Anesthesia-induced Developmental Neurotoxicity Research Articles

Ketamine counteracts sevoflurane-induced depressive-like behavior and synaptic plasticity impairments through the adenosine A2A receptor/ERK pathway in rats.

Ketamine is an ionic glutamic acid N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used in clinical anesthesia, and its rapid and lasting antidepressant effect has stimulated great interest in psychology research. However, the molecular mechanisms underlying its antidepressant action are still undetermined. Sevoflurane exposure early in life might induce developmental neurotoxicity and mood disorders. In this study, we evaluated the effect of ketamine against sevoflurane-induced depressive-like behavior and the underlying molecular mechanisms. Here, we reported that A2AR protein expression was upregulated in rats with depression induced by sevoflurane inhalation, which was reversed by ketamine. Pharmacological experiments showed that A2AR agonists could reverse the antidepressant effect of ketamine, decrease extracellular signal-regulated kinase (ERK) phosphorylation, reduce synaptic plasticity, and induce depressive-like behavior. Our results suggest that ketamine mediates ERK1/2 phosphorylation by downregulating A2AR expression and that p-ERK1/2 increases the production of synaptic-associated proteins, enhancing synaptic plasticity in the hippocampus and thereby ameliorating the depressive-like behavior induced by sevoflurane inhalation in rats. This research provides a framework for reducing anesthesia-induced developmental neurotoxicity and developing new antidepressants.

Controversies in anesthesia-induced developmental neurotoxicity.

Advances in the field of pediatric anesthesiology have enabled the performance of complex and life-saving procedures with minimal patient discomfort. However, preclinical studies over the past two decades have been reporting substantial neurotoxic potential of general anesthetics in young brain, thus challenging the safety of these agents in pediatric anesthesiology practice. Notwithstanding the overwhelming preclinical evidence, the translatability of these findings has proven inconsistent in human observational studies. The significant degree of anxiety and apprehension surrounding the uncertainty of long-term developmental outcomes following early exposure to anesthesia has prompted numerous studies around the world to investigate the putative mechanisms and translatability of preclinical findings regarding anesthesia-induced developmental neurotoxicity. Guided by the vast preclinical evidence, we aim to highlight relevant human findings presented in the currently available clinical literature.

Clinical investigations on anesthesia-induced developmental neurotoxicity: The knowns, the unknowns and future prospects.

Pre-clinical experimental evidence, along with a plausible biological rational suggests that exposure of neonates and young children to anesthesia may harm brain development. However, the translational relevance of these observations remains unsolved. While a variety of lasting morpho-functional effects can be attributed to early life exposure to anesthetics in laboratory animals, we do not have a convincing human phenotype that reflects any causal effects of general anesthetic exposure on brain development and functional outcome. This review is aimed to provide a comprehensive description of the current state of clinical research alongside exploring future challenges in this field by focusing on the critical appraisal of methodological approaches applied in clinical research into developmental anesthesia neurotoxicity.

Novel anesthetics in pediatric practice: is it time?

Steadily mounting evidence of anesthesia-induced developmental neurotoxicity has been a challenge in pediatric anesthesiology. Considering that presently used anesthetics have, in different animal models, been shown to cause lasting behavioral impairments when administered at the peak of brain development, the nagging question, 'Is it time for the development of a new anesthetic' must be pondered. The emerging 'soft analogs' of intravenous anesthetics aim to overcome the shortcomings of currently available clinical drugs. Remimazolam, a novel ester-analog of midazolam, is a well tolerated intravenous drug with beneficial pharmacological properties. Two novel etomidate analogs currently in development are causing less adrenocortical suppression while maintaining equally favorable hemodynamic stability and rapid metabolism. Quaternary lidocaine derivatives are explored as more potent and longer lasting alternatives to currently available local anesthetics. Xenon, a noble gas with anesthetic properties, is being considered as an anesthetic-sparing adjuvant in pediatric population. Finally, alphaxalone is being reevaluated in a new drug formulation because of its favorable pharmacological properties. Although a number of exciting anesthetic drugs are under development, there is currently no clear evidence to suggest their lack of neurotoxic properties in young brain. Well designed preclinical studies are needed to evaluate their neurotoxic potential.

Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity?

Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile.

Neonatal anesthesia and dysregulation of the epigenome†.

Each year, millions of infants and children are anesthetized for medical and surgical procedures. Yet, a substantial body of preclinical evidence suggests that anesthetics are neurotoxins that cause rapid and widespread apoptotic cell death in the brains of infant rodents and nonhuman primates. These animals have persistent impairments in cognition and behavior many weeks or months after anesthesia exposure, leading us to hypothesize that anesthetics do more than simply kill brain cells. Indeed, anesthetics cause chronic neuropathology in neurons that survive the insult, which then interferes with major aspects of brain development, synaptic plasticity, and neuronal function. Understanding the phenomenon of anesthesia-induced developmental neurotoxicity is of critical public health importance because clinical studies now report that anesthesia in human infancy is associated with cognitive and behavioral deficits. In our search for mechanistic explanations for why a young and pliable brain cannot fully recover from a relatively brief period of anesthesia, we have accumulated evidence that neonatal anesthesia can dysregulate epigenetic tags that influence gene transcription such as histone acetylation and DNA methylation. In this review, we briefly summarize the phenomenon of anesthesia-induced developmental neurotoxicity. We then discuss chronic neuropathology caused by neonatal anesthesia, including disturbances in cognition, socio-affective behavior, neuronal morphology, and synaptic plasticity. Finally, we present evidence of anesthesia-induced genetic and epigenetic dysregulation within the developing brain that may be transmitted intergenerationally to anesthesia-naïve offspring.

Anesthetic Exposure in Staged Versus Single-Stage Cleft Lip and Palate Repair: Can We Reduce Risk of Anesthesia-Induced Developmental Neurotoxicity?

Cleft lip and palate (CLP) repair is typically performed in a staged fashion, which requires multiple instances of anesthetic exposure during a critical period of infant neurodevelopment. One solution to this concern includes the implementation of a single-stage CLP repair performed between 6 and 12 months of age. This study aimed to compare total anesthetic exposure between single-stage and staged CLP repairs. A retrospective review of unilateral CLP repairs between 2013 and 2018 conducted at a single institution was performed. Patients underwent either traditional, staged lip and palate repair, or single-stage complete cleft repair, where palate, lip, alveolus, and nasal repair was performed simultaneously. Primary endpoints included: total surgical time and total anesthetic exposure. Secondary endpoints included: excess anesthesia time, recovery room time, length of stay, and type of anesthetic administered. Two hundred twenty-five (n = 225) unilateral CLP repairs were conducted at the Loma Linda University. Detailed anesthetic data for eighty-six (n = 86) single-stage and twenty-eight (n = 28) staged operations were available. There was a statistically significant decrease in anesthetic exposure in single-stage versus staged repairs (316 minutes versus 345 minutes, P = 0.017), despite similar procedure times (260 minutes versus 246 minutes, P = 0.224). This resulted in near double excess anesthetic exposure time in the staged group (98 minutes versus 56 minutes, P < 0.001), primarily occurring during induction. This analysis suggests that single-stage CLP repair can reduce wasted time under general anesthesia and potentially reduce harmful neuronal toxicity in the developmental period in this at-risk population.

Sirtuin 2 Inhibition Attenuates Sevoflurane-Induced Learning and Memory Deficits in Developing Rats via Modulating Microglial Activation.

