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Metformin attenuates sevoflurane-induced neurogenesis damage and cognitive impairment: involvement of the Nrf2/G6PD pathway

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Abstract

Anesthetics such as sevoflurane are commonly administered to infants and children. However, the possible neurotoxicity caused by prolonged or repetitive exposure to it should be a concern. The neuroprotective effects of metformin are observed in many models of neurological disorders. In this study, we investigated whether metformin could reduce the developmental neurotoxicity induced by sevoflurane exposure in neonatal rats and the potential mechanism. Postnatal day 7 (PND 7) Sprague-Dawley rats and neural stem cells (NSCs) were treated with normal saline or metformin before sevoflurane exposure. The Morris water maze (MWM) was used to observe spatial memory and learning at PND 35–42. Immunofluorescence staining was used to detect neurogenesis in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus at PND 14. MTT assays, immunofluorescence staining, and TUNEL staining were used to assess the viability, proliferation, differentiation, and apoptosis of NSCs. Western blotting and ELISA were used to assess the protein expression of cleaved caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), and glucose-6-phosphate dehydrogenase (G6PD) pathway-related molecules. Exposure to sevoflurane resulted in late cognitive defects, impaired neurogenesis in both the SVZ and SGZ, reduced NSC viability and proliferation, increased NSC apoptosis, and decreased protein expression of G6PD in vitro. Metformin pretreatment attenuated sevoflurane-induced cognitive functional decline and neurogenesis inhibition. Metformin pretreatment also increased the protein expression of Nrf2 and G6PD. However, treatment with the Nrf2 inhibitor, ML385 or the G6PD inhibitor, dehydroepiandrosterone (DHEA) reversed the protective effect of metformin on sevoflurane-induced NSC damage in vitro. Our findings suggested that metformin could reduce sevoflurane-induced neurogenesis damage and neurocognitive defects in the developing rat brain by influencing the Nrf2/G6PD signaling pathways.

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Data availability

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.

Abbreviations

PND 7:

Postnatal day 7

SD:

Sprague-Dawley

NSCs:

Neural stem cells

MWM:

Morris water maze

SVZ:

Subventricular zone

SGZ:

Subgranular zone

MTT:

3-(4,5)-Dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide

TUNEL:

Terminal dUTP nick-end labeling

ELISA:

Enzyme-Linked Immunosorbent Assay

Nrf2:

Nuclear factor erythroid 2-related factor 2

G6PD:

Glucose-6-phosphate dehydrogenase

DHEA:

Dehydroepiandrosterone

AMPK:

AMP-activated protein kinase

PPP:

Pentose phosphate pathway

NADPH:

Nicotinamide adenine dinucleotide phosphate

Ctrl:

Control

Sev:

Sevoflurane

Met:

Metformin

CO2 :

Carbon dioxide

O2 :

Oxygen

BrdU:

5-Bromo-2´-deoxyuridine

PBS:

Phosphate buffered saline

DMEM/F12:

Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12

EGF:

Epidermal growth factor

bFGF:

Basic fibroblast growth factor

FBS:

Fetal bovine serum

GSH:

Glutathione

HO-1:

Heme oxygenase-1

MCAO:

Middle cerebral artery occlusion

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2019YFE0115300), the National Natural Science Foundation of China (82071482), and the Key Research and Development Program of Shaanxi Province (2021KWZ-27).

Funding

This work was supported by the National Key Research and Development Program of China (2019YFE0115300), the National Natural Science Foundation of China (82071482), and the Key Research and Development Program of Shaanxi Province (2021KWZ-27).

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Authors and Affiliations

  1. Department of Anesthesiology, The Second Affiliated Hospital, Xi’an Jiaotong University, 157 # West 5 road, Xi’an, Shaanxi, 710004, China

    Pei Fan, Yuying Lu, Haidong Wei, Kui Wang, Pengyu Jia, Yuanyuan Zhang, Yan Zhang, Tianyue Wang, Liufei Yang, Jing Zhao & Pengbo Zhang

  2. Institute of Neurobiology, National Key Academic Subject of Physiology, Xi’an Jiaotong University, 76 # Yanta West Road, Xi’an, Shaanxi, 710061, China

    Shuyue Zhang, Haixia Lu, Xinlin Chen & Yong Liu

Authors
  1. Pei Fan
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  2. Yuying Lu
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  3. Haidong Wei
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  4. Kui Wang
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  5. Pengyu Jia
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  6. Yuanyuan Zhang
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  7. Yan Zhang
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  8. Tianyue Wang
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  9. Liufei Yang
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  10. Jing Zhao
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  11. Shuyue Zhang
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  13. Xinlin Chen
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  14. Yong Liu
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  15. Pengbo Zhang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Pei Fan and Yuying Lu. The first draft of the manuscript was written by Pei Fan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Pengbo Zhang.

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All applicable international and national guidelines for the care and use of animals were followed. All procedures performed in the study involving animals were approved by the Xi’an Jiaotong University Animal Care Committee (2020-14), in accordance with the ethical standards of Xi’an Jiaotong University.

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Fan, P., Lu, Y., Wei, H. et al. Metformin attenuates sevoflurane-induced neurogenesis damage and cognitive impairment: involvement of the Nrf2/G6PD pathway. Metab Brain Dis 38, 2037–2053 (2023). https://doi.org/10.1007/s11011-023-01218-2

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