The association between attention deficit hyperactivity disorder and general anaesthesia ‐ a narrative review

Xu, Lihua; Hu, Yuhan; Huang, Liping; Liu, Y.; Wang, B.; Xie, Linghua; Hu, Zhiyong

doi:10.1111/anae.14496

Cited by 18 publications

(22 citation statements)

References 60 publications

(100 reference statements)

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“…Anesthesia can induce neurotoxicity and neurocognitive impairments in young mice. 12 , 13 Previous data have shown that exposure to sevoflurane induces both learning deficits and abnormal social behaviors resembling autism spectrum disorders in neonatal mice. 14 , 15 Recent studies concluded that early exposure to anesthesia could have lasting effects on emotional and social development, and rodent behavioral models were an excellent instrument to investigate long-term socio-emotional general anesthesia-caused disorders in humans.…”

Section: Discussionmentioning

confidence: 99%

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice

Xu²,

Dai³

et al. 2021

Molecular Therapy - Nucleic Acids

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Long non-coding RNA (lncRNA) X-inactive specific transcript (Xist) is involved in apoptosis and inflammatory injury. This study aimed to assess the role of lncRNA Xist in sevoflurane-induced social and emotional impairment and neuronal apoptosis in neonatal mice and hippocampal neuronal cells. The performance in social and emotional tests and the expression levels of lncRNA Xist and microRNA (miR)-98-5p after sevoflurane exposure were measured. Moreover, the effects of suppression of lncRNA Xist on neuronal apoptosis and endoplasmic reticulum (ER) stress were determined. Subsequently, the association among lncRNA Xist, miR-98-5p, and ER degradation-enhancing α-mannosidase-like 1 protein (EDEM1) was explored. Our results showed that lncRNA Xist increased, miR-98-5p decreased, and social and emotional impairment appeared after sevoflurane exposure. Furthermore, suppression of lncRNA Xist improved sevoflurane-induced social and emotional impairment and reduced sevoflurane-induced neuronal apoptosis and ER stress in vivo and in vitro . Moreover, lncRNA Xist negatively regulated miR-98-5p expression, and it contributed to sevoflurane-induced neuronal apoptosis and ER stress by sponging miR-98-5p. Additionally, EDEM1 was identified as a target of miR-98-5p. Our findings revealed that the knockdown of lncRNA Xist ameliorates sevoflurane-induced social and emotional impairment through inhibiting neuronal apoptosis and ER stress by targeting the miR-98-5p/EDEM1 axis.

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Section: Discussionmentioning

confidence: 99%

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice

Xu²,

Dai³

et al. 2021

Molecular Therapy - Nucleic Acids

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“…Patients with ADHD show remarkable variation in complicating factors and neuropsychological weaknesses 5 . Previous studies suggested that the impaired development of dopaminergic neurons is related to ADHD development 6 . In addition to disorders in neurotransmitter system, other studies indicated that ADHD is caused by abnormal structural and functional synapses in mPFC 6,7 , which is responsible for behavioral inhibition and executive functions.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies suggested that the impaired development of dopaminergic neurons is related to ADHD development 6 . In addition to disorders in neurotransmitter system, other studies indicated that ADHD is caused by abnormal structural and functional synapses in mPFC 6,7 , which is responsible for behavioral inhibition and executive functions. Recently, clinical studies reported that repeated exposures to inhalational anesthetics in children is associated with the development of ADHD 6,[8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to disorders in neurotransmitter system, other studies indicated that ADHD is caused by abnormal structural and functional synapses in mPFC 6,7 , which is responsible for behavioral inhibition and executive functions. Recently, clinical studies reported that repeated exposures to inhalational anesthetics in children is associated with the development of ADHD 6,[8][9][10] . This finding was further supported by an animal study, which revealed that ketamine administration caused ADHD-like hyperactive behavior 11 .…”

Section: Introductionmentioning

confidence: 99%

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Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Xie

