Clinically Relevant Concentrations of Propofol but Not Midazolam Alter <i>In Vitro</i>  Dendritic Development of Isolated γ-Aminobutyric Acid-positive Interneurons

Vutskits, László; Gascon, Eduardo; Tassonyi, E.; Kiss, József Zoltán

doi:10.1097/00000542-200505000-00016

Cited by 107 publications

(78 citation statements)

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“…As previously reported, steady-state anesthesia levels of propofol are 2-5 mg/mL in humans and 20-60 mg/mL in animals (Feiner et al, 2005). Our results are consistent with previous reports showing that clinically relevant concentrations of propofol result in cell death of GABAergic neurocytes in neonates (Vutskits et al, 2005). In contrast, aggregating fetal (16 days of gestation) rat brain glial cells have been shown to develop resistance to propofol even at doses of 10 mg/mL (Honegger and Matthieu, 1996), although the reasons for the discrepancy observed still remain unclear.…”

Section: Figsupporting

confidence: 93%

microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes

Sun

Pei

2015

DNA and Cell Biology

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Although propofol exerts toxic effects on the developing central nervous system (CNS), it remains a first-choice anesthetic in the pediatric population. Astrocytes represent a major glial cell population whose role in CNS development is widely appreciated and that has been recently shown to be mediated in large part by microRNAs (miRNAs). In contrast, relatively little is known about the roles of miRNAs in developing astrocytes during propofol treatment. Here, miRNA microarray was used to profile fluctuations in miRNA expression in immature hippocampal astrocytes in response to propofol treatment, and results were subsequently validated using quantitative real-time polymerase chain reaction. Predictive analysis of genes targeted by propofol-regulated miRNAs indicated enrichment of genes in the gene ontology (GO) nervous system development and differentiation category, and in the Kyoto encyclopedia of genes and genomes (KEGG) apoptotic pathway category. A total of 24 (10 short-term dosage and 14 long-term dosage) miRNAs were significantly regulated, one of which was rno-miR-665. Ectopic overexpression and silencing of rno-miR-665 demonstrated its role in the neurotoxic effects of propofol on hippocampal immature astrocytes. We present evidence that the role of rnomiR-665 in anesthesia-induced disturbances in astroglia development may involve direct downregulation of the anti-apoptotic gene Bcl2l1, and subsequent increased caspase-3-mediated apoptosis. Our results shed light on the anesthetic mechanism of propofol and have implications for its use in the clinical setting.

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Section: Figsupporting

confidence: 93%

microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes

Sun

Pei

2015

DNA and Cell Biology

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“…Neuronal deficit in pathological conditions has been reported to induce disturbance of synapse formation (Nikzad et al, 2007), so the decrease of synaptic density induced by multiple propofol exposures may attribute to neuronal deficit to some extent. Additionally, propofol with clinically relevant concentrations can cause neurite retraction (Turina et al, 2008), growth cone collapse (Al-Jahdari et al, 2006) and a persistent decrease in dendritic growth (Vutskits et al, 2005), which suggests decreased synaptic density induced by propofol may result from its straight inhibition on synapse formation as well. The present study, for the first time, demonstrates that repeated but not single exposure to propofol during critical periods of synaptogenesis induces persistent synaptic loss both in hippocampus and the PrL, which suggests that the effects of propofol-induced inhibition of synapse formation are exposure times dependent.…”

Section: Discussionmentioning

confidence: 99%

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

et al. 2016

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-Propofol can induce acute neuronal apoptosis or long-term cognitive dysfunction when exposed at early age in rodents, but it is unclear how the neurotoxicity including neuronal apoptosis and synaptic loss will change in a dynamic manner with brain development after multiple or single exposure of propofol, and the role of neuronal apoptosis and synaptic loss in propofol-induced long-term cognitive impairment needs to be elucidated. In this study, we investigated dynamic changes of neuronal apoptosis, neuronal density, synaptic density in hippocampal CA1 region and the prelimbic cortex (PrL), and longterm cognitive function after multiple or single exposure of propofol in neonatal rats. Results showed that single exposure of propofol only induced great neuronal apoptosis and deficit at postnatal day 9(P9); while multiple exposures of propofol could induce significant neuronal apoptosis, neuronal deficit and synaptic loss at P9, P14, P21, or P35 compared with intact, and spatial learning and memory impairment from P36 to P41. Results suggest that single exposure of propofol only induces transient neuronal apoptosis and deficit, while multiple exposures of propofol induce persistent neuronal apoptosis, neuronal deficit, synaptic loss, and long-term cognitive impairment. Furthermore, persistent neuronal deficit and disturbances in synapse formation but not transient neuronal apoptosis may contribute to long-term cognitive impairment.

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“…Such neurotoxicity has now been demonstrated not only for isoflurane [1] but also for ketamine [2] , midazolam [2] , diazepam, pentobarbital [3] , thiopental [4] , N 2 O [5] and propofol [4,[6][7][8] . Pregnant women, newborns, and infants are often exposed to anesthetic agents during childbirth or for surgical procedures.…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function

2012

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Objective Sevoflurane is widely used in pediatric anesthesia and former studies showed that it causes neurodegeneration in the developing brain. The present study was carried out to investigate the effects of sevoflurane on neurogenesis, neurodegeneration and behavior. Methods We administered 5-bromodeoxyuridine, an S-phase marker, before, during, and after 4 h of sevoflurane given to rats on postnatal day 7 to assess dentate gyrus progenitor proliferation and Fluoro-Jade staining for degeneration. Spatial reference memory was tested 2 and 6 weeks after anesthesia. Results Sevoflurane decreased progenitor proliferation and increased cell death until at least 4 days after anesthesia. Spatial reference memory was not affected at 2 weeks but was affected at 6 weeks after sevoflurane administration. Conclusion Sevoflurane reduces neurogenesis and increases the death of progenitor cells in developing brain. This might mediate the lateonset neurocognitive outcome after sevoflurane application.

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Clinically Relevant Concentrations of Propofol but Not Midazolam Alter In Vitro Dendritic Development of Isolated γ-Aminobutyric Acid-positive Interneurons

Cited by 107 publications

References 0 publications

microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes

microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function

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