Isoflurane-induced Neuroapoptosis in the Neonatal Rhesus Macaque Brain

Brambrink, Ansgar M.; Evers, Alex S.; Avidan, Michael S.; Farber, Nuri B.; Smith, Derek J.; Zhang, Xuezhao; Dissen, Gregory A.; Creeley, Catherine E.; Olney, John W.

doi:10.1097/aln.0b013e3181d049cd

Cited by 566 publications

(473 citation statements)

References 33 publications

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“…To date there have been virtually no neurobehavioral studies of preterm fetal sheep that have sustained WMI. Greater clinical relevance of fetal sheep models of WMI also may be achieved by addressing common confounders of neonatal care that include the influence of nutritional status, stressors, painful exposures, and recurrent sedative and anesthetic exposure [128][129][130][131][132]. All are likely to adversely influence neonatal brain development and the impact of WMI on subsequent long-term motor and cognitive development via mechanisms that are currently not well understood.…”

Section: Final Conclusionmentioning

confidence: 99%

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

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Section: Final Conclusionmentioning

confidence: 99%

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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“…However, while apopotosis, as indicated by positive TUNEL staining, was present in all study groups, no significant difference was evident in its prevalence between groups. A potential explanation for this finding relates to the growing evidence that inhalational anesthetic agents such as isoflurane may induce neuronal apoptosis (31)(32)(33)(34). In terms of apoptotic effects, the relatively prolonged exposure of all study groups to isoflurane in our protocol may therefore have confounded any more subtle manifestations of CPB or Levo.…”

Section: Brain Injury In a Model Of Infant Bypassmentioning

confidence: 84%

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

et al. 2014

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Background:The effects of levosimendan (Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown. Methods: Eighteen 3-to 4-wk-old anesthetized lambs, instrumented with vascular catheters and aortic and right carotid artery flow probes, were allocated to non-CPB, CPB, or CPB+Levo groups (each n = 6). After 120 min CPB with 90 min aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 h. All lambs then underwent brain magnetic resonance imaging, followed by postmortem brain perfusion fixation for immunohistochemical studies. results: In CPB lambs, aortic (P < 0.05) and carotid artery (P < 0.01) blood flows fell by 29 and 30%, respectively, between 2 and 4 h after cross-clamp removal but were unchanged in the CPB+Levo group. No brain injury was detectable with magnetic resonance imaging in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P < 0.05), while white matter microglial density was higher (P < 0.05), but markers of cortical oxidative stress were less prevalent in CPB+Levo than CPB lambs. conclusion: While Levo prevented early postoperative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogeneous neuroglial activation and manifestation of markers of oxidative stress. n eurodevelopmental impairment affects up to one half of all survivors of infant heart surgery, with the spectrum ranging from gross and fine motor deficits, visuospatial difficulties, and impaired cognition to delay in speech and language development (1-5). The mechanisms contributing to brain injury in infants with congenital heart disease are complex and multifactorial, with no consistent improvement in neurodevelopmental outcomes achieved despite major advances in pediatric cardiac surgery and survival. A recent report from the Pediatric Heart Network and the National Heart, Lung, and Blood Institute working group reaffirmed the importance of trials aimed at evaluating novel therapies to address this problem (6).Younger infants undergoing surgery for congenital heart disease are most susceptible to developing brain injury (7,8).The perioperative interval represents a high-risk period with often extended duration of cardiopulmonary bypass (CPB) at the time of the first surgical procedure, as well as significant circulatory disturbance postoperatively. The avoidance of a low cardiac output (CO) state, which can complicate the postoperative course of a proportion of infants after cardiac surgery and which may contribute to later impairment, is a major focus of postoperative care after infant heart surgery. The PRIMACORP study demonstrated the efficacy of intravenous milrinone in preventing this phenomenon in a cohort of children undergoing intracardiac repairs (9). Our laboratory subsequently demonstrated that the inodilator levosimendan (Levo) (Simdax, Abbott, Botany, Australia) was at leas...

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“…Brains of both fetal [24] and neonatal rhesus macaques [8,11] display signs of neuronal apoptosis upon exposure to isoflurane (0.7 -1.5 Vol.% for 5 hours). In humans, there is epidemiological evidence to suggest a modestly elevated risk of adverse behavioural or developmental outcomes in children who were exposed to anaesthesia during early childhood [1,3,4].…”

Section: Resultsmentioning

confidence: 99%

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

Berns¹,

Wolter²,

Bührer³

et al. 2017

TOATJ

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Background:Anaesthetics are widely used in new-borns and preterm infants, although it is known that they may adversely affect the developing brain. Objective:We assessed the impact of the volatile anaesthetic, isoflurane, and the intravenous analgesic, fentanyl, on immature and mature embryonic neuronal cells. Methods:Primary neuronal cultures from embryonic rats (E18) cultured for 5 (immature) or 15 days (mature) in vitro (DIV), respectively, were exposed to isoflurane (1.5 Vol.%) or fentanyl (0.8 -200 ng/ml) for 24 hours. Experiments were repeated in the presence of the γ-amino butyric acid-A (GABA A ) receptor antagonists, bicuculline or picrotoxin (0.1 mmol/l), or the pancaspase inhibitor zVAD-fmk (20 nmol/l). Cell viability was assessed by methyltetrazolium (MTT) metabolism or lactate dehydrogenase (LDH) release. Results:Isoflurane reduced cell viability significantly in primary neuronal cells cultured for 5 DIV (Δ MTT -28 ±13%, Δ LDH +143 ±15%). Incubation with bicuculline, picrotoxin or zVAD-fmk protected the cells mostly from isoflurane toxicity. After 15 DIV, cell viability was not reduced by isoflurane. Viability of primary neurons cultured for 5 DIV did not change with fentanyl over the wide range of concentrations tested. Conclusion:Immature primary neurons may undergo apoptosis following exposure to isoflurane but are unaffected by fentanyl. Mature primary neurons were not affected by isoflurane exposure.

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Isoflurane-induced Neuroapoptosis in the Neonatal Rhesus Macaque Brain

Cited by 566 publications

References 33 publications

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

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