Anesthetic Neurotoxicity Research Articles

Inhibition of FOXO3 ameliorates ropivacaine-induced nerve cell damage through the miR-126-5p/TRAF6 axis.

Local anesthetics, such as ropivacaine (Ropi), are toxic to nerve cells. We aimed to explore the role of forkhead box O3 (FOXO3) in Ropi-induced nerve injury to provide a theoretical basis for reducing the anesthetic neurotoxicity. SK-N-SH cells were cultured and treated with different concentrations of Ropi. Cell viability, apoptosis, cytotoxicity (LDH/ROS/SOD), and levels of FOXO3, miR-126-5p, and tumor necrosis factor receptor-associated factor 6 (TRAF6) were detected. The enrichment of FOXO3 on the miR-126-5p promoter was analyzed. The binding relationships among FOXO3, miR-126-5p promoter sequence, and TRAF6 3'UTR sequence were verified. Combined experiments detected the regulatory role of FOXO3/miR-126-5p/TRAF6 in Ropi-induced nerve injury. FOXO3 was upregulated in Ropi-induced nerve cell damage. Inhibition of FOXO3 ameliorated Ropi-induced decreased cell viability, and increased apoptosis and cytotoxicity. FOXO3 bound to the miR-126-5p promoter and inhibited its expression, thereby counteracting miR-126-5p-induced repression. miR-126-5p inhibition and TRAF6 overexpression partially reversed the alleviative effect of FOXO3 inhibition on Ropi-induced nerve cell damage. In conclusion, FOXO3 aggravated the neurotoxicity of Ropi through miR-126-5p downregulation and TRAF6 upregulation, suggesting that FOXO3 inhibitor could be an adjuvant agent for local anesthetics, to alleviate local anesthetics-induced neurotoxicity.

Developmental Anesthesia Neurotoxicity: Lessons From the Heart

Developmental Anesthesia Neurotoxicity: Lessons From the Heart

Anesthetic neurotoxicity in the developing brain: an update on theinsights and implications for fetal surgery.

This review describes an in-depth analysis of the neurotoxicity associated with the anesthetic agents used during fetal surgery, intending to highlight the importance of understanding the effects of general anesthetics on the developing brain, particularly in the context of open fetal surgery, where high doses are applied to facilitate surgical access and augment uterine relaxation. We examined evidence from preclinical studies in rodents and primates, along with studies in human subjects, with the results collectively suggesting that general anesthetics can disrupt brain development and lead to long-lasting neurological deficits. Our review underscores the clinical implications of these findings, indicating an association between extensive anesthetic exposure in early life and subsequent cognitive deficits. The current standard of anesthetic care for fetal surgical procedures was scrutinized, and recommendations have been proposed to mitigate the risk of anesthetic neurotoxicity. These recommendations emphasize the need for careful selection of anesthetic techniques to minimize fetal exposure to potentially harmful agents. In conclusion, while the benefits of fetal surgery in addressing immediate risks often outweigh the potential neurotoxic effects of anesthesia, the long-term developmental impacts nevertheless warrant consideration. Our analysis suggests that the use of general anesthetics in fetal surgery, especially at high doses, poses a significant risk of developmental neurotoxicity. As such, it is imperative to explore safer alternatives, such as employing different methods of uterine relaxation and minimizing the use of general anesthetics, to achieve the necessary surgical conditions. Further research, particularly in clinical settings, is essential to fully understand the risks and benefits of anesthetic techniques in fetal surgery.

Exposure to Operative Anesthesia in Childhood and Subsequent Neurobehavioral Diagnoses: A Natural Experiment Using Appendectomy.

