Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity : Anesthesia & Analgesia

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Review Articles: Systematic Review Article

Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity

Pant, Tarun PhD*; DiStefano, Johanna K. PhD†; Logan, Sara PhD‡; Bosnjak, Zeljko J. PhD*,§

Author Information

From the *Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin

†Department of Diabetes and Fibrotic Disease Unit, Translational Genomic Research Institute, Phoenix, Arizona

Departments of ‡Pediatrics

§Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Published ahead of print 16 December 2020.

Accepted for publication November 2, 2020.

Funding: This study was supported, in part, by a National Institutes of Health research grant P01GM 066730 (to Z.J.B.) from the United States Public Health Services, Bethesda, MD. The funding body had no role in the design of the study, collection, analysis, and interpretation of data, and writing of the manuscript.

The authors declare no conflicts of interest.

T. Pant and J. K. DiStefano contributed equally to this study.

Reprints will not be available from the authors.

Address correspondence to Tarun Pant, PhD, Department of Medicine, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Rd, Milwaukee, WI 53226. Address e-mail to [email protected].

Anesthesia & Analgesia 132(6):p 1614-1625, June 2021. | DOI: 10.1213/ANE.0000000000005317
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Abstract

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. Changes in lncRNA expression have been linked with brain development, normal CNS processes, brain injuries, and the development of neurodegenerative diseases, and many lncRNAs are known to have brain-specific expression. Aberrant lncRNA expression has also been implicated in areas of growing importance in anesthesia-related research, including anesthetic-induced developmental neurotoxicity (AIDN), a condition defined by neurological changes occurring in patients repeatedly exposed to anesthesia, and the related condition of perioperative neurocognitive disorder (PND). In this review, we detail recent advances in PND and AIDN research and summarize the evidence supporting roles for lncRNAs in the brain under both normal and pathologic conditions. We also discuss lncRNAs that have been linked with PND and AIDN, and conclude with a discussion of the clinical potential for lncRNAs to serve as diagnostic and therapeutic targets for the prevention of these neurocognitive disorders and the challenges facing the identification and characterization of associated lncRNAs.

Anesthetic neurotoxicity refers to anesthetic-induced structural or functional alteration of the nervous system.1 It is estimated that in the United States alone, approximately 6 million pediatric patients (including 1.5 million infants) are administered anesthesia annually.2 Various studies using developmental animal models have demonstrated that anesthetics and sedatives cause neuroapoptosis and other neurodegenerative changes in the developing brain.3,4 Moreover, numerous retrospective studies in the pediatric population further substantiate that recurrent or lengthy exposure to anesthetics induces neurotoxicity in the developing brain, a condition referred to as anesthetic-induced developmental neurotoxicity (AIDN).5–8

In addition to the pediatric population, clinical studies from animal models and patients in the past few years report an increase in the incidence of central nervous system dysfunction, specifically cognitive decline, acute delirium, and longer-lasting postoperative cognitive dysfunction (POCD), which in general are referred to as perioperative neurocognitive disorders (PND).9,10 PND represent a life-threatening concern for some elderly patients undergoing surgical procedures.11,12 The combination of increasing incidence, lack of preventive and therapeutic strategies, a limited understanding of the molecular mechanisms underlying the aberrant response to anesthesia, and the overall financial burden of caring for affected individuals present challenges for improving the prognosis of patients with PND and AIDN. Identification and characterization of the molecular mechanisms underlying PND and AIDN disease pathogenesis may help to address this unmet clinical need by providing potential targets for drug development to prevent or treat these conditions.

Long noncoding RNA (lncRNAs) are biologically active transcripts having a minimum length of 200 nucleotides with significantly interrupted open reading frames, making them incompetent for protein translation.13–15 Although lncRNAs are not translated, they are nonetheless actively associated with the regulation of gene expression, establishing them as critical players of molecular, cellular, and biological events.13,16–18 There is ample evidence validating the role of lncRNAs in the proliferation, development, and aging of neurons.19–22 Moreover, emerging studies indicate that lncRNAs are dysregulated in rodents that developed postanesthesia neurotoxicity, and alterations in the expression of certain lncRNAs are associated with significant protection of brain cells, suggesting that these transcripts may confer neuroprotective properties.23,24 Detailed information regarding the functional role of lncRNAs in the pathophysiology of anesthetic neurotoxicity is, however, limited. The purpose of this review is to provide a general overview of lncRNAs in the brain under both normal and pathological conditions. We also summarize the role of lncRNAs in areas of growing importance in anesthesia-related research, including PND, and AIDN. Finally, we discuss possible strategies for the use of lncRNAs as diagnostic and therapeutic targets for PND and AIDN, and offer a perspective on specific challenges.

