Effect of Long-time Postnatal Exposure to Sevoflurane on Causing Attention-deficit/Hyperactivity Disorder in Rats

CHEN Ming-kai, OU Meng-chan, HAO Xue-chao, HUANG Han, ZHANG Dong-hang, CHEN Yuan-yuan, LIANG Peng, ZHOU Cheng, LI Yu

Abstract

To investigate whether long-term exposure to inhaled sevoflurane, a volatile anesthetic, causes abnormal activities and memory impairment related to attention-deficit/hyperactivity disorder (ADHD) in neonatal rats.  Methods  On postnatal day 5 (P5), Sprague-Dawley rats were randomly assigned to two sevoflurane subgroups and two control subgroups and underwent experimental intervention. The two sevoflurane (SEVO) subgroups were exposed to 3% sevoflurane for 2 h and 4 h respectively, while the two control subgroups were given pure oxygen for the same amount and duration. Behavioral tests, including open-field test (OFT), five-choice serial reaction time task (5-CSRTT), fear-conditioning (FC) and Morris water maze (MWM), were applied to evaluate changes in cognition, memory, anxiety and ADHD-related behavioral changes in the rats in adolescence (-P25) and in adulthood (-P65).  Results  In OFT, the SEVO 2 h and SEVO 4 h subgroups displayed activity level and exploratory behaviors similar to those of the control subgroups on P21 and P61, with no statistically significant difference identified in the data. 5-CSRTT results on P25 and P65 indicated no statistically significant difference between the SEVO subgroups and the control subgroups in regard to ADHD-related abnormal behaviors, including number of immature reaction, rate of correct response and omission rate. In the FC experiment, SEVO 4 h group had a shorter freezing period and longer period of freezing latency (P=0.029) in comparison to the control groups. The results of the MWM test showed that the escape latency period of rats in the SEVO 4 h group was significantly prolonged on the second day and the third day, compared to the control groups (P<0.05). The average swimming speed of SEVO groups did no exhibit any statistically significant difference on P69 or P76. The time the SEVO 4 h group spent in the target quadrant was significantly shorter than that of the control group (P=0.039) and percentage of distance traveled in the target quadrant was significantly reduced compared to that the control group (P=0.048).  Conclusion  The findings suggest that four hours of inhaled sevoflurane exposure in neonate rats may cause memory impairment, but does no increase risks for ADHD-related abnormal activities.

 

Keywords: Sevoflurane, ADHD, Cognition, Memory

 

Full Text:

PDF


References


HEMMINGS H C， AKABAS M H， GOLDSTEIN P A， et al. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci，2005，26(10): 503–510.

FRANKS N P. Molecular targets underlying general anaesthesia. Br J Pharmacol，2006，147(Suppl 1): S72–S81.

FRANKS N P. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci，2008，9(5): 370–386.

JEVTOVIC-TODOROVIC V， BRAMBRICK A. General anesthesia and young brain: what is new? J Neurosurg Anesthesiol，2018，30(3): 217–222. PEROUANSKY M， HEMMINGS H C. Neurotoxicity of general anesthetics: cause for concern? Anesthesiology，2009，111(6): 1365–1371.

LIU Y F， LIU C L， ZENG M T， et al. Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain. Exp Ther Med，2018，15(2): 2066–2073.

HAN X， LIU C L， ZHANG K， et al. Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats. Toxicol Lett，2018，285: 60–73.

LIU B， XIA J M， CHEN Y L， et al. Sevoflurane-induced endoplasmic reticulum stress contributes to neuroapoptosis and BACE-1 expression in the developing brain: the role of eIF2α. Neurotox Res，2017，31(2): 218–229.

DENG M， HOFACER R D， JIANG C， et al. Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions. Br J Anaesth，2014，113(3): 443–451.

ISTAPHANOUS G K， HOWARD J， NAN X， et al. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology， 2011，114(3): 578–587.

KODAMA M， SATOH Y， OTSUBO Y， et al. Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology，2011，115(5): 979–991.

ZHOU X， LI W D， CHEN X H， et al. Dose-dependent effects of sevoflurane exposure during early lifetime on apoptosis in hippocampus and neurocognitive outcomes in Sprague-Dawley rats. Int J Physiol Pathophysiol Pharmacol，2016，8(3): 111–119.

XIAO H Y， LIU B， CHEN Y L， et al. Learning, memory and synaptic plasticity in hippocampus in rats exposed to sevoflurane. Int J Dev Neurosci，2016，48: 38–49.