Observational studies of anesthetic neurotoxicity may be biased because children requiring anesthesia commonly have medical conditions associated with neurobehavioral problems. This study takes advantage of a natural experiment associated with appendicitis to determine whether anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes. This study identified 134,388 healthy children with appendectomy and examined the incidence of subsequent externalizing or behavioral disorders (conduct, impulse control, oppositional defiant, attention-deficit hyperactivity disorder) or internalizing or mood or anxiety disorders (depression, anxiety, or bipolar disorder) when compared to 671,940 matched healthy controls as identified in Medicaid data between 2001 and 2018. For comparison, this study also examined 154,887 otherwise healthy children admitted to the hospital for pneumonia, cellulitis, and gastroenteritis, of which only 8% received anesthesia, and compared them to 774,435 matched healthy controls. In addition, this study examined the difference-in-differences between matched appendectomy patients and their controls and matched medical admission patients and their controls. Compared to controls, children with appendectomy were more likely to have subsequent behavioral disorders (hazard ratio, 1.04; 95% CI, 1.01 to 1.06; P = 0.0010) and mood or anxiety disorders (hazard ratio, 1.15; 95% CI, 1.13 to 1.17; P < 0.0001). Relative to controls, children with medical admissions were also more likely to have subsequent behavioral (hazard ratio, 1.20; 95% CI, 1.18 to 1.22; P < 0.0001) and mood or anxiety (hazard ratio, 1.25; 95% CI, 1.23 to 1.27; P < 0.0001) disorders. Comparing the difference between matched appendectomy patients and their matched controls to the difference between matched medical patients and their matched controls, medical patients had more subsequent neurobehavioral problems than appendectomy patients. Although there is an association between neurobehavioral diagnoses and appendectomy, this association is not specific to anesthesia exposure and is stronger in medical admissions. Medical admissions, generally without anesthesia exposure, displayed significantly higher rates of these disorders than appendectomy-exposed patients.

Global Trends and Hotspots in Pediatric Anesthetic Neurotoxicity Research: A Bibliometric Analysis From 2000 to 2023.

The impact of general anesthetics on brain function development is one of the top frontier issues of public concern. However, little bibliometric analysis has investigated this territory systematically. Our study aimed to visualize the publications between 2000 and 2023 to inspire the trends and hotspots in anesthetic neurodevelopmental toxicity research. Publications from 2000 to 2023 were collected from the Web of Science Core Collection. CiteSpace was utilized to plot and analyze the network maps of countries, institutions, authors, journals, and keywords associated with these publications. A total of 864 publications, consisting of 786 original articles and 78 reviews, were extracted from 2000 to 2023. The annual publications have increased constantly over the past two decades. The USA and the People's Republic of China were the leading driving forces in this field. Harvard University was the most productive institution. Zhang Y published the most related articles, and Jevtovic-Todorovic V was mostly cited in this field. The most prolific journal was Pediatric Anesthesia, and the most frequently co-cited journal was Anesthesiology. Keywords were divided into nine clusters: "apoptosis", "propofol", "developing brain", "cognitive dysfunction", "neuronal cell degeneration", "brain", "neuroinflammation", "local anesthesia", and "oxygen therapy". The strongest citation bursts in earlier years were "learning disability", "cell death", and "cognitive function". The emerging trends in the coming years were "awake regional anesthesia", "behavioral outcome", and "infancy general anesthesia compared to spinal anesthesia". We concludethat anesthetic-induced neurotoxicity has received growing attention in the past two decades. Our findings evaluated the present status and research trends in this area, which may provide help for exploring further potential prospects on hot topics and frontiers.

A Scoping Review of the Mechanisms Underlying Developmental Anesthetic Neurotoxicity.

Although anesthesia makes painful or uncomfortable diagnostic and interventional health care procedures tolerable, it may also disrupt key cellular processes in neurons and glia, harm the developing brain, and thereby impair cognition and behavior in children. Many years of studies using in vitro, animal behavioral, retrospective database studies in humans, and several prospective clinical trials in humans have been invaluable in discerning the potential toxicity of anesthetics. The objective of this scoping review was to synthetize the evidence from preclinical studies for various mechanisms of toxicity across diverse experimental designs and relate their findings to those of recent clinical trials in real-world settings.

