Ketamine-induced neurotoxicity blocked by N -Methyl- d -aspartate is mediated through activation of PKC/ERK pathway in developing hippocampal neurons

Jiang, Sufang; Li, Xuze; Jin, Wei; Duan, Xiaofeng; Liu, Bo; Jiang-li, WU; Zhang, Rui; Wang, Ying; Kang, Ran; Huang, Lan

doi:10.1016/j.neulet.2018.02.051

Cited by 23 publications

(19 citation statements)

References 47 publications

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“…Ketamine has been shown to protect neurons and glial cells by attenuating glutamate-induced excitotoxicity and inhibiting an inflammatory response (19)(20)(21)26). However, the number of studies available on the relevant neurocellular mechanisms are limited (14,21,(27)(28)(29)(30), and hypoxia-induced neurotoxicity and potential amelioration through ketamine remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia‑exposed HT22 murine hippocampal neurons

et al. 2020

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Ketamine is a widely used drug in pediatric anesthesia, and both neurotoxic and neuroprotective effects have been associated with its use. There are only a few studies to date which have examined the effects of ketamine on neurons under hypoxic conditions, which may lead to severe brain damage and poor neurocognitive outcomes in neonates. In the present study, the effects of ketamine on cellular pathways associated with neurogenesis, extracellular matrix homeostasis and proliferation were examined in vitro in hypoxia-exposed neurons. Differentiated HT22 murine hippocampal neurons were treated with 1, 10 and 20 µM ketamine and cultured under hypoxic or normoxic conditions for 24 h followed by quantitative PCR analysis of relevant candidate genes. Ketamine treatment did not exert any notable effects on the mRNA expression levels of markers of neurogenesis (neuronal growth factor and syndecan 1), extracellular matrix homeostasis (matrix-metalloproteinase 2 and 9, tenascin C and tenascin R) or proliferation markers (Ki67 and proliferating cell nuclear antigen) compared with the respective untreated controls. However, there was a tendency towards downregulation of multiple cellular markers under hypoxic conditions and simultaneous ketamine treatment. No dose-dependent association was found in the ketamine treated groups for genetic markers of neurogenesis, extracellular matrix homeostasis or proliferation. Based on the results, ketamine may have increased the vulnerability of hippocampal neurons in vitro to hypoxia, independent of the dose. The results of the present study contribute to the ongoing discussion on the safety concerns around ketamine use in pediatric clinical practice from a laboratory perspective.

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Section: Introductionmentioning

confidence: 99%

Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia‑exposed HT22 murine hippocampal neurons

et al. 2020

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“…Ketamine also inhibits protein kinase C (PKC)/ERK to alter early and late apoptosis of hippocampal neurons, and activation of the excitatory N-methyl-D-aspartate receptor reverses ketamine-induced effects. The neurotoxic effect of ketamine is associated with the PKC/ERK signaling pathway in developing hippocampal neurons ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…The results of the present study were consistent with the results of previous studies, which indicated that YAP stimulates cell proliferation ( 9 , 36 ). Ketamine increases early and late apoptosis in the developing brain by inhibiting the PKC/ERK signaling pathway ( 34 ). The present study identified a potential mechanism underlying ketamine-induced apoptosis, highlighting the potential important role of YAP, which is different from previous studies that have suggested the involvement of other signaling pathways ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Yes‑associated protein protects and rescues SH‑SY5Y cells from ketamine‑induced apoptosis

