PI3K/Akt/mTOR pathway participates in neuroprotection by dexmedetomidine inhibits neuronic autophagy following traumatic brain injury in rats

Zhang, Man-He; Zhou, Xiumin; Gao, Junling; Wang, Kaijie

doi:10.5455/2320-6012.ijrms20141161

Cited by 6 publications

(2 citation statements)

References 25 publications

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“…50 Dexmedetomidine increases phosphorylated Akt and mammalian target of rapamycin concentrations as a mechanism of inhibiting neuronic autophagy. 51 In a previous study, we found that dexmedetomidine could reverse the downregulation of phosphorylated mammalian target of rapamycin in lung alveolar epithelial cell injury induced by hydrogen peroxide. 17 In this study, we observed prolonged dexmedetomidine treatment alone could increase mammalian target of rapamycin expression in the same cell line.…”

Section: Perioperative Medicinementioning

confidence: 89%

Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

et al. 2018

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Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Several factors within the perioperative period may influence postoperative metastatic spread. Dexmedetomidine and midazolam are widely used general anesthetics during surgery. The authors assessed their effects on human lung carcinoma (A549) and neuroglioma (H4) cell lines in vitro and in vivo. Methods Cell proliferation and migration were measured after dexmedetomidine (0.001 to 10 nM) or midazolam (0.01 to 400 μM) treatment. Expression of cell cycle and apoptosis markers were assessed by immunofluorescence. Mitochondrial membrane potential and reactive oxygen species were measured by JC-1 staining and flow cytometry. Antagonists atipamezole and flumazenil were used to study anesthetic mechanisms of action. Tumor burden after anesthetic treatment was investigated with a mouse xenograft model of lung carcinoma. Results Dexmedetomidine (1 nM) promoted cell proliferation (2.9-fold in A549 and 2-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), migration (2.2-fold in A549 and 1.9-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), and upregulated antiapoptotic proteins in vitro. In contrast, midazolam (400 μM) suppressed cancer cell migration (2.6-fold in A549 cells, P < 0.0001; n = 4), induced apoptosis via the intrinsic mitochondrial pathway, decreased mitochondrial membrane potential, and increased reactive oxygen species expression in vitro—effects partly attributable to peripheral benzodiazepine receptor activation. Furthermore, midazolam significantly reduced tumor burden in mice (1.7-fold vs. control; P < 0.05; n = 6 per group). Conclusions Midazolam possesses antitumorigenic properties partly mediated by the peripheral benzodiazepine receptor, whereas dexmedetomidine promotes cancer cell survival through signaling via the α2-adrenoceptor in lung carcinoma and neuroglioma cells.

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Section: Perioperative Medicinementioning

confidence: 89%

Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

et al. 2018

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“…Increased LC3-II and autophagosomes are observed in the experimental weight drop injury model of TBI [67], and caloric restriction after mild TBI results in increased Beclin 1, LC3, and mTOR [68]. TBI could inhibit PI3K/AKT/mTOR pathway [69], NRF2/ARE pathway [50], TLR4/NF-κB pathway [70], and activate FoxO3a [71] and Drp1 [72] proteins, which are in the upstream of autophagy and their regulation by TBI may promote autophagosome formation and cause BBB disruption [66].…”

Section: Post-tbi Cell Death Mechanismsmentioning

confidence: 99%

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

Sivandzade

Alqahtani

Cucullo

2020

IJMS

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Traumatic brain injury (TBI) is among the most pressing global health issues and prevalent causes of cerebrovascular and neurological disorders all over the world. In addition to the brain injury, TBI may also alter the systemic immune response. Thus, TBI patients become vulnerable to infections, have worse neurological outcomes, and exhibit a higher rate of mortality and morbidity. It is well established that brain injury leads to impairments of the blood–brain barrier (BBB) integrity and function, contributing to the loss of neural tissue and affecting the response to neuroprotective drugs. Thus, stabilization/protection of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage, and acute neurodegeneration. Herein, we present a review highlighting the significant post-traumatic effects of TBI on the cerebrovascular system. These include the loss of BBB integrity and selective permeability, impact on BBB transport mechanisms, post-traumatic cerebral edema formation, and significant pathophysiological factors that may further exacerbate post-traumatic BBB dysfunctions. Furthermore, we discuss the post-traumatic impacts of chronic smoking, which has been recently shown to act as a premorbid condition that impairs post-TBI recovery. Indeed, understanding the underlying molecular mechanisms associated with TBI damage is essential to better understand the pathogenesis and progression of post-traumatic secondary brain injury and the development of targeted treatments to improve outcomes and speed up the recovery process. Therapies aimed at restoring/protecting the BBB may reduce the post-traumatic burden of TBI by minimizing the impairment of brain homeostasis and help to restore an optimal microenvironment to support neuronal repair.

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Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway

Wang

Liu

et al. 2023

J Mol Histol

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PI3K/Akt/mTOR pathway participates in neuroprotection by dexmedetomidine inhibits neuronic autophagy following traumatic brain injury in rats

Cited by 6 publications

References 25 publications

Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway

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