Overview of LncRNAs

LncRNAs represent a heterogeneous class of noncoding RNAs that display a wide range of biological functions.25 LncRNAs are commonly classified according to their orientation to nearby protein-coding genes26–29: intergenic lncRNAs are transcripts located >1 kb from protein-coding genes; bidirectional lncRNAs refer to transcripts located in regions within 1 kb of promoters of protein-coding genes, but transcribed in the opposing direction; intronic lncRNAs are located in introns of protein-coding genes27,28; sense lncRNAs are transcribed from the same strand of a protein-coding gene and often overlap with one or more exons of that transcript; and antisense lncRNAs, which are similar to sense lncRNAs, but are transcribed from the opposite strand of a protein-coding gene.

LncRNAs are known to interact with DNA, RNA, and proteins,28,30–32 and have been shown to have a diverse array of functions that include directing chromatin-modifying complexes to specific genomic loci, providing molecular scaffolds, modulating transcriptional programs, regulating gene expression,28 and interacting with microRNAs (miRNAs) to regulate miRNA expression and activity.33 For example, BACE1_AS has been found to form dimers within the miRNA (miR-485-5p) binding site present on the mRNAs (BACE1), thereby regulating their transcriptional pattern.34 In addition, nuclear-enriched lncRNAs like NEAT 1_2 are found to serve as molecular scaffolds for numerous protein components and RNA granules upregulating molecular processes (paraspeckle formation), which is often seen in pathophysiological conditions like neurodegeneration.35,36 Certain lncRNA-like Meg3 serve as competitive endogenous RNAs (ceRNAs), competing for the micro-RNA (miR-21) binding site that regulates neurological functions.37 Other lncRNAs like Gomafu interact with the splicing factors regulating the alternative splicing of several RNA species, including mRNA that plays a critical role in psychotic and behavioral abnormalities.38,39

LncRNAs in the Brain

Microarray analysis of lncRNAs across different cells and tissues of the human body revealed that brain-specific clusters account for approximately 40% of differentially expressed lncRNAs.26 While lncRNAs are known to exhibit relatively low primary sequence conservation compared to protein-coding genes,40 those expressed specifically in the brain show greater sequence conservation than lncRNAs expressed elsewhere.41,42 Brain development is a complicated process comprised of distinct developmental stages, each requiring spatiotemporal patterns of gene expression that govern the proliferation, growth, and development of the brain.26,43–45 and are tightly regulated by genetic and epigenetic modifications within the genome.43,46,47 Expression patterns of orthologous brain-enriched lncRNAs appear to be conserved across diverse species,41 suggesting an important role for lncRNAs in brain development in mammalian evolution. Numerous studies have indicated that the developmental stage-specific expression of lncRNAs, such as BDNF-AS, Tuna, RMST, MALAT1, ES1, ES2, Evf1, and Evf2, in the brain corresponds with the regulation of an enormous array of cellular and molecular events.21,22,48–52 LncRNAs have been postulated to play a critical role in the developing nervous system and may even contribute to the evolution of increased brain complexity.53 Further, lncRNAs show strong region-specific expression patterns in the brain,54,55 suggesting that specific transcripts have functional relevance in discrete areas. These observations are consistent with studies delineating novel intersections between lncRNA expression or activity and biological processes related to learning and memory56 and synaptic plasticity.57 Conversely, changes in lncRNA expression have been implicated in neuronal aging, although whether these associations are causative remains to be determined.58

LncRNAs have been associated with a number of brain pathologies, including, but not limited to schizophrenia,59,60 autism spectrum disorder,61 glioblastoma,62 epilepsy,63 Alzheimer’s disease,57,64 and Parkinson’s disease.65 Notably, lncRNA expression in the brain changes in response to acute central nervous system (CNS) injuries, including traumatic brain injury66 and cerebral ischemic stroke.67 Most of these lncRNAs, including MALAT1, BDNF-AS, MEG3, NEAT1, TUG1, and GAS5, show increased expression under injurious conditions, and correspondingly, confer protective effects via modulation of proangiogenic and antiapoptotic or anti-inflammatory pathways.68 These findings suggest that lncRNAs mediate, at least in part, the relationship between acute injury and CNS response, and, as such, may serve as important mediators of external factors on overall brain function.

