Ketamine Interferes with the Proliferation and Differentiation of Neural Stem Cells in the Subventricular Zone of Neonatal Rats

Huang, He; Liu, Lu; Li, Bing; Zhao, Panpan; Xu, Chunmei; Zhu, Yangzi; Zhou, Chenghua; Wu, Yuqing

doi:10.1159/000369698

Cited by 34 publications

(31 citation statements)

References 35 publications

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“…Therefore, we investigated the effects of ketamine on NSCs obtained from embryonic day 18 rat anterior cortices. Recent studies have shown that ketamine alters the proliferation and differentiation of NSCs [29]. However, the effects of ketamine on NSCs were unclear.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Lü

Shan

et al. 2018

Cell Physiol Biochem

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“…injection of ketamine or multiple (six times) consecutive i.p. injections of ketamine at 1-h intervals, based on the methods described in previous studies (Huang et al, 2015, 2016), with modifications. For both single and multiple administrations, mice were randomly assigned to five groups, with 12 mice per group: saline-treated group, 10 mg/kg ketamine group, 20 mg/kg ketamine group, 40 mg/kg ketamine group, and 80 mg/kg ketamine group.…”

Section: Methodsmentioning

confidence: 99%

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration

Shen

Wen

et al. 2017

Front. Pharmacol.

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Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile, ketamine has been shown to modulate the levels of inflammatory cytokines. We hypothesized that the effects of ketamine on the central nervous system are associated with inflammatory cytokines. Therefore, we set out to establish acute and chronic ketamine administration models in C57BL/6 mice, to evaluate spatial recognition memory and emotional response, to analyze the changes in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the mouse hippocampus, employing behavioral tests, Western blot, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Our results showed that ketamine at the dose of 60 mg/kg induced spatial recognition memory deficit and reduced anxiety-like behaviors in mice after chronic administration. Moreover, we found that ketamine increased the hippocampal levels of IL-6 and IL-1β after single, multiple and long-term administration in a dose-dependent manner. However, the expression level of TNF-α differed in the mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α, whereas multiple and long-term administration decreased it significantly. We considered that TNF-α expression could be controlled by a bi-directional regulatory pathway, which was associated with the dose and duration of ketamine administration. Our results suggest that the alterations in the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α may be involved in the neurotoxicity of ketamine.

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“…In each section, measurements were performed in 5 regions, and planar area enclosed by each region was 50 μm×50 μm. The edges of the regions were defined based on structural details within the tissue section to ensure that fields did not overlap [30]. The density of positive cells was presented as the total number of positive cells within the SVZ and SGZ.…”

Section: Immnofluorescence Stainingmentioning

confidence: 99%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

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Ketamine Interferes with the Proliferation and Differentiation of Neural Stem Cells in the Subventricular Zone of Neonatal Rats

Cited by 34 publications

References 35 publications

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

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