The Effects of General Anesthetics on the Developing Brain of Fetus

The Effects of General Anesthetics on the Developing Brain of Fetus

Effects of general anesthetics on the cognitive function of pediatric patients: A review

The consequences induced by the use of general anesthetics and better options of the drugs in children and infants have been topics of controversy due to the concerns about their potential impact on cognitive function. To address these concerns and ensure the safety of pediatric general anesthesia, this paper reviews existing basic and clinical studies that have investigated the mechanisms of general anesthetics on pediatric cognitive function. In this paper, the basic research on neurotoxicity of general anesthetics and the clinical research on the effects of general anesthesia drugs on cognitive function in children in recent years were analyzed and summarized. Although some of the clinical studies have suggested that general anesthesia in children or infants may cause neurocognitive damage and a series of behavioral complications, the results of the retrospective studies need to be viewed with caution as they may lack effective control for relevant factors that could have impacts in the perioperative period. It remains uncertain whether general anesthetics affect the cognitive function of pediatric patients. Further research is needed to establish clear evidence-based recommendations for clinical prevention and treatment measures to minimize the potential risks associated with the use of general anesthetics.

The protective role of circ_0016760 downregulation against sevoflurane‑induced neurological impairment via modulating miR‑145 expression in aged rats.

Sevoflurane can produce toxicity to the hippocampal tissues of brain, leading to nerve damage, causing learning and cognitive dysfunction. CircRNAs have been indicated to act as a key mediator in anesthetic neurotoxicity. This study focused on the effect of circ_0016760 on sevoflurane‑induced neurological impairment. The GEO database (GSE147277) and RT‑qPCR were used to predict and measure the circ_0016760 expression. The interaction of circ_0016760 and miR‑145 was verified by dual‑luciferase reporter assay. The CCK‑8 assay, flow cytometry, ELISA, ROS kit, MWM test were carried out to measure the cell viability, apoptosis, inflammation indicators, ROS level, and cognitive and memory function of the rats. Sevoflurane exacerbated neurotoxicity by restraining cell viability, inducing cell apoptosis, neuroinflammation, and ROS generation, and causing learning and cognitive dysfunction. Circ_0016760 expression was increased in POCD patients from the GEO database and upregulated after sevoflurane exposure. miR‑145 was a target miRNA of circ_0016760. Silencing of circ_0016760 weakened the effect of sevoflurane on cell viability, cell apoptosis, inflammation‑related factors, oxidative stress, which could be reversed by miR‑145 inhibitor. The animal experiments results showed that circ_0016760 played a protective effect on regulating the cognitive behavior of sevoflurane‑treated aged rats, expression of inflammation cytokine, and oxidative stress factors through targeting miR‑145 in sevoflurane‑treated aged rat's hippocampal neurons. Our results revealed that silencing of circ_0016760 attenuated sevoflurane‑induced hippocampal neuron injury by regulating miR‑145 expression, which may provide potential insights into the treatment of sevoflurane‑induced neurological impairment.

Association between perioperative neuraxial local anesthetic neurotoxicity and arachnoiditis: a narrative review of published reports.

Arachnoiditis is a rare but devastating disorder caused by various insults, one of which is purported to be local anesthetic neurotoxicity following neuraxial blockade. However, the relationship between local anesthetics administered into the neuraxis and the development of arachnoiditis has not been clearly elucidated. We aimed to summarize the existing complex body of literature and characterize both the essential features and strength of any association between neuraxial local anesthetic neurotoxicity and arachnoiditis with a view toward mitigating risk, enhancing prevention, and refining informed consent discussions. We reviewed all published reports of arachnoiditis attributed to local anesthetic neurotoxicity following perioperative neuraxial anesthesia. This narrative review was based on a systematic search methodology, which included articles published up until December 2022. Thirty-eight articles were included, comprising 130 patients, over one-half of which were published prior to this century and inconsistent with modern practice. Neuraxial techniques included 78 epidurals, 48 spinals, and 5 combined spinal-epidurals, mostly for obstetrics. Reporting of essential procedural data was generally incomplete. Overall, at least 57% of patients experienced complicated needle/catheter insertion, including paresthesia, pain, or multiple attempts, irrespective of technique. The onset of neurological symptoms ranged from immediate to 8 years after neuraxial blockade, while the pathophysiology of arachnoiditis, if described, was heterogeneous. The existing literature attributing arachnoiditis to local anesthetic neurotoxicity is largely outdated, incomplete, and/or confounded by other potential causes, and thus insufficient to characterize the features and strength of any association.

