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      Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway

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          Abstract

          Background

          To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells.

          Methods

          Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR).

          Results

          In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats.

          Conclusion

          Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway.

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          Most cited references 38

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          Edaravone alleviates hypoxia-acidosis/reoxygenation-induced neuronal injury by activating ERK1/2.

          Edaravone, a free radical scavenger, is the first clinical drug of neuroprotection for ischemic stroke patients in the world, and has been shown to be an effective agent to alleviate cerebral ischemic injury. It has been established that acidosis is a common feature of cerebral ischemia and underlies the pathogenesis of ischemic stroke. In the present study, we investigated the role of edaravone in hypoxia-acidosis/reoxygenation (H-A/R)-induced neuronal injury that is partially mediated by the activation of acid-sensing ion channels (ASICs). Here, we observed that pretreatment of cultured neurons with edaravone largely reduced LDH release induced by acidosis or H-A/R. We also found that edaravone exhibited its neuroprotective roles by enhancing brain-derived neurotrophic factor (BDNF) and Bcl-2 expression, suppressing caspase-3 activity and promoting extracellular signal-regulated kinase1/2 (ERK1/2) activation. Furthermore, the addition of MEK (mitogen-activated protein kinase/ERK kinase) antagonists PD98059 and U0126 nearly abolished the beneficial effects of edaravone. Similarly, ASICs blockade produced the protective effects comparable to edaravone administration. These results indicate that edaravone is capable of attenuating H-A/R-mediated neurotoxicity at least partially through activating ERK1/2. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.
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            Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus

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              General Anesthetics Regulate Autophagy via Modulating the Inositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection and Cytotoxicity

              General anesthetics are both neuroprotective and neurotoxic with unclear mechanisms. General anesthetics may control cell survival via their effects on autophagy by activation of type 1 inositol triphosphate receptor (InsP3R-1). DT40 or SH-SY5Y cells with only or over 99% expression of InsP3R-1 were treated with isoflurane or propofol. Cell viability was determined by MTT reduction or LDH release assays. Apoptosis was determined by measuring Caspase-3 or by TUNEL assay. Autophagy activity was determined by measuring LC3 II and P62. We evaluated mitochondrial integrity using MitoTracker Green and cytosolic ATP levels. Fura2-AM was used to measure the concentrations of cytosolic calcium ([Ca2+]c). Propofol significantly increased peak and integrated calcium response (P < 0.001) in cells with InsP3R-1 but not in cells with triple knockout of InsP3R. Both propofol and isoflurane increased autophagy induction (P < 0.05) in an mTOR- and InsP3R- activity dependent manner. Short exposure to propofol adequately activated InsP3-1 to provide sufficient autophagy for cytoprotection, while prolonged exposure to propofol induced cell apoptosis via impairment of autophagy flux through over activation of InsP3-1. Propofol damaged mitochondria and decreased cytosolic ATP. The effects of general anesthetics on apoptosis and autophagy are closely integrated; both are caused by differential activation of the type 1 InsP3R.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                30 March 2021
                2021
                : 15
                : 1409-1422
                Affiliations
                [1 ]Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center , Shanghai, People’s Republic of China
                Author notes
                Correspondence: Hongwei Duan Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center , No. 2800 Gongwei Road, Shanghai, 201399, People’s Republic of China Email duanhongwei120@126.com
                Article
                294557
                10.2147/DDDT.S294557
                8020057
                © 2021 Yang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 38, Pages: 14
                Categories
                Original Research

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