CHUNG W， PARK S， HONG J， et al. Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors. Paediatr Anaesth，2015，25(10): 1033–1045.

BI C J， CAI Q P， SHAN Y Y， et al. Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. Biomed Pharmacother，2018，108: 1469–1476.

LIAO Z X， LI J H， MIAO L P， et al. Inhibition of RhoA activity does not rescue synaptic development abnormalities and long-term cognitive impairment after sevoflurane exposure. Neurochem Res，2021，46(3): 468–481.

XU L L， SHEN J J， DAI S B， et al. Tetramethylpyrazine attenuated sevoflurane-induced neurotoxicity by enhancing autophagy through GPR50/CREB pathway in SH-SY5Y cells. Am J Chin Med，2020，48(4): 945–966.

LIU B， OU G Y， CHEN Y L， et al. Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain. Brain Res Bull，2019，146: 28–39.

BARTELS D D， MCCANN M E， DAVIDSON A J， et al. Estimating pediatric general anesthesia exposure: quantifying duration and risk. Paediatr Anaesth，2018，28(6): 520–527.

MCCANN M E， SORIANO S G. Does general anesthesia affect neurodevelopment in infants and children? BMJ， 2019， 367: 16459[2020-08-05]. https://doi.org/10.1136/bmj.l6459.

ANDROPOULOS D B， AHMAD H B， HAQ T， et al. The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. Paediatr Anaesth，2014，24(3): 266–274.

GUERRA G G， ROBERTSON C M T， ALTON G Y， et al. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth，2011，21(9): 932–941.

FARAONE S V， ASHERSON P， BANASCHEWSKI T， et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers， 2015， 1: 15020[2020-08-05]. https://doi.org/10.1038/nrdp.2015.20.

CASTELLANOS F X， TANNOCK R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci，2002，3(8): 617–628.

ING C， SUN M， OLFSON M， et al. Age at exposure to surgery and anesthesia in children and association with mental disorder diagnosis. Anesth Analg，2017，125(6): 1988–1998.

HU D， FLICK R P， ZACCARIELLO M J， et al. Association between exposure of young children to procedures requiring general anesthesia and learning and behavioral outcomes in a population-based birth cohort. Anesthesiology，2017，127(2): 227–240.

TSAI C J， LEE C T C， LIANG S H Y， et al. Risk of ADHD after multiple exposures to general anesthesia: a nationwide retrospective cohort study. J Atten Disord，2018，22(3): 229–239.

SPRUNG J， FLICK R P， KATUSIC S K， et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc，2012，87(2): 120–129.

EFRON D， VUTSKITS L， DAVIDSON A J. Can we really suggest that anesthesia might cause attention-deficit/hyperactivity disorder?Anesthesiology，2017，127(2): 209–211.

SPRUNG J， SCHROEDER D R， HANSEN T G， et al. Is anesthetic exposure in early life associated with ADHD? Paediatr Anaesth，2014， 24(12): 1305–1306.

KO W R， LIAW Y P， HUANG J Y， et al. Exposure to general anesthesia in early life and the risk of attention deficit/hyperactivity disorder development: a nationwide, retrospective matched-cohort study. Paediatr Anaesth，2014，24(7): 741–748.

JI M H， WANG X M， SUN X R， et al. Environmental enrichment ameliorates neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments. J Mol Neurosci，2015，57(3): 358–365.

LIU G H， ZHU T G， ZHANG A H， et al. Heightened stress response and cognitive impairment after repeated neonatal sevoflurane exposures might be linked to excessive GABAAR-mediated depolarization. J Anesth，2016，30(5): 834–841.

XIA Y M， XU H， JIA C F， et al. Tanshinone ⅡA attenuates sevoflurane neurotoxicity in neonatal mice. Anesth Analg，2017，124(4): 1244–1252.

MURPHY K L， MCGAUGHY J， CROXSON P L， et al. Exposure to sevoflurane anesthesia during development does not impair aspects of attention during adulthood in rats. Neurotoxicol Teratol，2017，60: 87–94.

LI Y， YIN A Q， SUN X， et al. Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior. J Clin Invest，2017， 127(12): 4270–4284.

JEVTOVIC-TODOROVIC V. Developmental synaptogenesis and general anesthesia: a kiss of death? Curr Pharm Des，2012，18(38): 6225–6231.

VLISIDES P， XIE Z. Neurotoxicity of general anesthetics: an update. Curr Pharm Des，2012，18(38): 6232–6240.


Refbacks

  • There are currently no refbacks.