Sevoflurane is a widely used inhalational anesthetic in pediatric medicine that has been reported to have deleterious effects on the developing brain. Strategies to mitigate these detrimental effects are lacking. Sirtuin 2 (SIRT2) is a member of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases involved in a wide range of pathophysiological processes. SIRT2 inhibition has emerged as a promising treatment for an array of neurological disorders. However, the direct effects of SIRT2 on anesthesia-induced damage to the immature brain are unclear. Neonatal rats were exposed to 3% sevoflurane or 30% oxygen for 2h daily with or without SIRT2 inhibitor AK7 pretreatment from postnatal day 7 (P7) to P9. One cohort of rats were euthanized 6, 12, and/or 24h after the last gas exposure, and brain tissues were harvested for biochemical analysis and/or immunohistochemical examination. Cognitive functions were evaluated using the open field and Morris water maze tests on P25 and P28-32, respectively. SIRT2 was significantly up-regulated in neonatal rat hippocampus at 6 and 12h post-anesthesia. Pretreatment with SIRT2 inhibitor AK7 reversed sevoflurane-induced hippocampus-dependent cognitive impairments. Furthermore, AK7 administration mitigated sevoflurane-induced neuroinflammation and microglial activation. Concomitantly, AK7 inhibited pro-inflammatory/M1-related markers and increased anti-inflammatory/M2-related markers in microglia. AK7 might prevent sevoflurane-induced neuroinflammation by switching microglia from the M1 to M2 phenotype. Downregulation of SIRT2 may be a novel therapeutic target for alleviating anesthesia-induced developmental neurotoxicity.

Anesthesia-induced developmental neurotoxicity in children: past, present, and future.

Anesthesia-induced developmental neurotoxicity in children: past, present, and future.

Protective effects of TRPV1 inhibition against sevoflurane-induced cell death

Sevoflurane is a widely used inhalational anesthetic that can induce developmental neurotoxicity, leading to cognitive dysfunction. In this study, we assessed the role of transient receptor potential vanilloid 1 (TRPV1) in mediating sevoflurane activation and whether the TRPV1 antagonist could prevent anesthesia-induced cell death. Here, we demonstrated that the expression of TRPV1 was increased after sevoflurane treatment, and pretreatment with TRPV1 antagonist SB366791 could attenuate the effect of sevoflurane on TRPV1 expression. Moreover, the inhibition of TRPV1 could prevent sevoflurane-induced cell death. The findings of this study provide novel insights into the treatment of general anesthesia-induced developmental neurotoxicity and even cognitive impairment.

Erythropoietin Reduces Neurodegeneration and Long-Term Memory Deficits Following Sevoflurane Exposure in Neonatal Rats.

Exposure to general anesthetics induces neural apoptosis and degeneration in the immature neonatal brain. Erythropoietin (EPO) has been shown to protect neonatal animals against hypoxic-ischemic injury and general anesthesia-induced developmental neurotoxicity. However, preventive strategy caused by EPO against neurotoxicity due to general anesthesia is still uncertain. This study examined the effects of EPO administration on brain cytology and cognitive function in adolescent rats exposed to 3% sevoflurane as neonates. Seven-day-old rats received intraperitoneal saline (EPO 0U group) or EPO (60, 120, or 600U) 30min before exposure to 3% sevoflurane with 21% oxygen for 4h. The rats only received 21% oxygen without EPO and sevoflurane as the sham group. The Morris water maze task was performed time-dependently among the groups, 3weeks post-anesthesia exposure. Escape latency and % quadrant in the EPO 600U group were significantly reduced and increased, respectively, compared with those in the EPO 0U group 6weeks post-exposure. In addition, freezing time in response to the conditioned stimulus and the number of NeuN-positive cells in the hippocampal CA1 region were significantly increased in the EPO 120 and 600U groups than in the EPO 0U group 6weeks after exposure. Moreover, the statistical parameter mapping of positive cell density was increased in the EPO-treated rats. These results support the observations that pretreatment with EPO reduced long-term cognitive deficits and neuronal degeneration in cortex and hippocampus induced by sevoflurane exposure with low oxygen concentration in neonatal rats.

General Anesthesia and Young Brain: What is New?

Considering that growing population of very young children is exposed to general anesthesia every year, it is of utmost importance to understand how and whether such practice may affect the development and growth of their very immature and vulnerable brains. Compelling evidence from animal studies suggests that an early exposure to general anesthesia is detrimental to normal brain development leading to structural and functional impairments of neurons and glia, and long-lasting impairments in normal emotional and cognitive development. Although the evidence from animal studies is overwhelming and confirmed across species examined from rodents to non-human primates, the evidence from human studies is inconsistent and not conclusive at present. In this review we focus on new developments in animal studies of anesthesia-induced developmental neurotoxicity and summarize recent clinical studies while focusing on outcome measures and exposure variables in terms of their utility for assessing cognitive and behavioral development in children.

