|Year : 2021 | Volume
| Issue : 1 | Page : 37-42
Ketamine-induced neurotoxicity in neurodevelopment: A synopsis of main pathways based on recent in vivo experimental findings
Konstantina Kalopita1, Athanasios Armakolas1, Anastassios Philippou1, Apostolos Zarros2, Panagoula Angelogianni1
1 Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, Athens, Greece
2 Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
|Date of Submission||07-Dec-2019|
|Date of Acceptance||07-Jan-2020|
|Date of Web Publication||10-Apr-2021|
Dr. Apostolos Zarros
Lab 112, L1, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, Scotland
Source of Support: None, Conflict of Interest: None
Ketamine, a phencyclidine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as an anesthetic, analgesic, and sedative agent in daily pediatric practice. Experimental studies have suggested that early prenatal or postnatal exposure to ketamine can induce neuroapoptosis, and establish neurobehavioral deficits that are evident in adulthood. However, most of the currently available clinical evidence is derived from retrospective and observational clinical studies. We, herein, attempt a brief review of the cellular and molecular mechanisms suggested to mediate ketamine-induced developmental neurotoxicity, utilizing a selected number of recent in vivo experimental evidence.
Keywords: Ketamine, neurodevelopment, neurogenesis, NMDA receptors, oxidative stress
|How to cite this article:|
Kalopita K, Armakolas A, Philippou A, Zarros A, Angelogianni P. Ketamine-induced neurotoxicity in neurodevelopment: A synopsis of main pathways based on recent in vivo experimental findings. J Anaesthesiol Clin Pharmacol 2021;37:37-42
|How to cite this URL:|
Kalopita K, Armakolas A, Philippou A, Zarros A, Angelogianni P. Ketamine-induced neurotoxicity in neurodevelopment: A synopsis of main pathways based on recent in vivo experimental findings. J Anaesthesiol Clin Pharmacol [serial online] 2021 [cited 2021 Jun 25];37:37-42. Available from: https://www.joacp.org/text.asp?2021/37/1/37/313444
| Introduction|| |
Although intravenous anesthetic agents are typically considered as safe to be administered during pediatric surgery, preclinical and clinical evidence has recently emerged regarding their potential neurotoxicity. Several studies have demonstrated that anesthetic exposure in early age may lead to long-term cognitive impairment as well as learning deficits.,,, The United States Food and Drug Administration has raised the concern of pediatric anesthetic neurotoxicity as a major public health issue, and toward that direction, the Smart-Tots initiative has been carried out., Moreover, a number of clinical studies have been performed in recent years,, and symposia are now assessing both the preclinical and clinical data on the potential correlation between anesthetic exposure and developmental neurocognitive impairment. A central role in the ongoing debate on the potential developmental neurotoxicity of anesthetic agents is played by ketamine [Figure 1]a, a N-methyl-D-aspartate (NMDA) receptor antagonist that is widely used in the pediatric anesthesia practice and in sub-anesthetic doses for sedation during diagnostic procedures.