Similarly, lncRNA expression in the brain is affected by environmental exposures, including the recreational use of alcohol, work-related exposure to industrial chemicals, and pharmacological agents. An early study by Kryger et al69 reported significant upregulation of MALAT1 expression in the cerebellum, hippocampus, and brainstem, but not the frontal or motor cortex, of alcoholics. In contrast, MALAT1 expression was unchanged in the cortex of alcohol-treated rats but increased 24 hours after withdrawal, suggesting that MALAT1 expression may reflect differences in long-term versus short term use of alcohol. Upregulated MALAT1 expression was posited to contribute to increased excitatory synaptic responses and potentiation of the N-Methyl-D-aspartate (NMDA) receptor activity based on the known role of this lncRNA in the regulation of synapse formation.70

A growing body of research also supports lncRNA involvement in the brain-specific biological response to common pharmacological agents. For example, KCNQ1OT1 was upregulated in human brain microvascular endothelial cells in response to treatment with phenytoin, an antiepileptic drug, and was found to regulate levels of P-glycoprotein, a multidrug efflux transporter, by sponging miR-138-5p.71 Interestingly, downregulation of KCNQ1OT1 or overexpression of miR-138-5p corresponded with intracellular accumulation of antiepileptic drugs in phenytoin-resistant cells,71 suggesting that this lncRNA may represent a potential target for resolving resistance to antiepileptic therapies. Alternatively, lncRNAs may also confer protective effects in the presence of pharmacological agents. A recent investigation of metformin, an oral hypoglycemic agent commonly used in the treatment of type 2 diabetes, showed that the drug was able to protect against brain damage and attenuate oxidative stress injury resulting from middle cerebral artery occlusion, a model for transient cerebral ischemia, in adult male mice.72 Levels of the lncRNA H19 were higher, while those of miR-148-3p were lower, in treatment animals compared to controls, but were reduced with intraperitoneal injection of metformin. Using an oxygen–glucose deprivation treatment model, the authors showed that H19 worsened oxidative stress injury by sponging miR-148-3p, leading to increased levels of Rho-associated protein kinase 2 (Rock2). The in vivo and in vitro results suggest that the neuroprotective effects of metformin are initiated through the regulation of H19 levels, which lead to improvements in oxidative stress response.

Collectively, these studies demonstrate that lncRNAs are emerging not only as critical players in the pathogenesis of complex neurological diseases and brain pathologies but also as important mediators of environmental exposures on brain health. In addition to this diverse array of biological and cellular processes, mounting evidence indicates that lncRNAs may likewise modulate the long-term effects of anesthesia on neuronal communication and connections. In the remainder of this review, we will focus on lncRNAs associated with neuroinflammation, PND, and anesthesia-induced neurotoxicity in human, animal, and in vitro models.

PNDs: Clinical Perspective

The PND is a new classification of cognitive changes associated with surgery and anesthesia.9 PND was previously identified as POCD, and the new term is referred to a change in cognitive impairment identified in the preoperative or postoperative period.

One of the nonmodifiable risk factors for PND, which is found in various studies, is increased age.73 The incidence of PND in patients >60 years can be more than double as compared to those <60 years. Additional nonmodifiable risk factors for PND are fewer years of previous education and lower preoperative cognitive test scores.74 The older individuals are also more vulnerable to various neurodegenerative diseases (including Parkinson’s, Alzheimer’s, and others), affecting up to 55% of people aged ≥5575,76 placing them at a higher risk of cognitive dysfunction after surgery and anesthesia.11,77–79 Concerns have also been raised whether PND can lead to dementia. Although there are relatively limited data to substantiate this concern, it was shown that impaired cognition before surgery, or the presence of cardiovascular disease might be associated with a higher prevalence of dementia.80 Future studies will be necessary to better understand whether certain subgroups of patients with cerebrovascular disease are more likely of developing PND and other impairments of brain function.

