Anesthesia-induced developmental neurotoxicity

Numerous animal models have been used to study developmental neurotoxicity associated with short-term or prolonged exposure of common general anesthetics at clinically relevant concentrations. Pediatric anesthesia models using the nonhuman primate (NHP) may more accurately reflect the human condition because of their phylogenetic similarity to humans with regard to reproduction, development, neuroanatomy, and cognition. Although they are not as widely used as other animal models, the contribution of NHP models in the study of anesthetic-induced developmental neurotoxicity has been essential...

Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits...

The effects of general anesthetics on the developing brain have aroused much attention in recent years. Sevoflurane, a commonly used inhalation anesthetic especially in pediatric anesthesia, can induce developmental neurotoxicity. In this study, the differentially expressed mRNAs in the hippocampus of newborn rats exposed to 3% sevoflurane for 6 h were detected by RNA-Sequencing. Those data indicated that the mRNA of Klotho was increased after exposure to sevoflurane. Moreover, the protein expression of Klotho was assayed by Western Blot...

Background: Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and children's parents. Dexmedetomidine (DEX) is widely used in sedation as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure...

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...

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...

OBJECTIVE: This study aimed to investigate whether long noncoding RNA sprouty receptor tyrosine kinase signaling antagonist 4-intronic transcript 1 (SPRY4-IT1) is involved in the regulation of ketamine-induced neurotoxicity. METHODS: Human embryonic stem cells (hESCs) were induced into neurons in vitro and treated with ketamine. Apoptosis and neurite degeneration assays were used to determine ketamine-induced neurotoxicity and qRT-PCR to determine SPRY4-IT1 expression...

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...

PURPOSE: For over 150 years of anesthetic practice, it was believed that the effects of general anesthetics were temporary and not adverse. A growing number of studies over the past 2 decades, however, have identified structural and cognitive abnormalities, especially in the developing brain. Despite the growing evidence of anesthetic-induced neurotoxicity in animal studies, the evidence to date in humans has been inconsistent and unclear. Sevoflurane, a commonly used inhalational agent in pediatric anesthesia, is an agent of choice for inhalational induction due to its rapid activity and low blood-gas solubility...

In this study, LRCF, a long noncoding RNA (lncRNA) related to cognitive function, which was first discovered and named by our group, was shown to be involved in the propofol-induced proliferation and apoptosis of oligodendrocytes (OLGs). Our systematic study showed that LRCF expression differs in OLGs of mice of different ages. We found that neonatal mice with a high level of LRCF typically showed greater propofol-induced injury of OLGs. Mechanistic research has shown that LRCF can block the HIF-1α/miR138-5p/Caspase-3 pathway by binding to miR138-5p to form a microRNA (miRNA) sponge and result in cell damage through HIF-1α/Caspase-3 pathway in propofol induced OLGs...

Sevoflurane, the most commonly used inhaled anesthetic in pediatric anesthesia, has been reported to induce cognitive impairment in developing brain in preclinical and clinical settings. However, the mechanism and therapeutic measures of this developmental neurotoxicity need to be further investigated. Resveratrol, a natural polyphenolic agent, has been reported to improve cognitive function in neurological disorders and aging models through anti-inflammatory activity. However, its effect on sevoflurane-induced cognitive impairment in developing mice remains unknown...

Preclinical investigations in animal models have consistently demonstrated neurobiological changes and life-long cognitive deficits following exposure to widely used anesthetics early in life. However, the mechanisms by which these exposures affect brain function remain poorly understood, therefore, limiting the efficacy of current diagnostic and therapeutic options in human studies. The human brain exhibits an abundant expression of long noncoding RNAs (lncRNAs). These biologically active transcripts play critical roles in a diverse array of functions, including epigenetic regulation...

For decades, the neurotoxicity caused by anesthetics in mammalian brain development has gained increasing attention. Exposure to anesthetics leads to neurotoxicity and apoptosis of nerve cells, which in turn induces cognitive dysfunction. Although most of the data came from animal studies, general anesthetics have been shown to have adverse effects on cognitive function in infants and young children in recent years. This concern has led to a number of retrospective studies that observed an association between general anesthesia in pregnant women and neurobehavioral problems in fetuses or offspring...

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...

Exposure to general anesthesia has been reported to induce neurotoxicity, impair learning, memory, attention, motor functions, as well as affect behavior in adult rodents and nonhuman primates. Though many have speculated similar effects in humans, previous literature has shown conflicting findings. To investigate the differences in risk of developmental delay among young children exposed to general anesthesia compared to matched unexposed individuals, a population-based cohort study was conducted with a longitudinal dataset spanning 2000 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD)...

Mounting evidence has shown that general anesthetic agents commonly used clinically can cause anesthetic-related neurotoxicity in the developing brains of mammals, potentially causing long-term neurological impairment. This results in growing interest and concern among the public. Here, we present an overview of the relevant findings from non-human primates, arguably the very best model for studies of developmental neurotoxicity. These studies have shown that varying degrees of neurodegeneration occur as a result of anesthesia type, duration/dose of exposure, the timing of exposure, and brain region of interest, combined with subsequent alterations in cognitive assessments...

General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates...

Xenon is a rare noble gas that was introduced into clinical practice more than 70 years ago. Xenon's clinical properties are predicated by its ability to fit into preformed cavities of macromolecules thereby altering their biological functions. One such action targets the NMDA-subtype of the glutamate receptors thereby inhibiting its excitatory action. As the glutamate receptors are pivotal for both anesthesia and acute neurological injury, its clinical use has included both general anesthesia as well as neuroprotection...

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...

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