et al. 2020

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Ketamine is a widely used intravenous anesthetic; however, basic and clinical studies have demonstrated that prolonged exposure can cause irreversible injury to the immature human brain. Yes-associated protein (YAP) is the main effector of the Hippo signaling pathway, which serves an important role in regulating tissue homeostasis and organ size during development. However, whether YAP mediates ketamine-induced apoptosis is not completely understood. Based on the functions of YAP during apoptosis resistance and cell self-renewal regulation, the present study hypothesized that YAP serves a role during ketamine-induced apoptosis. An in vitro model was utilized to investigate the effects of ketamine on neurotoxicity and to further investigate the role of YAP in ketamine-induced apoptosis using techniques including CCK-8 assay, flow cytometry and western blotting. The present study assessed the effects of YAP overexpression and knockdown on the expression of typical apoptotic markers in SH-SY5Y cells. Ketamine induced apoptosis in a dose-dependent manner, which was regulated by YAP. Following YAP overexpression, ketamine-treated SH-SY5Y cells displayed increased activity and viability, whereas expression levels of the apoptotic markers were decreased compared with the negative control group. By contrast, ketamine-induced apoptosis was enhanced following YAP knockdown. Collectively, the results of the present study indicated that YAP may serve an important role during ketamine-induced neurotoxicity, and alterations to YAP signaling may counteract ketamine-induced apoptosis. The neuroprotective effect of YAP activation may serve as a novel pharmacological target for the treatment of ketamine-induced neurotoxicity via neurogenesis normalization.

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“…In Aplysia neurons it has been suggested that the dissociative anesthetic, ketamine, depresses cholinergic responses by affecting gating at postsynaptic membranes (Ikemoto, 1986). Ketamine started to be developed in the 1950s and proved potent in analgesia (Mion, 2017), but prolonged exposure may induce neurotoxicity and neuroapoptosis via the PKC/ERK pathway in cultured hippocampal neurons, while activation of excitatory NMDA receptors reverses these effects (Jiang et al, 2018). In some neural stem cell derived neurons, ketamine neurotoxicity appears to be due to NMDA-receptor mediated calcium influx (Wang et al, 2017).…”

Section: Actions Of Clinical Anesthetics On Gastropod Molluscsmentioning

confidence: 99%

Sense and Insensibility – An Appraisal of the Effects of Clinical Anesthetics on Gastropod and Cephalopod Molluscs as a Step to Improved Welfare of Cephalopods

et al. 2018

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Recent progress in animal welfare legislation stresses the need to treat cephalopod molluscs, such as Octopus vulgaris, humanely, to have regard for their wellbeing and to reduce their pain and suffering resulting from experimental procedures. Thus, appropriate measures for their sedation and analgesia are being introduced. Clinical anesthetics are renowned for their ability to produce unconsciousness in vertebrate species, but their exact mechanisms of action still elude investigators. In vertebrates it can prove difficult to specify the differences of response of particular neuron types given the multiplicity of neurons in the CNS. However, gastropod molluscs such as Aplysia, Lymnaea, or Helix, with their large uniquely identifiable nerve cells, make studies on the cellular, subcellular, network and behavioral actions of anesthetics much more feasible, particularly as identified cells may also be studied in culture, isolated from the rest of the nervous system. To date, the sorts of study outlined above have never been performed on cephalopods in the same way as on gastropods. However, criteria previously applied to gastropods and vertebrates have proved successful in developing a method for humanely anesthetizing Octopus with clinical doses of isoflurane, i.e., changes in respiratory rate, color pattern and withdrawal responses. However, in the long term, further refinements will be needed, including recordings from the CNS of intact animals in the presence of a variety of different anesthetic agents and their adjuvants. Clues as to their likely responsiveness to other appropriate anesthetic agents and muscle relaxants can be gained from background studies on gastropods such as Lymnaea, given their evolutionary history.

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Ketamine-induced neurotoxicity blocked by N -Methyl- d -aspartate is mediated through activation of PKC/ERK pathway in developing hippocampal neurons

Cited by 23 publications

References 47 publications

Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia‑exposed HT22 murine hippocampal neurons

Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia‑exposed HT22 murine hippocampal neurons

Yes‑associated protein protects and rescues SH‑SY5Y cells from ketamine‑induced apoptosis

Sense and Insensibility – An Appraisal of the Effects of Clinical Anesthetics on Gastropod and Cephalopod Molluscs as a Step to Improved Welfare of Cephalopods

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