Although the clinical symptoms for the PND disorders are reasonably well-defined, the underlying molecular mechanisms are largely unknown, with limited diagnosis and/or therapeutic strategy to reduce the incidence of PND. Nevertheless, using temporal association of delayed neurocognitive recovery with perioperative period, it appears that anesthesia or surgery are responsible for subsequent events leading to neuroinflammation. Recent clinical studies highlight the importance of inflammatory dysfunction in patients developing PND, including elevated proinflammatory cytokines81 and microglial activation.82 Moreover, the current evidence suggests that neuroinflammation after surgery plays a key role in PND; with or without the presence of anesthetics83,84; although anesthetics can contribute to PND (especially in the presence of preexisting vulnerabilities).85

Association of LncRNAs With PNDs

During the past decade, researchers have successfully developed numerous rodent models of PND, which have been extremely beneficial in improving the knowledge of the underlying pathophysiological mechanisms of PND.86–88 Unlike human studies, these animal models have proven to be extremely advantageous, opening the possibility to design studies considering cofounding factors like age-matched controls and the ability to separate the anesthetic impact from the underlying pathology requiring any pharmacological intervention. In the current section, we summarize the role of lncRNAs as biomarkers for diagnostic purposes and their molecular mode of action in PND. Moreover, we also highlight the potential of lncRNAs as therapeutic targets in PND and in determining novel diagnostic and therapeutic targets.

Recently, several microarray-based studies have been reported to profile the whole genome using biological fluids and tissues to investigate the involvement of lncRNA in PND. Intriguingly, most of these studies further attribute these lncRNAs’ crucial role with aberrant expression in developing and maintaining PND disorders.89,90 For instance, to date, 4 microarray-based studies have been conducted for the characterization of ncRNAs in PND, one of which investigated the altered lncRNA profiles in the hippocampal tissue using a mouse model of orthopedic surgery-induced POCD. In total, 175 lncRNAs, 117 mRNAs, and 26 miRNAs were differentially expressed between POCD and non-POCD mice. Interestingly, some of the differentially expressed lncRNAs were found to serve as ligands, with potential interactions with transcriptional factors like CREB and STAT 3, which have been associated with cognitive dysfunction.89

The second study explored circulating lncRNAs and mRNAs associated with POCD pathogenesis in human patients requiring hip or knee replacement surgery. The study found 68 lncRNAs and 115 mRNAs that were differentially expressed in the POCD group relative to the non-POCD group 30 days postsurgery. Specific differentially expressed lncRNAs were found to modulate histone deacetylases (HDAC), which have been previously linked to several neurodegenerative conditions.90 The third microarray study investigated the hippocampal gene expression in nephrectomy-induced POCD mice and paired controls 3 days postsurgery. Approximately 850 and 700 lncRNAs and mRNAs were differentially expressed between the 2 groups. Bioinformatic analysis of the aberrantly expressed genes revealed enrichment in surgery-induced apoptotic and inflammatory pathways, which was consistent with the previous studies on the hippocampus tissues in POCD models.91 Finally, the fourth study focused on circular RNAs (circRNAs) in serum samples of POCD patients requiring cardiac valve replacement surgery under cardiopulmonary bypass. Overall, 10,198 circRNAs were analyzed, 210 of which were differentially expressed in the POCD versus the non-POCD group.92

In addition to the microarray analysis, whole transcriptome sequencing technology has also been used to explore the dexmedetomidine (Dex)-induced lncRNA expression patterns in the hippocampus and their potential role in mitigating POCD in rats. In total, 60 lncRNAs were reported to be deregulated in the Dex-treated group versus control. Among these dysregulated lncRNAs, LOC102546895 was found to serve as a negative modulator of neuronal apoptosis in microglial cells. Downregulation of LOC102546895 corresponded with reduced expression of Neuronal Per-Arnt-Sim domain protein 4 (Npas4) and significantly increased proliferation of microglial cells due to reduced apoptosis.93

In brief, the microarray analysis using the above-mentioned animal models of PND has contributed to a better understanding of PND pathogenesis. However, further studies are necessary to validate the associations between lncRNAs and target mRNAs, elucidate the manner in which specific lncRNAs modulate the expression of mRNAs, and to demonstrate a functional contribution to PND pathogenesis before therapeutic targets and potential biomarkers can be considered for clinical applications.