Developmental neurotoxicity of general anesthesia: underlying mechanisms, prevention, and treatment

Background More and more animal studies have demonstrated that general anesthesia can cause apoptosis in developing neurons. Epidemiological studies also demonstrate that long time or repetitive general anesthesia significantly increases the risk of postoperative cognitive dysfunction in young children less than 3 years old. However, the mechanisms of general anesthesia-induced developmental neurotoxicity is still unclear, meanwhile, no effective strategy for prevention and treatment has been found. Objective To explore the potential strategies for prevention and treatment by reviewing the mechanisms underlying developmental neurotoxicity of general anesthetics. Content General anesthetics modulate a variety of molecules in developing neurons and initiate or exacerbate apoptosis. First, as developing neurons contain high concentrations of Cl-, enhancement of γ-aminobutyric acid (GABA) A receptors by general anesthetics strengthens efflux of Cl- upon GABA stimulation, and subsequently leads to excitotoxicity of neurons. Second, upregulation of calcium-permeable N-methyl-D-aspanate(NMDA) receptors by ketamine may result in calcium overload. Third, general anesthetics inhibit the transformation of brain derived neurotrophic factor(BDNF) from prototype to mature one, which may induce apoptosis through p75 neurotrophin receptor(P75NTR) pathway. Fourth, some general anesthetics also cause accumulation of reactive oxygen species(ROS). Together with calcium overload, ROS induces mitochondrial malfunction. The neuronal apoptosis after general anesthesia can be followed by dysfunction of neural network and confer cognitive deficits. Accumulating studies found that targeting related ion channels, controlling calcium overload, reducing ROS production, and attenuating apoptosis can effectively protect neurons from degeneration following general anesthesia. Trend General anesthesia can cause apoptosis in developing neurons by targeting a variety of molecules, and these molecules or processes involving these molecules can be potential targets to prevent and treat general anesthesia-induced malfunctions. Key words: Neurotoxicity; Anesthesia general; Development; Apoptosis; Prevention and treatment

Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity (AIDN): A Translational Neuroscience Approach

Anesthesia cannot be avoided in many cases when surgery is required, particularly in children. Recent investigations in animals have raised concerns that anesthesia exposure may lead to neuronal apoptosis, known as anesthesia-induced developmental neurotoxicity (AIDN). Furthermore, some clinical studies in children have suggested that anesthesia exposure may lead to neurodevelopmental deficits later in life. Nonetheless, an ideal animal model for preclinical study has yet to be developed. The neonatal piglet represents a valuable model for preclinical study, as they share a striking number of developmental similarities with humans. The anatomy and physiology of piglets allow for implementation of rigorous human perioperative conditions in both survival and non-survival procedures. Femoral artery catheterization allows for close monitoring, thus enabling prompt correction of any deviation of the piglet's vital signs and chemistries. In addition, there are multiple developmental similarities between piglets and human neonates. The techniques required to use piglets for experimentation will require experience to master. A pediatric anesthesiologist is a critical member of the investigative team. We describe, in a general sense, the appropriate use of a piglet model for neurodevelopmental study.

Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity (AIDN): A Translational Neuroscience Approach.

Anesthesia cannot be avoided in many cases when surgery is required, particularly in children. Recent investigations in animals have raised concerns that anesthesia exposure may lead to neuronal apoptosis, known as anesthesia-induced developmental neurotoxicity (AIDN). Furthermore, some clinical studies in children have suggested that anesthesia exposure may lead to neurodevelopmental deficits later in life. Nonetheless, an ideal animal model for preclinical study has yet to be developed. The neonatal piglet represents a valuable model for preclinical study, as they share a striking number of developmental similarities with humans.The anatomy and physiology of piglets allow for implementation of rigorous human perioperative conditions in both survival and non-survival procedures. Femoral artery catheterization allows for close monitoring, thus enabling prompt correction of any deviation of the piglet's vital signs and chemistries. In addition, there are multiple developmental similarities between piglets and human neonates. The techniques required to use piglets for experimentation will require experience to master. A pediatric anesthesiologist is a critical member of the investigative team. We describe, in a general sense, the appropriate use of a piglet model for neurodevelopmental study.

