Protective effect of acetyl-l-carnitine on propofol-induced toxicity in embryonic neural stem cells

Liu, Fang; Rainosek, Shuo W.; Sadovova, Natalya; Fogle, Charles M.; Patterson, Tucker A.; Hanig, Joseph P.; Paule, Merle G.; Slikker, William; Wang, Cheng

doi:10.1016/j.neuro.2014.03.011

Cited by 58 publications

(45 citation statements)

References 50 publications

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“…We first examined the potential toxic effect of ketamine on cultured neural stem cells. In contrast to our previous propofol (a GABA receptor agonist) data [29], the dose-response data of ketamine revealed no significant effects on the release of LDH (necrotic cell damage) and MTT uptake (mitochondrial and/or cell viability) when neural stem cells were exposed to concentrations less than 500 μM, which is an extremely high concentration of ketamine. These data strongly suggest that ketamine at clinically relevant concentrations (e.g., 10 μM) did not cause significant damage on cultured neural stem cells.…”

Section: Discussioncontrasting

confidence: 99%

“…These data strongly suggest that ketamine at clinically relevant concentrations (e.g., 10 μM) did not cause significant damage on cultured neural stem cells. It should be mentioned that these data differ from our previous in vitro propofol (a GABA receptor agonist) data using the same neural stem cell model [29]. Using a similar exposure duration (24 h), a clinically relevant concentration of propofol produced increased neural stem cell damage, and this type of damage was closely associated with a significant reduction in neural stem cell proliferation rate when neural stem cells were maintained in growth medium [29].…”

Section: Discussioncontrasting

confidence: 76%

“…Ketamine-induced neuronal damage was further confirmed by an increased number of TUNEL-positive cells. TUNEL assay labels broken DNA strands, often associated with apoptotic cell death [22,29]. However, quantitative analyses demonstrated that, although there were slightly increased numbers of GFAP-positive astrocytes in the ketamine group, no significant effects in the number of O4-positive oligodendrocytes and GFAP-positive astrocytes were detected in the ketamine-exposed culture in differentiation conditions.…”

Section: Discussionmentioning

confidence: 98%

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Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells

et al. 2015

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Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neuronal damage when exposure occurs during development. The precise mechanisms are not completely understood. To evaluate the degree of ketamine-induced neuronal toxicity, neural stem cells were isolated from gestational day 16 rat fetuses. On the eighth day in culture, proliferating neural stem cells were exposed for 24 h to ketamine at 1, 10, 100, and 500 μM. To determine the effect of ketamine on differentiated stem cells, separate cultures of neural stem cells were maintained in transition medium (DIV 6) for 1 day and kept in differentiation medium for another 3 days. Differentiated neural cells were exposed for 24 h to 10 μM ketamine. Markers of cellular proliferation and differentiation, mitochondrial health, cell death/damage, and oxidative damage were monitored to determine: (1) the effects of ketamine on neural stem cell proliferation and neural stem cell differentiation; (2) the nature and degree of ketamine-induced toxicity in proliferating neural stem cells and differentiated neural cells; and (3) to provide information regarding receptor expression and possible mechanisms underlying ketamine toxicity. After ketamine exposure at a clinically relevant concentration (10 μM), neural stem cell proliferation was not significantly affected and oxidative DNA damage was not induced. No significant effect on mitochondrial viability (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) in neural stem cell cultures (growth medium) was observed at ketamine concentrations up to 500 μM. However, quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10 μM ketamine-exposed cultures in differentiation medium, compared with the controls. No significant changes in the number of GFAP-positive astrocytes and O4-positive oligodendrocytes (in differentiation medium) were detected from ketamine-exposed cultures. The discussion focuses on: (1) the doses and time-course over which ketamine is associated with damage of neural cells; (2) how ketamine directs or signals neural stem cells/neural cells to undergo apoptosis or necrosis; (3) how functional neuronal transmitter receptors affect neurotoxicity induced by ketamine; and (4) advantages of using neural stem cell models to study critical issues related to ketamine anesthesia.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 98%

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Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells

et al. 2015

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“…We have previously reported on the pathogenic role of oxidative stress in anesthetic-induced developmental neurotoxicity and the neuroprotection conferred by L-carnitines, including acetyl-L-carnitine (ALC) [6,18,19,20]. The supplement of ALC has been shown to attenuate the neuronal injury by presumably normalizing mitochondrial energy metabolites, stabilizing mitochondrial membranes, and enhancing antioxidant activities [21].…”

Section: Introductionmentioning

confidence: 99%

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

Liu¹,

Zhang²,

Liu³

et al. 2017

J Drug Alcohol Res

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Background. In studies on anesthetic-induced developmental neurotoxicity, the animals' physiological status and the depth of anesthesia during anesthesia need to be monitored. In addition, blood borne indicators of prolonged sevoflurane exposure have yet to be explored. The nonhuman primate model could have more advantages over rodent model in these aspects. Methods. Twentyseven rhesus monkeys [postnatal day (PND) 5 or 6] were monitored for their physiological status during the eight-hour exposures to 2.5% sevoflurane or room air. Plasma samples collected during the exposures were analyzed for proinflammatory mediators. Tissue from the frontal cortex was examined via electron microscopy (EM) four hours following the exposure in a subgroup of animals. Micro-positron emission tomography (microPET) using the radiolabeled ligand [ 18 F]FEPPA, which binds to activated microglia and astrocytes in the central nervous system (CNS), was performed one day following the exposure. Results. Key physiological metrics observed in PND 5/6 monkeys undergoing anesthesia were not altered significantly in comparison with those for control animals. Sevoflurane-induced neural damage was confirmed by EM observations. Increased production of interleukin (IL)-6 and CCL-2 was detected in plasma at the end of the eight-hour sevoflurane exposure, and enhanced uptake of [ 18 F]FEPPA was observed in the frontal cortical region the day following anesthesia. The coincident increase in proinflammatory mediators in the peripheral circulation suggested that this sevofluraneinduced response may be used as an indicator of anesthetic-induced developmental neurotoxicity. Conclusions. The valuable information obtained in these studies demonstrates the usefulness of the nonhuman primate model in the evaluation of anesthetic-induced developmental neurotoxicity. The elevation of IL-6 and CCL-2 may be the useful indicator of anesthetic-induced developmental neurotoxicity.

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“…On the other hand, ketamine at concentrations ranging from 1 to 500 mM did not cause significant toxicity in NSCs. 32 In addition, ketamine may have dual effects of both increasing and inhibiting human NSCs proliferation and inducing neuronal death in a time-and dose-dependent manner. [33][34][35][36] We have focused on studying the role of intracellular calcium regulation in GA mediated effects on autophagy and neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Dual effects of neuroprotection and neurotoxicity by general anesthetics on neural stem cells: Role of autophagy

Wang¹,

Wang²,

Wei³

2017

JESR

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General anesthetics (GAs) are widely used for various essential surgical or medical procedures. Recent studies implicate the GAs has dual effects of neuroprotection and neurotoxicity on neurogenesis with unclear mechanisms. This minireview summarizes recent studies on GAs mediated effects on neurogenesis and proposed mechanisms, with focus on autophagy regulation and intracellular calcium homeostasis.

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Protective effect of acetyl-l-carnitine on propofol-induced toxicity in embryonic neural stem cells

Cited by 58 publications

References 50 publications

Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells

Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

Dual effects of neuroprotection and neurotoxicity by general anesthetics on neural stem cells: Role of autophagy

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