|Figure 1: Pathways of ketamine-induced developmental neurotoxicity. (a): Chemical structure of ketamine. (b): It is well-established that ketamine deregulates the NMDA receptors' expression and as a result increases the neuronal susceptibility to the excitotoxic effects of Glu; the latter leads to a deregulation of the neuronal Ca2+ signaling and—among other effects on the neuronal machinery—triggers the generation of oxidative stress and, in some cases, even the mitochondrial apoptotic pathway.,,,, Recent experimental evidence suggests that the same deregulation of the NMDA receptors' expression leads to premature differentiation of NPCs. (c): Ketamine has been reported to downregulate Notch 1α, that in turn is expected to affect negatively the ligand-dependent Notch signaling in the proneural domain. The latter inhibition would upregulate Ngn1 in the NPCs and decrease the possibility of neuronal survival in differentiated neurons. In the first case, the ketamine-induced upregulation of the Ngn1 expression could lead to an upregulation of NeuroD expression (a critical factor for neuronal differentiation), leading to premature neuronal differentiation. The fact that Kanungo et al. reported a downregulation of the NeuroD expression was suggested by the authors themselves to be a result of fewer surviving differentiated neurons as a result of the exposure to ketamine. Elements in blue color background indicate an increase, upregulation or enhancement, while elements in red color background indicate a decrease, downregulation or inhibition, as a result of the exposure to ketamine. Ca2+: calcium; Glu: glutamate; NeuroD: neurogenic differentiation (transcription factor); Ngn1: neurogenin-1; NMDA: N-methyl-D-aspartate; Notch 1α: neurogenic locus notch homolog protein 1 alpha; NPCs: neural progenitor cells|
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Most of the currently available clinical evidence is derived from retrospective and observational clinical studies, and thus, very little can be concluded from them with regard to the mechanisms involved. We, herein, attempt a brief review of the cellular and molecular mechanisms suggested to mediate ketamine-induced developmental neurotoxicity, utilizing a selected number of recent in vivo experimental evidence [Table 1].,,,,,,,,,,,,, Nevertheless, the translational value of the preclinical data discussed in this review is interpreted with caution.
|Table 1: Selected recent (2009-2019) in vivo experimental studies providing critical insight to the cellular and molecular mechanisms underlying ketamine-induced developmental neurotoxicity|
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Main pathways of ketamine-induced developmental neurotoxicity
Neuroapoptosis, a major consequence of ketamine's developmental toxicity and one of the first to be reported, is now known to be not only dose-dependent, but also time-evolving and dependent on the exposure time-window.,,,,, Caspase-3 protein level increase as well as the induction of neuroapoptosis seems to be “hallmarks” of ketamine-induced developmental neurotoxicity in both rodents and non-human primates.,,, Recent in vivo experimental evidence suggests that neuroapoptosis is only an aspect of a more complex pathophysiological cascade involved in ketamine-induced developmental neurotoxicity [Figure 1]b. Specifically, the deregulation of the NMDA receptors' expression (overexpression) and the induction of oxidative stress as a result of increased cellular susceptibility to glutamate (Glu) and calcium (Ca2+) mobilization are evident and/or implied by a number of studies in rodents.,,,,,,
Deregulation of NMDA receptors' expression
As the antagonistic action on the NMDA receptor is one of the main mechanisms of the anesthetic and analgesic effect of ketamine, it comes as no surprise that a study performed on Sprague-Dawley rats has revealed a major and fulminant ketamine-induced upregulation of NMDA receptor subunit NR1 in the PND7 frontal cortex. An earlier study investigating gene expression profiling in frontal cortical areas of age-matched (PND7) Sprague-Dawley rats that received ketamine, identified perturbations and confirmed an upregulation of NMDA receptors.
The deregulation of the expression of the NMDA receptors contributes to the neuronal susceptibility to the excitotoxic effects of Glu after the clearance of ketamine, leading to a major deregulation of the neuronal Ca2+-signaling, and to the generation of oxidative stress. Moreover, due to the fact that Glu is an established regulator of neural progenitor cell (NPC) differentiation, and as NMDA receptors are considered to promote neuronal differentiation (through the overexpression of NeuroD as a result of neuronal excitation), premature neuronal differentiation becomes an additional consequence of the exposure to ketamine during neurodevelopment [Figure 1]b.
