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.[1 2 3 4 5 6 7 8 9 10 ketamine [Figure 1a ], 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 Ca
2+ signaling and—among other effects on the neuronal machinery—triggers the generation of
oxidative stress and, in some cases, even the mitochondrial apoptotic pathway.[
15 18 19 22 23 ] Recent experimental evidence suggests that the same deregulation of the
NMDA receptors ' expression leads to premature differentiation of NPCs.[
26 ] (c):
Ketamine has been reported to downregulate
Notch 1α ,[
17 ] 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 .[
17 ] 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 . Ca
2+ : 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
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 ].[11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Table 1: Selected recent (2009-2019) in vivo experimental studies providing critical insight to the cellular and molecular mechanisms underlying ketamine -induced developmental neurotoxicity
Main pathways of ketamine -induced developmental neurotoxicity
Neuroapoptosis, a major consequence of ketamine 's developmental toxicity and one of the first to be reported,[2 15 20 24 12 14 26 27 28 29 ketamine -induced developmental neurotoxicity in both rodents and non-human primates.[12 15 19 22 in vivo experimental evidence suggests that neuroapoptosis is only an aspect of a more complex pathophysiological cascade involved in ketamine -induced developmental neurotoxicity [Figure 1b ]. 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.[15 18 19 20 21 22 23
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.[20 ketamine , identified perturbations and confirmed an upregulation of NMDA receptors .[21
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 .[20 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 1b ].[26
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 .[15 18 19 22 ketamine -exposed rat brains has been associated with a downregulation of critical components of the extracellular signal regulated kinase (ERK) signaling cascade,[15 18 30 19 23
Deregulation of neurogenesis through premature neuronal differentiation
An experimental study on transgenic zebrafish embryos[17 ketamine -induced developmental neurotoxicity through the manipulation of differentiating and differentiated neurons [Figure 1c ]. 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 1 α gene, (ii) downregulate the expression of the motor neuron-inducing NeuroD and Gli2b , and (iii) upregulate the expression of Ngn1 .[17
The reported ketamine -induced downregulation of Notch 1 α[17 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.[26 NeuroD expression has been reported[17 ketamine [Figure 1c ].
This—yet to be confirmed in mammals—mode of ketamine -induced developmental neurotoxicity could explain the findings of Aligny et al .[11 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.[13
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 ”.[16 ketamine -induced developmental neurotoxicity, with important leads regarding neuronal migration and glial growth, has been performed by Huang et al .[14 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.[14
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,[12 ketamine seem to exist,[11 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.[13 ketamine during neurodevelopment is strongly dependent on the experimental conditions employed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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