Anesthetic-Induced Neurotoxicity: Rodents to Humans

Brain development is an intricate process that is characterized by events like synaptogenesis, neurogenesis, and structural remodeling of neurons.94–96 The animal models of neurotoxicity have been extremely useful in deciphering the underlying mechanisms of AIDN. Several studies using animal models have demonstrated that frequent or lengthy exposure of the developing brain (growth spurt period) to anesthetics and sedative drugs can cause detrimental outcomes such as neuronal damage, cognitive impairment, and neurodevelopmental deficits.3,97–99

During the past couple of decades, it has been illustrated that anesthetics affect the brain through various mechanisms, including suppressed neural stem cell proliferation, altered neurogenesis, neurite retraction, dendrite growth reduction, etc. Eventually, the brain develops local inflammation, oxidative stress, aberrant receptor expression (NMDA/gamma-aminobutyric acid [GABA]), dysregulation in survival pathways, autophagy, suppressed neuronal growth, and neuronal apoptosis (Figure).100–102 These pathological changes in the structure and function of the brain as a result of anesthetic exposure are defined as AIDN. Though animal studies provide sufficient evidence to support the fact that anesthetics have adverse effects on the neurodevelopmental processes, the clinical data from human studies illustrate varied outcomes from postanesthetic exposure.

F1
Figure.:
Downstream molecules of lncRNAs and their role in AIDN pathophysiology. Exposure to anesthetics alters the expression upregulated (red) and downregulated (green) of lncRNAs MALAT-1, BDNF-AS, Rik-203, TUG-1 contributing toward the pathophysiology of AIDN. Changes in the expression of these lncRNAs subsequently influences oxidative stress, inflammation, neuronal apoptosis, cognitive function, and neuronal growth and differentiation. AIDN, anesthetic-induced developmental neurotoxicity; BDNF-AS, brain-derived neurotrophic factor antisense RNA transcripts; lncRNAs, long noncoding RNAs; MALAT-1, metastasis-associated lung adenocarcinoma transcript 1; Rik-203, lncRNA Rik-203; TUG-1, taurine-upregulated gene 1.

Of the children that are annually exposed to anesthesia, approximately 20% are <5 years.103 Preclinical investigations have consistently demonstrated neuroanatomical changes and life-long cognitive deficits following exposure to common anesthetics early in life. Recent reports from clinical studies, such as the pediatric anesthesia neurodevelopment assessment (PANDA) and the general anesthesia compared to spinal anesthesia (GAS) trials have indicated that a single anesthesia exposure or short sevoflurane exposure (<1 hour) to healthy children <3 years of age do not cause significant adverse effects.104,105 On the other hand, the Mayo Anesthesia Safety in Kids Study found that multiple exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.106 Because of the contradictory data from these recent studies, future investigations are warranted in the area of AIDN.

In short, the results from experimental research have been useful in providing a better understanding of anesthesia-induced neurotoxicity. However, the field still faces several practical challenges, such as the inability to scaling up animal work, which primarily involves optimization of the exposure dose and duration in the animal as seen in humans. Moreover, it would be intriguing to compare how the pediatric versus adult population would respond to anesthetics having different exposure times (short versus long-term exposures) and if different types of surgeries (cardiac versus noncardiac) have differential outcomes regarding their neurotoxicity. Future investigation and experimentation should help to improve the diagnosis and the therapeutics of AIDN.

Alteration, Regulation, and Function of Specific LncRNAs in AIDN

Anesthetic exposure elicits a series of pathophysiological events in specific regions of the brain.6,107–109 Recently, numerous lncRNAs and mRNAs were found to be dysregulated in the brain after anesthetic exposure. However, the functional role of the dysregulated lncRNA in AIDN remains poorly understood. To gain a mechanistic insight about the regulatory role of the altered lncRNAs in the underlying mechanisms and how these transcripts might contribute to the pathophysiology of AIDN, techniques like microarray profiling and RNA sequencing have been used to measure lncRNA and mRNA expression, followed by bioinformatic analysis. In adult mice administered propofol, 146 lncRNAs and 1103 mRNAs were differentially expressed at 6 hours postsedation compared with controls.110 The altered lncRNA-associated mRNA were found to be enriched for FoxO pathway–related proteins, phosphoinositide 3-kinases (PI3K) and protein kinase B (AKT), which might be associated with propofol-induced neurotoxicity contributing to hippocampal dysfunctionality. We recently profiled the expression of 35,923 lncRNAs and 24,881 mRNAs in the neonatal mouse hippocampus at 3 hours postpropofol exposure.23 We observed differential expression of 159 lncRNAs and 100 mRNAs (fold change ≥|2.0|, P < .05). Bioinformatic analysis revealed enrichment of differentially expressed transcripts in pathways related to neurodegeneration, including calcium handling, apoptosis, autophagy, and synaptogenesis.

