Ketamine Activates Cell Cycle Signaling and Apoptosis in the Neonatal Rat Brain

Soriano, Sulpicio G.; Liu, Qian; Li, Jing; Liu, Jiaren; Han, Xiao; Kanter, Jennifer L.; Bajic, Dusica; Ibla, Juan C.

doi:10.1097/aln.0b013e3181d3e0c2

Cited by 106 publications

(63 citation statements)

References 26 publications

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“…In studies with seven-day-old rats where loss of pyramidal neurons was induced, levels of caspase 3 were increased in the hippocampus upon administration of sevofl urane, propofol and ketamine (17,(21)(22)(23)(24). In our study, cortex caspase 3 levels were found to be signifi cantly higher in the sevofl urane group compared to the control group.…”

Section: G D Hsupporting

confidence: 55%

Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats

Özer¹,

Çeribaşı²,

Çeribaşı³

et al. 2017

BLL

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OBJECTIVE: To evaluate the early and late effects of sevofl urane on the neonatal brain. BACKGROUND: Sevofl urane is the most used anaesthetics in neonatal subjects. METHODS: The study included 7-day-old male Wistar-Albino rats (n = 30), which were divided into the two groups according to the anaesthetic received: sevofl urane (S) and control group (C). Half of each group was sacrifi ced six hours after anaesthesia (early, E) while the remaining subjects were sacrifi ced six weeks later (late, L). The serum brain-derived-neurotrophic factor (BDNF), brain BDNF and caspase-3 were evaluated. In addition, elevated plus arm test and Morris water test were performed in the late group. RESULTS: BDNF levels were higher in the late groups than in the early ones (p < 0.05). BDNF levels in cerebral cortex were higher in the Group CE than in the Group CL and SL (p < 0.05). There was a signifi cant negative correlation between serum BDNF and cortex BDNF levels (p = 0.003, r = -0.425). Cortex caspase 3 levels were signifi cantly higher in the Groups SE and SL than in the Group CE and CL (p < 0.05). There was no signifi cant difference between the groups in the terms of open arm index, locomotor activity and Morris water test. CONCLUSIONS: Although sevofl urane induced apoptosis, it didn't affect BDNF levels and showed no longterm negative effects on learning and anxiety in neonatal rats (Tab. 1, Fig. 3, Ref. 26). Text in PDF www.elis.sk.

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Section: G D Hsupporting

confidence: 55%

Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats

Özer¹,

Çeribaşı²,

Çeribaşı³

et al. 2017

BLL

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“…Changes in the neuronal cytoskeleton have also been observed, possibly via the p75 NTR receptor and subsequent RhoA activation [28]. Altered neurogenesis and abnormal re-entry into the cell cycle has also been observed [29,30]. Lastly, anesthetics have been shown to impair mitochondrial function [31].…”

Section: Effects Other Than Apoptosismentioning

confidence: 97%

Anesthesia and Apoptosis in the Developing Brain: An Update

Davidson

deGraaff

2012

Curr Anesthesiol Rep

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There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Numerous animal and in vitro studies have demonstrated that general anaesthetics cause a variety of potentially harmful effects on the developing brain. An increased level of neuronal apoptosis is one such effect. In some studies, exposed animals have experienced long-lasting neurobehavioural changes. These effects occur at very specific stages of development and are dose-dependent. There are several plausible mechanisms for these deleterious effects; however, the exact mechanism remains unclear. Most importantly, histological and behavioral effects have been demonstrated in non-human primates. Human research evaluating the long-term effects of anaesthesia on brain development is limited and, to date, has been limited to retrospective observational cohort studies. The results of these studies have not been consistent, with some demonstrating an association between surgery and adverse neurobehavioral outcome and others showing no association. Furthermore, these cohort studies have numerous weaknesses and limitations. An ongoing randomized clinical trial aims to provide clear evidence regarding the clinical safety of anesthetics up to 1 h in neonates and older children.

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“…Ketamine is an NMDA receptor antagonist that is widely used in pediatric anesthesia, and sub-anesthetic doses of ketamine are frequently used for perioperative sedation, analgesia, and other diagnostic procedures in pediatric patients. It is also known that ketamine can cause neuronal apoptosis in the developing mammalian brain [2,3,4,5,6,7,8,13,14] and, consequently, long-term defects in learning and memory [3,46]. When immature neurons are exposed to blockers of NMDA receptors, these cells activate a compensatory mechanism following withdrawal that causes increased expression of NMDA receptors, leading to increased sensitivity to extracellular glutamate.…”

Section: Discussionmentioning

confidence: 99%

“…The first preclinical study investigating neurotoxicity in the early stages of central nervous system (CNS) development following exposure to NMDA receptor antagonists was reported in 1999 [1]. Since then, a series of animal experiments have shown that repeated administration of ketamine can trigger neurodegeneration in the developing brain, leading to long-term defects in cognitive behavior [2,3,4,5,6,7,8,9]. The mechanism leading from ketamine uptake to neuronal cell death remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1a Pathway in Developing Rats

Jia

Huang

Lü

et al. 2014

Cell Physiol Biochem

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Background: Recent animal experiments have suggested that ketamine administration during development might induce widespread neurodegeneration and long-term cognitive deficits. The underlying mechanism is not fully understood. Methods: Immature rat hippocampal neurons and newborn rats underwent repeated exposure to ketamine, ketamine+inhibitor of hypoxia-inducible factor (HIF)-1α(YC-1), ketamine+inhibitor of reactive oxygen species(ROS) (L-carnitine) or ketamine+Ca²⁺ blocker(nimodipine). Apoptosis of the hippocampal neurons was analyzed by TUNEL and flow cytometry. Intracellular ROS were measured using 2',7'-dichlorofluorescein diacetate. The expression of HIF- 1α and apoptosis-related proteins was analyzed by western blot or qPCR. As these rats grew, behavioral tests were performed to evaluate cognitive function. Results: The apoptotic rate in the ketamine group was significantly higher than that in the other groups, and the intracellular ROS levels in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. The expression of HIF- 1α, p53, BNIP3 and cleaved caspase-3 proteins increased, and the ratio of Bcl-2/Bax decreased in the ketamine group. The transcriptional levels of HIF-1α in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. Cognitive deficits were found only in the ketamine group. Conclusion: We suggest that ketamine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1α pathway.

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Ketamine Activates Cell Cycle Signaling and Apoptosis in the Neonatal Rat Brain

Abstract: These findings support a model in which ketamine induces aberrant cell cycle reentry, leading to apoptotic cell death in the developing rat brain.

Cited by 106 publications

References 26 publications

Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats

Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats

Anesthesia and Apoptosis in the Developing Brain: An Update

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1a Pathway in Developing Rats

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