Ketamine Enhances Human Neural Stem Cell Proliferation and Induces Neuronal Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Pathway

Bai, Xiaowen; Yan, Yasheng; Canfield, Scott G.; Muravyeva, Maria; Kikuchi, Chika; Žaja, Ivan; Corbett, John A.; Bošnjak, Željko J.

doi:10.1213/ane.0b013e3182860fc9

Cited by 165 publications

(172 citation statements)

References 57 publications

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“…Having considered both the dose and duration, we exposed NSCs to 100 μM ketamine for 24 h to establish a ketamine injury model; this dosage was also based on the clinically relevant dose of ketamine. In the present study, we showed that ketamine decreased NSC viability and proliferation and increased apoptosis, which is consistent with previous studies [2,31].…”

Section: Discussionsupporting

confidence: 93%

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Lü

Shan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ketamine inhibits the proliferation of neural stem cells (NSCs) and disturbs normal neurogenesis. Dexmedetomidine provides neuroprotection against volatile anesthetic-induced neuroapoptosis and cognitive impairment in the developing brain. Whether it may protect NSCs from ketamine-induced injury remains unknown. In this study, we investigated the protective effects of dexmedetomidine on ketamine-exposed NSCs and explored the mechanisms potentially involved. Methods: Primary NSC cultures were characterized using immunofluorescence. Cell viability was determined using a Cell Counting Kit 8 assay. Proliferation and apoptosis were assessed with BrdU incorporation and TUNEL assays, respectively. Protein levels of cleaved caspase-3, phosphorylated protein kinase B (p-Akt), and glycogen synthase kinase-3β (p-GSK-3β) were quantified using western blotting. Results: Ket-amine significantly decreased NSC viability and proliferation and increased their apoptosis. Dexmedetomidine increased NSC proliferation and decreased their apoptosis in a dose-dependent manner. Furthermore, dexmedetomidine pretreatment notably augmented the viability and proliferation of ketamine-exposed NSCs and reduced their apoptosis. Moreover, dexmedetomidine lessened caspase-3 activation and increased p-Akt and p-GSK-3β levels in NSCs exposed to ketamine. The protective effects of dexmedetomidine on ketamine-exposed NSCs could be partly reversed by the PI3K inhibitor LY294002. Conclusions: Collectively, these findings indicate that dexmedetomidine may protect NSCs from ketamine-induced injury via the PI3K/Akt/GSK-3β signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Lü

Shan

et al. 2018

Cell Physiol Biochem

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“…Our results were different from previous finding by Bai et al which reported that exposure to 100 µM ketamine for 6 hours could promote the proliferation of NSCs from human embryonic stem cells (hESCs) in vitro [21]. This discrepancy may be attributed to the different NSCs source and ketamine exposure duration.…”

Section: Discussioncontrasting

confidence: 99%

Ketamine Inhibits Proliferation of Neural Stem Cell from Neonatal Rat Hippocampusin Vitro

Wu¹,

Liang²,

Huang³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Ketamine is a widely used anesthetic in obstetric and pediatric anesthesia. In the developing brain, the widespread neuron apoptosis triggered by ketamine has been demonstrated. However, little is known about its effect on neural stem cells (NSCs) function. This study aimed to investigate the effect of ketamine on proliferation of NSCs from neonatal rat hippocampus. Methods: Neural stem cells were isolated from the hippocampus of Sprague-Dawley rats on postnatal day 3. In dose-response experiments, cultured neural stem cells (NSCs) were exposed to different concentrations of ketamine (0-1000 µM) for 24 hrs. The proliferative activity of NSCs was evaluated by 5-Bromo-2′-deoxyuridine (BrdU) incorporation assay. Apoptosis of neural stem cells were assessed using caspase-3 by western blot. The intracellular Ca²⁺ concentration ([Ca²⁺]i) in NSCs was analyzed by flow cytometry. The activation of protein kinase C-α (PKCα) and the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot analysis. Results: Clinical relevant concentration of ketamine (10, 20 and 50 µM) did not markedly alter the proliferation of NSCs from neonatal rat hippocampus in vitro. However, ketamine (200, 500, 800 and 1000μM) significantly inhibited the proliferation of NSCs and did not affect the expression of caspase-3. Meanwhile, ketamine (200, 500, 800 and 1000μM) also markedly decreased [Ca²⁺]i as well as suppressed PKCα activation and ERK1/2 phosphorylation in NSCs. A combination of subthreshold concentrations of ketamine (100 μM) and Ca²⁺ channel blocker verapamil (2.5 μM), PKCα inhibitor chelerythrine (2.5 μM) or ERK1/2 kinase inhibitor PD98059 (5 μM) significantly produced suprathreshold effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation. Conclusion: Ketamine inhibited proliferation of NSCs from neonatal rat hippocampus in vitro. Suppressing Ca²⁺-PKCα-ERK1/2 signaling pathway may be involved in this inhibitory effect of ketamine on NSCs proliferation.

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“…The anesthetic ketamine has been shown to be neurotoxic, and hPSC-derived neurons were used to study the mechanism. Ketamine increased neural stem cell proliferation and caused neuronal apoptosis in a mitochondrion-dependent mechanism (52).…”

Section: Neuronsmentioning

confidence: 99%

Stem Cells and Stem Cell-derived Tissues and Their Use in Safety Assessment

Kolaja

2014

Journal of Biological Chemistry

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Toxicology has long relied on animal models in a tedious approach to understanding risk of exposure to an uncharacterized molecule. Stem cell-derived tissues can be made in high purity, quality, and quantity to enable a new approach to this problem. Currently, stem cell-derived tissues are primarily "generic" genetic backgrounds; the future will see the integration of various genetic backgrounds and complex three-dimensional models to create truly unique in vitro organoids. This minireview focuses on the state of the art of a number of stem cell-derived tissues and details their application in toxicology.Delineating the toxicological profile of a new molecular entity is an incremental investigation across in silico, in vitro, and in vivo models that culminates in an informed opinion of risk. Many of these assessments are conducted to comply with regulatory guidance documents and rely heavily on the use of animal toxicology studies. This approach is slow and costly and still results in unappreciated "surprises" when preclinical animal data uncover intractable toxicity that has an unclear correlation with the drug's effect in humans. Primary cell culture has long been the preferred cell-based system for in vitro research; however, ample and consistent supply, uncontrolled phenotypic variation in viability and function, and a progressive loss of in vivo properties when cultured among other constraints provide room for improved models of predicting human adverse responses.

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Ketamine Enhances Human Neural Stem Cell Proliferation and Induces Neuronal Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Pathway

Cited by 165 publications

References 57 publications

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Ketamine Inhibits Proliferation of Neural Stem Cell from Neonatal Rat Hippocampusin Vitro

Stem Cells and Stem Cell-derived Tissues and Their Use in Safety Assessment

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