The lncRNA and mRNA expression profiles in hippocampal tissue identified in these 2 studies were remarkably different between adult and neonatal mice, perhaps reflecting the dynamic expression patterns across developmental brain stages. The results suggest that the expression pattern of lncRNA is not only sensitive to age, but also to the duration of exposure to anesthetics. Studies to characterize strongly dysregulated lncRNAs and mRNAs may provide important clues to the pathogenesis of AIDN.

Table. - Experimental Evidence of AIDN in Rodents
Type of anesthetics Exposure time (h) Cell type Species LncRNAs Regulation during AIDN Function in AIDN References
Bupivacaine 2 DRG neurons Mice MALAT-1 Down Elevated oxidative stress and apoptosis Zhao et al111
Sevoflurane 6 Hippocampal neurons Rats MALAT-1 Up Increase apoptosis, inflammation, mitigates spatial learning, and cognitive function Hu et al112
Ketamine 2 Embryonic neural stem cells Rats BDNF-AS Up Suppress neurite outgrowth and elevates neuronal apoptosis Zhen et al113
Sevoflurane 2 Hippocampal neurons Mice Rik-203 Down Inhibit neuronal apoptosis Zhang et al24
Ketamine 12 Hippocampal neurons Rats TUG-1 Up Inhibit neuronal apoptosis Cao et al114
Abbreviations: AIDN, anesthetic-induced developmental neurotoxicity; BDNF-AS, brain-derived neurotrophic factor antisense RNA transcripts; DRG, dorsal root ganglia; lncRNAs, long noncoding RNAs; MALAT-1, metastasis-associated lung adenocarcinoma transcript 1; Rik-203, lncRNA Rik-203; TUG-1, taurine-upregulated gene 1.

In the next sections, we discuss specific lncRNAs that have been identified as promising candidates in the diagnosis and treatment of AIDN (Table).

Metastasis-Associated Lung Adenocarcinoma Transcript 1

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved intergenic noncoding transcript predominantly localized in the nuclear speckles and related to RNA metabolism (premRNA processing, splicing, and export), epigenetic modulation (posttranscriptional and posttranslational), and gene regulation in different biological processes.115–117 MALAT1 is the most abundantly expressed lncRNA in the nervous system and has been shown to play a stage-specific role in neurodevelopmental processes.70,118

Recently, MALAT1 has been shown to regulate the development of AIDN. These studies have reported the protective effect of MALAT-1 in anesthetic (bupivacaine)-exposed neonatal mouse dorsal root ganglia (DRG) neurons and human neuroblastoma cells. Knockdown of MALAT1 expression was found to promote apoptosis in anesthetic-exposed mouse DRG neurons, while MALAT1 overexpression significantly attenuated oxidative stress and apoptosis by regulating the miR-101-3p-/PDCD4 axis and mitigating bupivacaine-induced neurotoxicity. Based on these in vitro experiments, MALAT1 upregulation may therefore represent a survival strategy against bupivacaine neurotoxicity.111

In animal models, sevoflurane-treated rats developed pathological spatial learning and memory changes, as well as neuronal apoptosis in the hippocampus. Suppression of MALAT1 in the hippocampal neurons mitigated the apoptosis induced by sevoflurane anesthesia, leading to improved spatial learning and memory function.112 Together, these studies provide preliminary evidence suggesting that MALAT1 expression in the brain exhibits specific responses toward different anesthetics and may regulate critical pathogenic pathways that are relevant to AIDN. Further studies are necessary to determine whether MALAT1 may represent a potential therapeutic target in the treatment of anesthetic-induced neurotoxicity.

Brain-Derived Neurotrophic Factor Antisense RNA Transcript

Brain-derived neurotrophic factor antisense RNA transcript (BDNF-AS) is a naturally conserved antisense RNA transcript with no protein-coding potential that functions to regulate the expression of BDNF in various brain cell populations. BDNF-AS has been shown to interfere with the localization of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and H3K27me3 in the BDNF promoter region, leading to downregulated BDNF expression and changes in neuronal outgrowth and differentiation in both in vitro and in vivo experiments.48 Like MALAT1, the expression of BDNF-AS is significantly upregulated in neurons exposed to anesthetics. Furthermore, the knockdown of BDNF-AS using small interfering RNA (siRNA) in mouse embryonic neural stem cell–derived neurons results in improved neurite outgrowth and attenuation of neural apoptosis via activation of the Trkβ signaling pathway.113

LncRNA Rik-203 (C130071C03Rik)