Mitochondrial dysfunction and oxidative stress/mitochondrial apoptotic pathway
The deregulation of the neuronal Ca2+ signaling as a result of the increased susceptibility to the excitotoxic effects of Glu has been reported to provoke mitochondrial dysfunction and the generation of oxidative stress in the hippocampi of rats exposed to ketamine during neurodevelopment.,,, Mitochondrial dysfunction in ketamine-exposed rat brains has been associated with a downregulation of critical components of the extracellular signal regulated kinase (ERK) signaling cascade,, implying a decreased capacity to perform critical gene transcription and translation. In the hippocampus, the latter could result to an impairment of synaptic consolidation and to a difficulty in the maintenance of long-term potentiation. Also, triggering of the mitochondrial apoptotic pathway has been reported to evolve autophagy and caspase-1-dependent pyroptosis in rodents.,
Deregulation of neurogenesis through premature neuronal differentiation
An experimental study on transgenic zebrafish embryos has put forward a new candidate pathway of ketamine-induced developmental neurotoxicity through the manipulation of differentiating and differentiated neurons [Figure 1]c. More specifically, zebrafish embryos were exposed to 0.5 and 2 mM of ketamine for 2 or 20 h; when administered for 20 h, ketamine at 2 mM was found not only to decrease cranial and motor neuron populations, and the axon length of the latter, but also to: (i) suppress the expression of the Notch 1α gene, (ii) downregulate the expression of the motor neuron-inducing NeuroD and Gli2b, and (iii) upregulate the expression of Ngn1.
The reported ketamine-induced downregulation of Notch 1α is expected to affect negatively the ligand-dependent Notch signaling in the proneural domain. The latter inhibition would upregulate Ngn1 in the NPCs and decrease the possibility of neuronal survival in differentiated neurons. In the first case, the ketamine-induced upregulation of the Ngn1 expression could lead to an upregulation of NeuroD expression, leading to premature neuronal differentiation. A downregulation of the NeuroD expression has been reported and it was suggested to be a result of fewer surviving differentiated neurons as a result of the exposure to ketamine [Figure 1]c.
This—yet to be confirmed in mammals—mode of ketamine-induced developmental neurotoxicity could explain the findings of Aligny et al. on FVB-Tg(GadGFP) 45704Swn transgenic mice, where both the migration and the cytomorphology of GABAergic interneurons in the cortical layers II-IV were significantly affected by maternal exposure to ketamine from GD15 to GD20. It could also account for the dose-dependent inhibition of cell proliferation in critical rat neurogenic regions such as the ventricular and the subventricular zones by a single intraperitoneal injection of ketamine on GD 17.
Other findings of interest
Interestingly, the reduction of parvalbumin-expressing interneurons in the adult murine medial prefrontal cortex as a result of exposure to ketamine during the PND7 to PND11 time-window seems to be compatible with the expression of a phenotype that could act as a model for the experimental simulation of the “cognitive and negative symptoms of schizophrenia”. Moreover, a critical and noteworthy study for the understanding of the role of the hippocampus in the ketamine-induced developmental neurotoxicity, with important leads regarding neuronal migration and glial growth, has been performed by Huang et al. In that well-designed study on Sprague-Dawley rats, ketamine-exposed rats on PND7 demonstrated a transient disruption of their neural stem cell proliferation and differentiation, and an inhibition of neuronal migration and in the granule cell layer of the hippocampal dentate gyrus upon reaching PND37 and PND44, which were accompanied by reduced growth of astrocytes in the hippocampal dentate gyrus.
The “bigger picture” and translational perspectives
Despite the progress recorded regarding the understanding of the neurodevelopmental toxicity of ketamine, the clinical translation of the aforementioned experimental findings should be done with caution and only after considering that: (i) in clinical pediatric or obstetric practice, ketamine is rarely used as a stand-alone anesthetic agent, (ii) sex-dependent differences with regards to the developmental neurotoxicity of ketamine seem to exist, and (iii) in vivo experimental studies involving a maternal exposure to ketamine rarely provide details of the maternal hemodynamic and respiratory stability; the latter being a critical interfering factor for the reliability of that type of study. The pathways presented in this review seem to form a bigger picture in which the extent and the nature of the neuronal susceptibility to ketamine during neurodevelopment is strongly dependent on the experimental conditions employed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al.
Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011;128:e1053-61.
Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al.
Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4.
Vutskits L, Davidson A. Update on developmental anesthesia neurotoxicity. Curr Opin Anaesthesiol 2017;30:337-42.
Walters JL, Paule MG. Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity. Neurotoxicol Teratol 2017;60:2-23.
Kuehn BM. FDA considers data on potential risks of anesthesia use in infants, children. JAMA 2011;305:1749-50, 1753.