A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies

The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia.

Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity

Thousands of infants and children undergo complicated surgical procedures that require prolonged periods of anesthesia and/or sedation each year. A growing body of preclinical research suggests pediatric anesthetics are harmful to the developing brain; yet, the extent to which these effects generalize to the clinical setting remains unclear. As there will be a continuing need for surgical and other interventions requiring sedation and/or anesthesia during the neonatal period, it seems clear that research efforts should focus on determining the extent to which general anesthetics can affect the developing brain as well as determining strategies for preventing or ameliorating the adverse effects associated with exposure to such agents. The purpose of this paper is to provide a review of the preclinical literature examining the effects of general anesthesia on brain and behavioral development. This paper will detail the effects of different anesthetic agents on various indices of neurotoxicity and functional outcomes as well as provide a review of potential protective compounds and suggestions for areas of future research.

Minimally invasive biomarkers of general anesthetic-induced developmental neurotoxicity

The association of general anesthesia with developmental neurotoxicity, while nearly impossible to study in pediatric populations, is clearly demonstrable in a variety of animal models from rodents to nonhuman primates. Nearly all general anesthetics tested have been shown to cause abnormal brain cell death in animals when administered during periods of rapid brain growth. The ability to repeatedly assess in the same subjects adverse effects induced by general anesthetics provides significant power to address the time course of important events associated with exposures. Minimally-invasive procedures provide the opportunity to bridge the preclinical/clinical gap by providing the means to more easily translate findings from the animal laboratory to the human clinic. Positron Emission Tomography or PET is a tool with great promise for realizing this goal. PET for small animals (microPET) is providing valuable data on the life cycle of general anesthetic induced neurotoxicity. PET radioligands (annexin V and DFNSH) targeting apoptotic processes have demonstrated that a single bout of general anesthesia effected during a vulnerable period of CNS development can result in prolonged apoptotic signals lasting for several weeks in the rat. A marker of cellular proliferation (FLT) has demonstrated in rodents that general anesthesia-induced inhibition of neural progenitor cell proliferation is evident when assessed a full 2weeks after exposure. Activated glia express Translocator Protein (TSPO) which can be used as a marker of presumed neuroinflammatory processes and a PET ligand for the TSPO (FEPPA) has been used to track this process in both rat and nonhuman primate models. It has been shown that single bouts of general anesthesia can result in elevated TSPO expression lasting for over a week. These examples demonstrate the utility of specific PET tracers to inform, in a minimally-invasive fashion, processes associated with general anesthesia-induced developmental neurotoxicity. The fact that PET procedures are also used clinically suggests an opportunity to confirm in humans what has been repeatedly observed in animals.

Molecular pathways of mitochondrial dysfunctions: possible cause of cell death in anesthesia-induced developmental neurotoxicity.

The effect of anesthesia on the developing brain has attracted more attention and arguments. This review summarizes various studies on developmental neurotoxicity induced by anesthesia, particularly focuses on the function of the mitochondrial dysfunction. Experimental results present evidence that general anesthesia can cause mitochondrial dysfunction via complex pathways, including oxidative stress, electron transport chain dysfunction, mitochondrial dynamics, calcium homeostasis, and mitochondrion-dependent apoptotic pathway. Hence, the molecular processes of mitochondrial dysfunction should be understood to develop novel therapeutic strategies that can prevent anesthesia-induced neurotoxicity and provide neuroprotection against developmental central nervous system.

Adverse effect of inhalational anesthetics on the developing brain

We did a PubMed search and summarized studies on the potential adverse effect of anesthetics especially neurotoxicity in the developing brain, so named anesthesia-induced developmental neurotoxicity. Even though many experimental studies using animal models indicated some adverse effect of anesthetics, more evidence is needed before a recommendation can be made to change the way those anesthetics are used in the pediatric population. Two large clinical trials are underway and may provide insight to the potential human neurotoxic effect of anesthetics.