizures occur along with an increased expression of phospho-mTOR and GLUT-1 in the cerebral cortex and hippocampus, as evidenced by immunohistochemistry and western blot analyses.…”

Section: Ischemic/hemorragic Stroke and Brain Traumamentioning

confidence: 99%

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mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

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mTOR is involved in stroke-induced seizures and the anti-seizure effect of mild hypothermia

Cited by 4 publications

References 31 publications

Influence of digital hypothermia on lamellar events related to IL‐6/gp130 signalling in equine sepsis‐related laminitis

Influence of digital hypothermia on lamellar events related to IL‐6/gp130 signalling in equine sepsis‐related laminitis

A study on the protective mechanism of mTOR inhibitor Everolimus on brain injury after epilepsy

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

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