C130071C03Rik is a highly conserved, intergenic lncRNA that has been implicated in brain development.40 C130071C03Rik, and its human ortholog LINC00461, which share 83% homology in a 2.5 kb region within exon 3, are dysregulated in human and mouse glioma tissues. LINC00461 may function as a ceRNA, binding miR-411-5p, which leads to the upregulation of the miR-411-5p target, topoisomerase 2 α (TOP2A), and alleviates glioma.119

C130071C03Rik was recently identified to be an important regulator of neural differentiation. C57BL/J6 mice exposed to sevoflurane (3%) anesthesia for 2 hours daily at 6, 7, and 8 days after birth showed reduced hippocampal levels of C130071C03Rik, corresponding with altered neural differentiation. MiR-101a-3p was identified as a target of C130071C03Rik. Consequently, knockdown of C130071C03Rik led to increased levels miR-101a-3p and decreased levels of the miR-101a-3p target, glycogen synthase kinase 3 β (Gsk3β), and inhibition of neural differentiation.24 Taken together, these findings indicate that decreased expression of C130071C03Rik following anesthetic exposure inhibits neural differentiation through modulating the miR-101a-3p/Gsk3β axis.

Taurine-Upregulated Gene 1

Taurine-upregulated gene 1 (TUG1) is a 7.1 kb vascular enriched polyadenylated lncRNA found to be highly expressed in retinal cells and pancreas and has been associated with several vital functions.120,121 TUG1 is also found to promote tumor development and metastasis in several cancer types, primarily prostate, hepatocellular, esophageal, and bladder.122–124 Furthermore, under ischemia, TUG1 is upregulated in specific regions of the brain, binding miRNA-9 and modulating its expression, thereby mitigating the neuronal viability both in vivo and in vitro. The knockdown of TUG1 results in the improvement of neuron viability.125

Recently, the expression level of TUG1 transcripts has been reported to be upregulated in rat hippocampal neurons induced by ketamine for 12 hours. The knockdown of TUG-1 using si-TUG1 significantly attenuates neuronal apoptosis via regulating of the p38/mitogen-activated protein kinase (MAPK) signaling pathway.114

In short, brain-specific TUG-1 is upregulated postanesthetic exposure, and siRNA-mediated knockdown mitigates AIDN via regulating the p38/MAPK signaling pathway.

LncRNA as Diagnostic and Therapeutic Tools in PNDs and Anesthetic-Induced Developmental Neurotoxicity: Future Challenges

Altered expression of circulating lncRNAs in various neurological disorders provides a basis on which to consider a potential clinical role for noninvasive, accurate disease diagnosis.126,127 In addition, attempts to modify the expression of a few lncRNAs in models of brain injuries have led to better outcomes,113,128,129 suggesting that in the future, brain-specific lncRNAs may serve as promising therapeutic targets to further enhance the efficacy of existing clinical practices for various neurodegenerative diseases. However, at this time, in-depth, comprehensive analyses are necessary to gain a better understanding of the role of lncRNAs in neurological disease development and pathogenesis.

Likewise, the emerging role of lncRNA as regulatory molecules in critical biological, cellular, and molecular events with their tissue-specific expression pattern not only depicts their associated complexity but also opens the possibility of lncRNAs to serve as accurate diagnostic biomarkers and potential therapeutic targets specifically for future PND and AIDN-based research. However, their potential to improve the diagnosis of or to serve as a therapeutic target in PND and AIDN depends on a few critical questions: (1) do lncRNA contribute to PND and AIDN pathophysiology? It will be important to evaluate the signature patterns of brain-specific lncRNAs and mRNAs in the pediatric and adult patients’ postanesthetic exposure and validate further that the proposed lncRNA candidates contribute toward PND and AIDN pathogenesis; (2) What is the clinical relevance of these lncRNAs? To offer a panel of lncRNAs having the potential to serve as a reliable biomarker in clinics, it would be essential to check that the changed expression signature is precisely due to PND and AIDN, as opposed to a consequence of PND and AIDN; and (3) How many brain-specific lncRNAs can be detected in biological fluids, and how stable are they in the circulation? The tissue-specific expression pattern of lncRNAs makes them an ideal biomarker; however, it might be challenging to detect them in biological fluids. Moreover, the half-life of lncRNAs could be another limitation.

