Ketamine-induced Neuroapoptosis in the Fetal and Neonatal Rhesus Macaque Brain

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

doi:10.1097/aln.0b013e318242b2cd

Cited by 394 publications

(279 citation statements)

References 46 publications

(90 reference statements)

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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%

“…benzodiazepines, are known to cause apoptotic death of neurons in the brains of newborn animals [7,8], associated with long-term cognitive deficits [9]. Induction of general anaesthesia in infants mostly involves volatile anaesthetics.…”

Section: Introductionmentioning

confidence: 99%

“…Exposure to isoflurane, which affects various cell types outside and inside the brain [8,24], causes a panoply of cardiorespiratory and metabolic side effects [10]. Its use in newborn rodents is associated with considerable mortality [25].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

Berns¹,

Wolter²,

Bührer³

et al. 2017

TOATJ

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“…Another patient in that same case series complained of dysphoria after the initial ketamine bolus and asked that drug is discontinued [19]. Due to our study design we are not able to comment on the long term effect of ketamine, more specifically neuroapoptosis, which has been recently raised as major concern and potentially results from the exposure of the developing brain to ketamine [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Low-dose Ketamine for Children and Adolescents with Acute Sickle Cell Disease Related Pain: A Single Center Experience

Neri¹,

Pestieau

Young³

et al. 2014

J Anesth Clin Res

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Background: Opioids are the mainstay of therapy for painful vasoocclusive episodes (VOEs) in sickle cell disease (SCD). Based on limited studies, low-dose ketamine could be a useful adjuvant analgesic for refractory SCD pain, but its safety and efficacy has not been evaluated in pediatric SCD. Procedure:Using retrospective chart review we recorded and compared characteristics of hospitalizations of 33 children with SCD hospitalized with VOE who were treated with low-dose ketamine and opioid PCA vs. a paired hospitalization where the same patients received opioid PCA without ketamine. We seek to 1) describe a single center experience using adjuvant low-dose ketamine with opioid PCA for sickle cell related pain, 2) retrospectively explore the safety and efficacy of adjuvant low-dose ketamine for pain management, and 3) determine ketamine's effect on opioid consumption in children and adolescents hospitalized with VOE. Results:During hospitalizations where patients received ketamine, pain scores and opioid use were higher (6.48 vs. 5.99; p=0.002 and 0.040 mg/kg/h vs. 0.032 mg/kg/h; p=0.004 respectively) compared to hospitalizations without ketamine. In 3 patients, ketamine was discontinued due to temporary and reversible psychotomimetic effects. There were no additional short term side effects of ketamine.Conclusions: Low-dose ketamine has an acceptable short-term safety profile for patients with SCD hospitalized for VOE. Lack of an opioid sparing effect of ketamine likely represents use of low-dose ketamine for patients presenting with more severe VOE pain. Prospective randomized studies of adjuvant low-dose ketamine for SCD pain are warranted to determine efficacy and long-term safety.

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“…Large numbers of studies with conventional animal models have revealed that ketamine can cause neuronal apoptosis during the critical period of the developing brain [7][8][9][10][11][12]. Also a preliminary clinical study indicated that exposure to ketamine over 3 times was detrimental to neurodevelopment in infants [13].…”

Section: Introductionmentioning

confidence: 99%

Zebrafish as a New Platform Used in Exploration of Ketamine-Induced Neurodevelopmental Toxicity

Ruan¹

2015

J Clin Exp Pathol

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We have modified the abstract as 'Previous studies have already found out that commonly used anesthetic, ketamine, has toxic effects on neurodevelopment. Unlike most rodent models just focusing on neuronal apoptosis caused by ketamine, early stages of neuron development abnormality in zebrafish can be assessed in vivo because of the transparent embryos and larve. And also thanks to its cost-efficiency and quick reproduction, large-scale behavior analyses and gene screens can be conducted in zebrafish. Besides, the whole genome of zebrafish has already been sequenced and its gene functions are highly conserved during evolution, which makes the experiments more reliable on zebrafish model. So Zebrafish has obvious advantages in the researches of ketamine neurotoxicity over the conventional animal models (such as mice). Within this paper we illuminate how we can use this model to study ketamine neurotoxicity. In the future, along with more advanced genetic technologies joining this platform will not only make up for conventional models to deeply understand neurodevelopmental toxicity of ketamine, but also might provide the unique insight to the field of neurodevelopment and neurotoxicity impaired by other drugs

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Ketamine-induced Neuroapoptosis in the Fetal and Neonatal Rhesus Macaque Brain

Cited by 394 publications

References 46 publications

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

Low-dose Ketamine for Children and Adolescents with Acute Sickle Cell Disease Related Pain: A Single Center Experience

Zebrafish as a New Platform Used in Exploration of Ketamine-Induced Neurodevelopmental Toxicity

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