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Methylene Blue Protects Against Sevoflurane-Induced Cognitive Dysfunction by Suppressing Drp1 deSUMOylation in Aged Mice

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Abstract

Exposure to sevoflurane and other inhalational anesthetics can induce cognitive impairment in elderly patients. Studies have indicated that methylene blue (MB) has beneficial effects on multiple neurodegenerative diseases and the mechanism involves mitochondrial function preservation. However, whether MB can attenuate the cognitive decline induced by sevoflurane in aged mice requires further investigation. Forty-five 18-month-old C57/BL mice were used to establish a model of sevoflurane-induced cognitive impairment in which the mice were exposed to 3% sevoflurane for 2 h. Mice in the MB group were intraperitoneally injected with MB at a dose of 5 mg/kg before sevoflurane inhalation. The Morris water maze test was used to evaluate the learning and memory performances. We also examined changes in mitochondrial morphology as well as the expression and interaction of related proteins in the aged hippocampus. Parkin, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), mitochondrial dynamin-related protein 1 (Drp1), small ubiquitin-like modifier (SUMO2/3), SUMO-specific proteases 3 (SENP3), and ubiquitin‐like conjugating enzyme 9 expression in the mouse hippocampus was detected by western blotting, and SUMO2/3-Drp1 was examined by coimmunoprecipitation. Exposure to sevoflurane increased SENP3 expression and Drp1 deSUMOylation in the aged hippocampus and resulted in cognitive deficiency. MB attenuated sevoflurane-induced memory loss and mitochondrial fragmentation and decreased Drp1 deSUMOylation in the aged hippocampus. This neuroprotective effect provides a mechanistic explanation for how the SUMOylation status of Drp1 acts as a key switch in the cognitive dysfunction induced by sevoflurane.

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Abbreviations

MB:

Methylene blue

BNIP3:

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

Drp1:

Mitochondrial dynamin-related protein 1

MWM:

Morris water maze test

SUMO2/3:

Small ubiquitin-like modifier

SENP3:

SUMO-specific proteases 3

UBC9:

Ubiquitin‐like conjugating enzyme 9

Con:

Control group

Sev:

Sevoflurane group

Sev + MB:

Sevoflurane + methylene blue group

References

  1. Geng YJ, Wu QH, Zhang RQ (2017) Effect of propofol, sevoflurane, and isoflurane on postoperative cognitive dysfunction following laparoscopic cholecystectomy in elderly patients: a randomized controlled trial. J Clin Anesth 38:165–171

    Article  CAS  Google Scholar 

  2. Qiao Y, Feng H, Zhao T et al (2015) Postoperative cognitive dysfunction after inhalational anesthesia in elderly patients undergoing major surgery: the influence of anesthetic technique, cerebral injury and systemic inflammation. BMC Anesthesiol 15:154

    Article  Google Scholar 

  3. Xu F, Armstrong R, Urrego D et al (2016) The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity. Mol Brain 9:35

    Article  Google Scholar 

  4. Shan Y, Sun S, Yang F et al (2018) Dexmedetomidine protects the developing rat brain against the neurotoxicity wrought by sevoflurane: role of autophagy and Drp1-Bax signaling. Drug Des Devel Ther 12:3617–3624

    Article  CAS  Google Scholar 

  5. Fonseca TB, Sánchez-Guerrero Á, Milosevic I et al (2019) Mitochondrial fission requires DRP1 but not dynamins. Nature 570(7761):E34–E42

    Article  CAS  Google Scholar 

  6. Zuo W, Zhang S, Xia CY et al (2014) Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage. Neuropharmacology 86:103–115

    Article  CAS  Google Scholar 

  7. Zuo W, Yang PF, Chen J (2016) Drp-1, a potential therapeutic target for brain ischaemic stroke. Br J Pharmacol 173:1665–1677

    Article  CAS  Google Scholar 

  8. Yeh ET, Gong L, Kamitani T (2000) Ubiquitin-like proteins: new wines in new bottles. Gene 248:1–14

    Article  CAS  Google Scholar 

  9. Gareau JR, Lima CD (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11:861–871

    Article  CAS  Google Scholar 

  10. Yeh ET (2009) SUMOylation and De-SUMOylation: wrestling with life's processes. J Biol Chem 284:8223–8227

    Article  CAS  Google Scholar 

  11. Guo C, Wilkinson KA, Evans AJ (2017) SENP3-mediated deSUMOylation of Drp1 facilitates interaction with Mff to promote cell death. Sci Rep 7:43811

    Article  Google Scholar 

  12. Gao L, Zhao Y, He J et al (2018) The desumoylating enzyme sentrin-specific protease 3 contributes to myocardial ischemia reperfusion injury. J Genet Genomics 45:125–135

    Article  Google Scholar 

  13. An J, Zhou Y, Zhang M et al (2019) Exenatide alleviates mitochondrial dysfunction and cognitive impairment in the 5xFAD mouse model of Alzheimer's disease. Behav Brain Res 370:111932

