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Sirtuin 2 Inhibition Attenuates Sevoflurane-Induced Learning and Memory Deficits in Developing Rats via Modulating Microglial Activation


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. Neonatal rats were exposed to 3% sevoflurane or 30% oxygen for 2 h daily with or without SIRT2 inhibitor AK7 pretreatment from postnatal day 7 (P7) to P9. One cohort of rats were euthanized 6, 12, and/or 24 h after the last gas exposure, and brain tissues were harvested for biochemical analysis and/or immunohistochemical examination. Cognitive functions were evaluated using the open field and Morris water maze tests on P25 and P28–32, respectively. SIRT2 was significantly up-regulated in neonatal rat hippocampus at 6 and 12 h post-anesthesia. Pretreatment with SIRT2 inhibitor AK7 reversed sevoflurane-induced hippocampus-dependent cognitive impairments. Furthermore, AK7 administration mitigated sevoflurane-induced neuroinflammation and microglial activation. Concomitantly, AK7 inhibited pro-inflammatory/M1-related markers and increased anti-inflammatory/M2-related markers in microglia. AK7 might prevent sevoflurane-induced neuroinflammation by switching microglia from the M1 to M2 phenotype. Downregulation of SIRT2 may be a novel therapeutic target for alleviating anesthesia-induced developmental neurotoxicity.

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Nicotinamide adenine dinucleotide


Histone deacetylases


Central nervous system


Parkinson’s disease


Huntington’s disease




Morris water maze


Histone acetyltransferases


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This work was supported by the National Nature Science Foundation of China (Nos. 81870838, 81671311), the Key Research and Development Program of Liaoning Province (No. 2018225004), and the Outstanding Scientific Fund of Shengjing Hospital (No. 201708).

Author information




ZW and PZ conceived and designed experiments. ZW, YZ (Yi Zhang) and YZ (Yinong Zhang) performed experiments, generated and analyzed the data. ZW wrote the manuscript with the help of PZ. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ping Zhao.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Ethics Committee of Shengjing Hospital of China Medical University, where these studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Supplementary Fig.

 1 Expressions of acetylated α-tubulin in the hippocampus of rats in each group. (a) Representative western blotting images for the expression levels of acetylated α-tubulin. (b) Quantification of acetylated α-tubulin normalized to α-tubulin. n = 5 per group. Data are expressed as mean ± SD of control mean values. One-way ANOVA followed by Tukey post hoc multiple comparison tests was used for data analysis. **P < 0.01, compared with CON group; ##P < 0.01, compared with SEV group. Supplementary material 1 (JPEG 172 kb)

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Wu, Z., Zhang, Y., Zhang, Y. et al. Sirtuin 2 Inhibition Attenuates Sevoflurane-Induced Learning and Memory Deficits in Developing Rats via Modulating Microglial Activation. Cell Mol Neurobiol 40, 437–446 (2020).

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  • SIRT2
  • Learning and memory deficits
  • Microglia
  • Hippocampus
  • Neuroinflammation