Liu

et al. 2020

Transl Psychiatry

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Sevoflurane, in particular multiple exposures, has been reported to cause the abnormal neurological development including attention-deficit/hyperactivity disorder (ADHD). This study is to investigate ADHD-like impulsivity in adult mice after repeated sevoflurane exposures at the neonatal stage. Six-day-old pups were exposed to 60% oxygen in the presence or absence of 3% sevoflurane for 2 h and the treatment was administrated once daily for three consecutive days. To assess the impulsivity, the cliff avoidance reaction (CAR) was carried out at the 8th week. Our results showed that repeated sevoflurane treatment increased the number of jumps and shortened the jumping latency in the CAR test. The cortices were harvested for immunostaining to detect c-Fos and calmodulin-dependent protein kinase IIα (CaMKIIα) expression in the medial prefrontal cortex (mPFC). We found that mPFC neurons, especially excitatory neurons, were highly activated and related to impulsive behavior. The activation viruses (AAV-CaMKIIα-hM3Dq) were injected to evaluate the effects of specific activation of mPFC excitatory neurons on impulsive behavior in the presence of clozapine-N-oxide (CNO). Likewise, the inhibitory viruses (AAV-CaMKIIα-hM4Di) were injected in the sevoflurane group to explore whether the mPFC excitatory neuronal inhibition reduced the impulsivity. Our results revealed that chemogenetic activation of mPFC excitatory neurons induced impulsive behavior whereas inhibition of mPFC excitatory neurons partially rescued the deficit. These results indicate that repeated sevoflurane exposures at the critical time induce impulsive behavior accompanied with overactivation of mPFC excitatory neurons in adult stages. This work may further extend to understand the ADHD-like impulsive behavior of the anesthetic neurotoxicity.

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“…Alcohol abuse, anxious/depressed basal mood, low educational level and genetic susceptibility are identi ed as the risk factors for cognitive dysfunction [4,5]. Accumulating evidence revealed that anesthesia may provoke persistent abnormalities of neuronal circuits by affecting neuronal differentiation and synaptogenesis, and pharmacotoxic effects exacerbated the impairment of cognitive domains [6,7]. Sevo urane, as an inhaled volatile anesthetic agent, is widely used in pediatric practice [8].…”

Section: Introductionmentioning

confidence: 99%

Egr2 Upregulation Induced Mitochondrial Iron Overload Implicating in Cognitive Deficits after Sevoflurane Administration

Chen

Zhang

et al. 2020

Preprint

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Background: Sevoflurane inhalation initiated cognitive deficits implicated in mitochondrial dysfunction, synaptogenesis impairment and neuroinflammation. Egr2 plays a crucial role in maintaining cognitive function. Therefore, we attempted to clarify the potential correlation regarding Egr2 expression and cognitive deficits induced by sevoflurane administration. Methods: Animals received sevoflurane anesthesia, and the behavioral tests including Morris water maze, novel object recognition test and trace fear conditioning were performed. Then, the Golgi-Cox staining and Nissl staining were employed to detect the effect of sevoflurane inhalation in hippocampal neurons. Meanwhile, bioinformatics analysis was implemented, and western blot (WB) and bisulfite sequencing PCR (BSP) technique were utilized to validate this hypothesis. Moreover, the level of lipid peroxidation, mitochondrial membrane potential, morphology and membrane permeability, and cytoplasm calcium levels were investigated after Egr2 interference by using JC-1 probe, MitoTracker staining, Mitochondrial permeability transition pore (mPTP) assay, and Fluo calcium indicators, respectively. Additionally, Prussian blue staining was used to evaluate the iron content.Results: The behavioral tests indicated that the cognitive function was significantly attenuated after sevoflurane administration. The Golgi-Cox staining displayed that the dendritic length, density and nodes were significantly reduced, and the typical neuropathological changes including neuron loss, nucleus shrinkaged and disappearance of Nissl bodies were observed by Nissl staining. Moreover, bioinformatics analysis showed that the Egr2 expression was significantly upregulated, and WB and BSP confirmed this result. Additionally, the results suggested that sevoflurane administration elevated the cytoplasm calcium levels, reduced the mitochondrial membrane potential and triggered the opening of mPTP. Prussian blue staining showed that the iron deposition was apparently increased. However, Egr2 level downregulation partly reversed these above changes.Conclusion: These findings demonstrated that sevoflurane administration elicited mitochondrial dysfunction and iron dyshomeostasis, and eventually resulted in cognitive impairments, whereas suppressing Egr2 expression partly improved this pathological process.

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The association between attention deficit hyperactivity disorder and general anaesthesia ‐ a narrative review

Cited by 18 publications

References 60 publications

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Egr2 Upregulation Induced Mitochondrial Iron Overload Implicating in Cognitive Deficits after Sevoflurane Administration

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