LncRNAs may be promising targets and candidates as biomarkers of PND and AIDN diagnosis and treatment. However, at present, the function and regulation of thousands of lncRNAs in PND and AIDN are still ambiguous. To gain the mechanistic insight into the altered lncRNA’s regulatory role, it is essential to have a methodology coupled with rigorous statistical testing of hypotheses and mathematical analyses, providing meaningful interpretation to the data obtained through high throughput technologies like microarray or RNA sequencing. With the advent of high throughput technologies, extensive data set analyses have become increasingly common, leading to the evolution in applying statistical analyses to be performed. One such example can be seen in most of these PND and AIDN studies conducted in the past to test multiple hypotheses simultaneously (multiple comparisons), which often require proper statistical adjustments (Benjamini-Hochberg, Bonferroni, Holm). Although the adjustment for multiple comparisons remains mandatory, unfortunately, the data sets of a few of these genetic studies failed to apply the corrections, leading to a false statistical inference and diminishing the overall scientific rigor. It is crucial to have statistical corrections for multiple comparisons in future research, allowing the readers to provide mechanistic insight into the underlying biology of the condition being studied. It would also be important to have studies that are appropriately powered without the need for statistical adjustments.

The previous points raise important challenges in this field. Nevertheless, if they can be solved, lncRNAs might prove to be helpful biomarkers and possibly therapeutic targets.

CONCLUSIONS AND FUTURE PERSPECTIVES

Anesthetic neurotoxicity is a complicated process that affects numerous signaling pathways in the brain.130–134 The underlying mechanisms associated with its pathophysiology have yet to be fully elucidated. Furthermore, at present, a cost-effective approach for the clinical diagnosis and treatment of anesthetic neurotoxicity is lacking. Mounting evidence from studies conducted in animal models have clearly shown that exposure to anesthetics induces neurotoxicity.135–137 Recent studies have shown that exposure to anesthetics also changes the expression of specific lncRNAs to date; however, these data are limited, and the mechanisms are poorly understood. It is imperative that we gain a better mechanistic insight into how anesthetic exposure leads to neurotoxicity to prevent severe outcomes in the developing brain. Despite the limited data, only a few lncRNAs may be playing a regulatory role in the pathological processes of anesthetic-induced neurotoxicity. Functional characterization of lncRNAs associated with these processes is expected to improve our current understanding of the underlying mechanisms of AIDN and PND. Thus, further investigation and functional validation of anesthesia-induced lncRNAs in the brain may potentially lead to improved methods for detecting, treating, and possibly preventing AIDN and PND.

DISCLOSURES

Name: Tarun Pant, PhD.

Contribution: This author helped conceive the idea and concept of the review article, collect and prepare the literature, design and write the original manuscript, edit the figure and the table, revise the initial manuscript, and approve the final manuscript.

Name: Johanna K. DiStefano, PhD.

Contribution: This author is an equal, first author contributor. This author helped collect and prepare the literature, design and write the original manuscript, revise the initial manuscript, and approved the final manuscript.

Name: Sara Logan, PhD.

Contribution: This author helped interpret the literature, revise the initial manuscript, and approve the final manuscript.

Name: Zeljko J. Bosnjak, PhD.

Contribution: This author helped conceive the concept of the review article, write the original manuscript, revise the initial manuscript, and approve the final manuscript.

This manuscript was handled by: Gregory J. Crosby, MD.

GLOSSARY

AIDN
anesthetic-induced developmental neurotoxicity
AKT
protein kinase B
BDNF-AS
brain-derived neurotrophic factor antisense RNA transcripts
ceRNA
competitive endogenous RNA
circRNA
circular RNAs
CNS
central nervous system
Dex
dexmedetomidine
DRG
dorsal root ganglia
EZH2
enhancer of zeste 2 polycomb repressive complex 2 subunit
GABA
gamma-aminobutyric acid
GAS
general anesthesia compared to spinal anesthesia
Gsk3β
glycogen synthase kinase 3 β
HDAC
histone deacetylases
lncRNA
long noncoding RNAs
MALAT1
metastasis-associated lung adenocarcinoma transcript 1
MAPK
mitogen-activated protein kinase
miRNA
microRNA
NMDA
N-Methyl-D-aspartate
Npas4
neuronal Per-Arnt-Sim domain protein 4
PANDA
pediatric anesthesia neurodevelopment assessment
PI3K
phosphoinositide 3-kinases
PND
perioperative neurocognitive disorders
POCD
postoperative cognitive dysfunction
Rik-203
lncRNA Rik-203
Rock2
Rho-associated protein kinase 2
TOP2A
topoisomerase 2 α
siRNA
small interfering RNA
TUG1
taurine-upregulated gene 1

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