Ramsay JG, Rappaport BA. SmartTots: A multidisciplinary effort to determine anesthetic safety in young children. Anesth Analg 2011;113:963-4.
Ramsay JG, Roizen M. SmartTots: A public-private partnership between the United States Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS). Paediatr Anaesth 2012;22:969-72.
Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, et al.
Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomised controlled trial. Lancet 2016;387:239-50.
Gleich SJ, Flick R, Hu D, Zaccariello MJ, Colligan RC, Katusic SK, et al.
Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study. Contemp Clin Trials 2015;41:45-54.
Lee JJ, Sun LS, Levy RJ. Report on the Sixth Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) Symposium, “Anesthesia and Neurodevelopment in Children”. J Neurosurg Anesthesiol 2019;31:103-7.
Aligny C, Roux C, Dourmap N, Ramdani Y, Do-Rego JC, Jégou S, et al.
Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice. Cell Death Dis 2014;5:e1311.
Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, et al.
Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012;116:372-84.
Dong C, Rovnaghi CR, Anand KJ. Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions. Acta Anaesthesiol Scand 2016;60:579-87.
Huang H, Liu CM, Sun J, Hao T, Xu CM, Wang D, et al.
Ketamine affects the neurogenesis of the hippocampal dentate gyrus in 7-day-old rats. Neurotox Res 2016;30:185-98.
Huang L, Liu Y, Jin W, Ji X, Dong Z. Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain. Brain Res 2012;1476:164-71.
Jeevakumar V, Driskill C, Paine A, Sobhanian M, Vakil H, Morris B, et al.
Ketamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice. Behav Brain Res 2015;282:165-75.
Kanungo J, Cuevas E, Ali SF, Paule MG. Ketamine induces motor neuron toxicity and alters neurogenic and proneural gene expression in zebrafish. J Appl Toxicol 2013;33:410-7.
Li X, Guo C, Li Y, Li L, Wang Y, Zhang Y, et al.
Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway. Oncotarget 2017;8:32433-49.
Li Y, Li X, Zhao J, Li L, Wang Y, Zhang Y, et al.
Midazolam attenuates autophagy and apoptosis caused by ketamine by decreasing reactive oxygen species in the hippocampus of fetal rats. Neuroscience 2018;388:460-71.
Liu F, Paule MG, Ali S, Wang C. Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain. Curr Neuropharmacol 2011;9:256-61.
Shi Q, Guo L, Patterson TA, Dial S, Li Q, Sadovova N, et al.
Gene expression profiling in the developing rat brain exposed to ketamine. Neuroscience 2010;166:852-63.
Yan J, Huang Y, Lu Y, Chen J, Jiang H. Repeated administration of ketamine can induce hippocampal neurodegeneration and long-term cognitive impairment via the ROS/HIF-1α pathway in developing rats. Cell Physiol Biochem 2014;33:1715-32.
Ye Z, Li Q, Guo Q, Xiong Y, Guo D, Yang H, et al.
Ketamine induces hippocampal apoptosis through a mechanism associated with the caspase-1 dependent pyroptosis. Neuropharmacology 2018;128:63-75.
Zhao T, Li C, Wei W, Zhang H, Ma D, Song X, et al.
Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat. Sci Rep 2016;6:26865.
Disma N, Hansen TG. Pediatric anesthesia and neurotoxicity: Can findings be translated from animals to humans? Minerva Anestesiol 2016;82:791-6.
Dong C, Anand KJ. Developmental neurotoxicity of ketamine in pediatric clinical use. Toxicol Lett 2013;220:53-60.
Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 2013;106-107:1-16.
Zanghi CN, Jevtovic-Todorovic V. A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies. Neurotoxicol Teratol 2017;60:24-32.
Cheung HM, Yew DTW. Effects of perinatal exposure to ketamine on the developing brain. Front Neurosci 2019;13:138.
Zarros A, Byrne AM, Boomkamp SD, Tsakiris S, Baillie GS. Lanthanum-induced neurotoxicity: Solving the riddle of its involvement in cognitive impairment? Arch Toxicol 2013;87:2031-5.