Anesthesia and the developing brain

Jevtović-Todorović, Vesna

doi:10.1097/aco.0b013e3283487247

Cited by 51 publications

(22 citation statements)

References 30 publications

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“…For example, despite evidence from the present study demonstrating protection of DIV 7 neurons from isoflurane toxicity by DIV 7 astrocytes, previous studies 1 have demonstrated isoflurane-induced neuronal cell death in vivo at post-natal day 7 (PND 7). DIV 7 cultured brain cells are unlikely to fully recapitulate the phenotypes of cells developing in vivo , and in particular, the ratio of astrocytes to neurons in culture is likely higher than seen in vivo at this age and may contribute to the difference between these observations.…”

Section: Discussioncontrasting

confidence: 99%

“…1 A primary mechanism contributing to anesthetic neurotoxicity during this period has been attributed to modulation of brain-derived neurotrophic factor (BDNF), 2, 3 a central regulator of neurogenesis, 4 synaptogenesis 5 and neurotransmission. 6 In addition to playing a critical role in normal brain development 7 , BDNF signaling is instrumental to learning and long-term memory consolidation 8, 9 and repair of the brain and spinal cord following injury in the adult.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor

2015

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Background Isoflurane induces cell death in neurons undergoing synaptogenesis via increased production of pro-brain derived neurotrophic factor (proBDNF) and activation of post-synaptic p75 neurotrophin receptor (p75NTR). Astrocytes express p75NTR but their role in neuronal p75NTR mediated cell death remains unclear. We investigated whether astrocytes have the capacity to buffer increases in proBDNF and protect against isoflurane/p75NTR neurotoxicity. Methods Cell death was assessed in day-in-vitro (DIV) 7 mouse primary neuronal cultures alone or in co-culture with age-matched or DIV 21 astrocytes with propidium iodide 24 hours following 1 hour exposure to 2% isoflurane or recombinant proBDNF. Astrocyte-targeted knockdown of p75NTR in co-culture was achieved with small interfering RNA and astrocyte-specific transfection reagent and verified with immunofluorescence microscopy. proBDNF levels were assessed by enzyme-linked immunosorbent assay. Each experiment used 6–8 replicate cultures/condition, and was repeated at least three times. Results Exposure to isoflurane significantly (p<0.05) increased neuronal cell death in primary neuronal cultures (1.5±0.7 fold, mean±SD) but not in co-culture with DIV 7 (1.0±0.5 fold) or DIV 21 astrocytes (1.2±1.2 fold). Exogenous proBDNF dose dependently induced neuronal cell death in both primary neuronal and co-cultures, an effect enhanced by astrocyte p75NTR inhibition. Astrocyte-targeted p75NTR knockdown in co-cultures increased media proBDNF (1.2±0.1 fold) and augmented isoflurane induced neuronal cell death (3.8±3.1 fold). Conclusions The presence of astrocytes provides protection to growing neurons by buffering elevated levels of proBDNF induced by isoflurane. These findings may hold clinical significance for the neonatal and injured brain where elevated levels of proBDNF impair neurogenesis.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor

2015

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“…Environmental enrichment of the offspring has reduced the long term neurotoxicity of neonatal sevoflurane exposure in mice [27]. We caution that animal studies cannot directly predict the toxicities in humans [36,37]. …”

Section: Discussionmentioning

confidence: 99%

Propofol Exposure in Pregnant Rats Induces Neurotoxicity and Persistent Learning Deficit in the Offspring

Xiong

Alhashem

et al. 2014

Brain Sciences

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Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal changes would lead to long-term behavioral deficits in the offspring. In this study, propofol (0.4 mg/kg/min, IV, 2 h), saline, or intralipid solution was administered to pregnant rats on gestational day 18. We detected increased levels of cleaved caspase-3 in fetal brain at 6 h after propofol exposure. The neuronal density of the hippocampus of offspring was reduced significantly on postnatal day 10 (P10) and P28. Synaptophysin levels were also significantly reduced on P28. Furthermore, exploratory and learning behaviors of offspring rats (started at P28) were assessed in open-field trial and eight-arm radial maze. The offspring from propofol-treated dams showed significantly less exploratory activity in the open-field test and less spatial learning in the eight-arm radial maze. Thus, this study suggested that propofol exposure during pregnancy in rat increased cleaved caspsase-3 levels in fetal brain, deletion of neurons, reduced synaptophysin levels in the hippocampal region, and persistent learning deficits in the offspring.

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“…1–3 The increasing concern is based on preclinical studies demonstrating increases in the number of cells undergoing apoptosis following anesthesia exposure(s) in the developing rodent brain, associated with long-term behavioral changes. 4–9 Although this has also been seen in young, non-human primate brain, 10–12 these important studies fall short of providing direct evidence of similar anesthesia-induced neurotoxicity in neonates and young children.…”

Section: Introductionmentioning

confidence: 99%

Brain Maturation in Neonatal Rodents Is Impeded by Sevoflurane Anesthesia

et al. 2015

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Background A wealth of data shows neuronal demise after general anesthesia in the very young rodent brain. Here we apply proton magnetic resonance spectroscopy (1HMRS), testing the hypothesis that neurotoxic exposure during peak synaptogenesis can be tracked via changes in neuronal metabolites. Methods 1HMRS spectra was acquired in the brain (thalamus) of neonatal rat pups 24- and 48 h after sevoflurane exposure on post-natal day (PND) 7 and 15, and in unexposed, sham controls. A repeated measure ANOVA was performed to examine if changes in metabolites were different between exposed and unexposed groups. Sevoflurane-induced neurotoxicity on PND7 was confirmed by immunohistochemistry. Results In unexposed PND7 pups (N=21), concentration of NAA ([NAA]) increased by 16% from PND8 to PND9, whereas in exposed PND7 pups (N=19), [NAA] did not change and concentration of choline compounds ([GPC+PCh]) decreased by 25%. In PND15 rats, [NAA] increased from PND16 to PND17 for both the exposed (N=14) and unexposed (N=16) groups. Two-way ANOVA for PND7 pups demonstrated changes over time observed in [NAA] (p=0.031) and [GPC+PCh] (p=0.024) were different between those two groups. Conclusions We demonstrated that normal [NAA] increase from PND8 to PND9 was impeded in sevoflurane-exposed rats when exposed at PND7; however, not impeded when exposed on PND15. Furthermore, we showed that non-invasive 1HMRS is sufficiently sensitive to detect subtle differences in developmental time trajectory of [NAA]. This is potentially clinically relevant since 1HMRS can be applied across species, and may be useful in providing evidence of neurotoxicity in the human neonatal brain.

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Anesthesia and the developing brain

Cited by 51 publications

References 30 publications

Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor

Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor

Propofol Exposure in Pregnant Rats Induces Neurotoxicity and Persistent Learning Deficit in the Offspring

Brain Maturation in Neonatal Rodents Is Impeded by Sevoflurane Anesthesia

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