Effect of Anesthesia During Pregnancy, Delivery, and Childhood on Autism Spectrum Disorder: A Systematic Review and Meta-analysis.

To investigate the association between exposure to anesthesia during three periods of pregnancy, delivery, and childhood and autism spectrum disorder (ASD). PubMed, Scopus, Web of Science, Embase, Google Scholar, PsycArticles, and PsycINFO were searched from the date of database inception to 1 December 2022. Studies reported the association between exposure to anesthesia during pregnancy, delivery, and childhood and ASD were included. Extracted variables included hazard ratio (HR), relative risk or odds ratio, standard error, and 95% confidence interval (CI). Effect estimates were pooled using random-effects meta-analysis. In total, 16 studies including 8,156,608 individuals were included in the meta-analysis. Labor epidural anesthesia during delivery was associated with ASD in the general population (adjusted HR = 1.16, 95% CI, 1.06-1.28) but not in the sibling population (adjusted HR = 1.06, 95% CI, 0.98-1.15). Other anesthesia during delivery was not associated with ASD (general population: adjusted HR = 1.08, 95% CI, 0.99-1.17; sibling population: adjusted HR = 1.20, 95% CI, 0.81-1.79). Three studies suggested that exposure to anesthesia during pregnancy was associated with ASD in offspring (adjusted HR = 2.15, 95% CI, 1.32-3.48). There was no significant association between exposure to general anesthesia during childhood and ASD (adjusted HR = 1.02, 95% CI, 0.60-1.72). This meta-analysis did not confirm the association between exposure to anesthesia during labour and ASD. Previous observational studies used the neurotoxicity of anesthesia to biologically explain significant associations, but in fact different controls for confounding factors led to differences in associations. The evidence for pregnancy and childhood was limited given the small number of studies in these periods.

A Spatial Memory Deficit in Male But Not Female Rats After Neonatal Diazepam Exposure: A New Model for Developmental Sedative Neurotoxicity.

Developmental anesthetic neurotoxicity is well described in animal models for GABAergic, sedating drugs. Here we investigate the role of the benzodiazepine, diazepam on spatial and recognition memory of young adult rats after neonatal exposure. On postnatal day 7, male (n = 30) and female (n = 30) rats were exposed to diazepam (30 mg/kg intraperitoneally) or vehicle. On postnatal day 42, animals started a series of behavioral tests including Barnes maze (spatial memory), object recognition battery (recognition memory), and open field and elevated plus maze (anxiety). In a separate cohort, blood gases were obtained from diazepam-exposed animals and compared to isoflurane-exposed animals (1 MAC for 4 hours). Male animals exposed to diazepam had impaired performance in the Barnes maze and were unable to differentiate the goal quadrant from chance (1-sample t test; tdiazepam/male (14) = 1.49, P = .158). Female rats exposed to diazepam performed the same as the vehicle controls ( tdiazepam/female (12) = 3.4, P = .005, tvehicle/female (14) = 3.62, P = .003, tvehicle/male (13) = 4.76, P < .001). There were no statistical differences in either males or females in measures of recognition memory, anxiety, or locomotor activity in other behavioral tests. Physiologic measurements of arterial blood gases taken from animals under sedation with diazepam were much less aberrant than those exposed to the volatile anesthetic isoflurane by t test (pH diazepam [M = 7.56, standard deviation {SD} = 0.11] versus pH Isoflurane [M = 7.15, SD = 0.02], t (10) = 8.93, P < .001; Paco 2diazepam [M = 32.8 mm Hg, SD = 10.1] versus Paco 2Isoflurane [M = 91.8 mm Hg, SD = 5.8], t (10) = 8.93, P < .001). The spatial memory results are consistent with volatile anesthetic suggesting a model in which development of the GABA system plays a critical role in determining susceptibility to behavioral deficits.