    Article  Google Scholar 

  14. Fernandez A, Meechan DW, Karpinski BA et al (2019) Mitochondrial dysfunction leads to cortical under-connectivity and cognitive impairment. Neuron 102:1127–42.e3

    Article  CAS  Google Scholar 

  15. Gonzalez-Lima F, Barksdale BR, Rojas JC (2014) Mitochondrial respiration as a target for neuroprotection and cognitive enhancement. Biochem Pharmacol 88(4):584–593

    Article  CAS  Google Scholar 

  16. Wainwright M, Crossley KB (2002) Methylene blue–a therapeutic dye for all seasons? J Chemother 14:431–443

    Article  CAS  Google Scholar 

  17. Lin X, Wu BB, Xing QY et al (2015) Methylene blue, a potential therapeutic target for mitochondria dysfunction. Int Immunopharmacol 28:1106–1107

    Article  CAS  Google Scholar 

  18. Tucker D, Lu Y, Zhang Q (2018) From mitochondrial function to neuroprotection-an emerging role for methylene blue. Mol Neurobiol. 55(6):5137–5153

    Article  CAS  Google Scholar 

  19. Peng S, Zhang Y, Li GJ, Zhang DX et al (2012) The effect of sevoflurane on the expression of M1 acetylcholine receptor in the hippocampus and cognitive function of aged rats. Mol Cell Biochem. 361(1–2):229–233

    Article  CAS  Google Scholar 

  20. Yan WJ, Wang DB, Ren DQ et al (2019) AMPKα1 overexpression improves postoperative cognitive dysfunction in aged rats through AMPK-Sirt1 and autophagy signaling. J Cell Biochem. 120:11633–11641

    Article  CAS  Google Scholar 

  21. Fang F, Lin W, Ling X et al (2016) The hippocampal cyclin D1 expression is involved in postoperative cognitive dysfunction after sevoflurane exposure in aged mice. Life Sci 160:34–40

    Article  CAS  Google Scholar 

  22. Xu F, Armstrong R, Urrego D et al (2016) The mitochondiral division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity. Mol Brain 9:35

    Article  Google Scholar 

  23. Vutskits L, Xie Z (2016) Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 17:705–717

    Article  CAS  Google Scholar 

  24. Lu H, Liufu N, Dong Y et al (2017) Sevoflurane acts on ubiquitination-proteasome pathway to reduce postsynaptic density 95 protein levels in young mice. Anesthesiology 127:961–975

    Article  CAS  Google Scholar 

  25. Rojas JC, Bruchey AK, Gonzalez-Lima F (2012) Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol 96:32–45

    Article  CAS  Google Scholar 

  26. Gureev AP, Syromyatnikov MY, Gorbacheva TM et al (2016) Methylene blue improves sensorimotor phenotype and decreases anxiety in parallel with activating brain mitochondria biogenesis in mid-age mice. Neurosci Res 113:19–27

    Article  CAS  Google Scholar 

  27. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  Google Scholar 

  28. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–560

    Article  CAS  Google Scholar 

  29. Rikka S, Quinsay MN, Thomas RL et al (2011) Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover. Cell Death Differ 18:721–731

    Article  CAS  Google Scholar 

  30. Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439–450

    Article  CAS  Google Scholar 

  31. Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J et al (2009) SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J 23:3917–3927

    Article  CAS  Google Scholar 

  32. Guo C, Hildick KL, Luo J et al (2013) SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. EMBO J 32:1514–1528

    Article  CAS  Google Scholar 

  33. Hay RT (2007) SUMO-specific proteases: a twist in the tail. Trends Cell Biol 17:370–376

    Article  CAS  Google Scholar 

  34. Gong L, Yeh ET (2006) Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 281:15869–15877

    Article  CAS  Google Scholar 

  35. Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19

    Article  CAS  Google Scholar 

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Acknowledgement

This research was supported by the National Natural Science Foundation of China (Grant Nos. 81801082 and 81771160) and the Hubei Provincial Natural Science Foundation (Grant No. 2019CFB102).

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Author notes

  1. Feng Zheng and Peng Fang have contributed equally to this study.

  2. Chang Chen and Zongze Zhang have contributed equally to this study.

Authors and Affiliations

  1. Department of Anesthesiology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China

    Feng Zheng, Peng Fang, Jing Chang, Qi Zhong, Ting Chen, Chang Chen & Zongze Zhang

  2. Department of Geriatrics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, China

    Min Chen

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  1. Feng Zheng
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Contributions

FZ and PF helped carry out the animal experiments and western blotting. JC helped record experimental data. MC, QZ and TC helped analyze the data. CC (Chang Chen) and ZZZ (Zongze Zhang) helped design the experiments and write the manuscript.

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Correspondence to Chang Chen or Zongze Zhang.

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Zheng, F., Fang, P., Chang, J. et al. Methylene Blue Protects Against Sevoflurane-Induced Cognitive Dysfunction by Suppressing Drp1 deSUMOylation in Aged Mice. Neurochem Res 45, 956–963 (2020). https://doi.org/10.1007/s11064-020-02976-6

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  • DOI: https://doi.org/10.1007/s11064-020-02976-6

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