Sevoflurane upregulates neuron death process-related Ddit4 expression by NMDAR in the hippocampus.

Postoperative cognitive dysfunction (POCD) is a serious and common complication induced by anesthesia and surgery. Neuronal apoptosis induced by general anesthetic neurotoxicity is a high-risk factor. However, a comprehensive analysis of general anesthesia-regulated gene expression patterns and further research on molecular mechanisms are lacking. Here, we performed bioinformatics analysis of gene expression in the hippocampus of aged rats that received sevoflurane anesthesia in GSE139220 from the GEO database, found a total of 226 differentially expressed genes (DEGs) and investigated hub genes according to the number of biological processes in which the genes were enriched and performed screening by 12 algorithms with cytoHubba in Cytoscape. Among the screened hub genes, Agt, Cdkn1a, Ddit4, and Rhob are related to the neuronal death process. We further confirmed that these genes, especially Ddit4, were upregulated in the hippocampus of aged mice that received sevoflurane anesthesia. NMDAR, the core target receptor of sevoflurane, rather than GABAAR, mediates the sevoflurane regulation of DDIT4 expression. Our study screened sevoflurane-regulated DEGs and focused on the neuronal death process to reveal DDIT4 as a potential target mediated by NMDAR, which may provide a new target for the treatment of sevoflurane neurotoxicity.

A bibliometric analysis of the neurotoxicity of anesthesia in the developing brain from 2002 to 2021.

The neurotoxicity effects of anesthetic exposure on the developing brain have been one of the current research hotspots and numerous articles were published in the past decades. However, the quality and comparative information of these articles have not been reported. This research aimed to provide a comprehensive overview of the current state of the field by investigating research hotspots and publication trends concerning the neurotoxicity of anesthesia in the developing brain. On 15 June 2022, we searched articles on the neurotoxicity of anesthesia in the developing brain through the Science Citation Index databases from 2002 to 2021. Data of the author, title, publication, funding agency, date of publication, abstract, type of literature, country, journal, keywords, number of citations, and research direction were collected for further analysis. We searched and analyzed 414 articles in English on the field of neurotoxicity of anesthesia in the developing brain from 2002 to 2021. The country with the largest number of publications was The United States (US) (n = 226), which also had the largest total number of citations (10,419). Research in this field reached a small peak in 2017. Furthermore, the largest number of articles were published in three journals, Anesthesiology, Anesthesia and Analgesia, and Pediatric Anesthesia. The top 20 articles that were cited most often were studied. In addition, the top hotspots of this area in clinical investigations and basic research were analyzed separately. This study provided an overview of the development in the neurotoxicity of anesthesia in the developing brain using bibliometric analysis. Current clinical studies in this area were mainly retrospective; in the future, we should place more emphasis on prospective, multicenter, long-term monitoring clinical studies. More basic research was also needed on the mechanisms of neurotoxicity of anesthesia in the developing brain.

Single-cell Genomics: A Quantum Leap toward Understanding Complexity?

Single-cell Genomics: A Quantum Leap toward Understanding Complexity?

Dexmedetomidine-mediated neuroprotection against sevoflurane-induced brain development abnormality in fetal mice brain.

Brain development is susceptible to external influences during the gestation period so the neurotoxicity of anesthetics has gained a lot of attention. We aimed to investigate the neurotoxicity of sevoflurane to fetal mice brain as well as the neuroprotective effects of dexmedetomidine. Pregnant mice were treated with 2.5% sevoflurane for 6 hours. The changes in fetal brain development were assayed with immunofluorescence and western blot. The pregnant mice were intraperitoneally injected with dexmedetomidine or vehicle from gestation day (G) 12.5 to G15.5. Our results showed maternal sevoflurane exposure could not only inhibit neurogenesis but also lead to precocious generation of astrocytes in fetal mice brains. The fetal mice brain of sevoflurane group exhibited a significant inhibition in the activity of Wnt signaling and the expression of CyclinD1, Ngn2. Chronic dexmedetomidine administration could minimize the negative effects caused by sevoflurane by activating the Wnt signaling pathway. This study has uncovered a Wnt signaling-related mechanism of the neurotoxicity of sevoflurane and confirmed the neuroprotective effect of dexmedetomidine, which could provide pre-clinical evidence for clinical decision-making.

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice.

General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator (Crem), cAMP responsive element-binding protein 1 (Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin (Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.

Angelicin Alleviates Maternal Isoflurane Exposure-Induced Offspring Cognitive Defects Through the Carbonic Anhydrase 4/Aquaporin-4 Pathway.

An increasing number of studies reveal the deleterious effects of isoflurane (Iso) exposure during pregnancy on offspring cognition. However, no effective therapeutic strategy for Iso-induced deleterious effects has been well developed. Angelicin exerts an anti-inflammatory effect on neurons and glial cells. This study investigated the roles and mechanism of action of angelicin in Iso-induced neurotoxicity in vitro and in vivo. After exposing C57BL/6J mice on embryonic day 15 (E15) to Iso for 3 and 6h, respectively, neonatal mice on embryonic day 18 (E18) displayed obvious anesthetic neurotoxicity, which was revealed by the elevation of cerebral inflammatory factors and blood-brain barrier (BBB) permeability and cognitive dysfunction in mice. Angelicin treatment could not only significantly reduce the Iso-induced embryonic inflammation and BBB disruption but also improve the cognitive dysfunction of offspring mice. Iso exposure resulted in an increase of carbonic anhydrase (CA) 4 and aquaporin-4 (AQP4) expression at both mRNA and protein levels in vascular endothelial cells and mouse brain tissue collected from neonatal mice on E18. Remarkably, the Iso-induced upregulation of CA4 and AQP4 expression could be partially reversed by angelicin treatment. Moreover, GSK1016790A, an AQP4 agonist, was used to confirm the role of AQP4 in the protective effect of angelicin. Results showed that GSK1016790A abolished the therapeutic effect of angelicin on Iso-induced inflammation and BBB disruption in the embryonic brain and on the cognitive function of offspring mice. In conclusion, angelicin may serve as a potential therapeutic for Iso-induced neurotoxicity in neonatal mice by regulating the CA4/AQP4 pathway.

Foot drop on the opposite side after spinal anesthesia for ankle fracture surgery: a case report

Neurological complications after spinal anesthesia have been rarely reported. Persistent neurological dysfunction due to spinal cord or nerve root injury is a serious complication of lumbar anesthesia and manifests as leg pain, numbness, and weakness after initial recovery from anesthesia. We herein report a case of foot drop on the opposite side after spinal anesthesia for ankle fracture surgery. The patient’s symptoms completely disappeared after 3 months, and we consider that her neurological complications were likely caused by the neurotoxicity of local anesthetics.

Cytotoxicity of Local Anesthetics on Bone, Joint, and Muscle Tissues: A Narrative Review of the Current Literature.

Local anesthetics are commonly used in surgical procedures to control pain in patients. Whilst the cardiotoxicity and neurotoxicity of local anesthetics have received much attention, the cytotoxicity they exert against bone, joint, and muscle tissues has yet to be well recognized. This review aimed to raise awareness regarding how local anesthetics may cause tissue damage and provide a deeper understanding of the mechanisms of local anesthetic-induced cytotoxicity. We summarized the latest progress on the cytotoxicity of local anesthetics and the underlying mechanisms and discussed potential strategies to reduce it. We found that the toxic effects of local anesthetics on bone, joint, and muscle tissues were time- and concentration-dependent in vitro. Local anesthetics induced apoptosis, necrosis, and autophagy through specific cellular pathways. Altogether, this review indicates that toxicity of local anesthetics may be avoided by rationally selecting the appropriate anesthetic, limiting the total amount, and determining the lowest effective concentration and duration.