Bicuculline and Bumetanide Attenuate Sevoflurane-Induced Impairment of Myelination and Cognition in Young Mice

Sevoflurane (Sevo) is one of the most commonly used general anesthetics for infants and young children. We investigated whether Sevo impairs neurological functions, myelination, and cognition via the γ-aminobutyric acid A receptor (GABAAR) and Na+–K+–2Cl– cotransporter (NKCC1) in neonatal mice. On p...

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Published in:ACS chemical neuroscience 2023-03, Vol.14 (6), p.1146-1155
Main Authors: Fu, Ningning, Wang, Yangyang, Zhu, Ruilou, Li, Ningning, Zeng, Shuang, Miao, Mengrong, Yang, Yitian, Sun, Mingyang, Zhang, Jiaqiang
Format: Article
Language:English
Subjects:
Anesthetics, Inhalation - toxicity
Animals
Animals, Newborn
Bicuculline - pharmacology
Bumetanide - pharmacology
Cognition
gamma-Aminobutyric Acid
Mice
Sevoflurane - pharmacology
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Summary:Sevoflurane (Sevo) is one of the most commonly used general anesthetics for infants and young children. We investigated whether Sevo impairs neurological functions, myelination, and cognition via the γ-aminobutyric acid A receptor (GABAAR) and Na+–K+–2Cl– cotransporter (NKCC1) in neonatal mice. On postnatal days 5–7, mice were exposed to 3% Sevo for 2 h. On postnatal day 14, mouse brains were dissected, and oligodendrocyte precursor cell line level lentivirus knockdown of GABRB3, immunofluorescence, and transwell migration assays were performed. Finally, behavioral tests were conducted. Multiple Sevo exposure groups exhibited increased neuronal apoptosis levels and decreased neurofilament protein levels in the mouse cortex compared with the control group. Sevo exposure inhibited the proliferation, differentiation, and migration of the oligodendrocyte precursor cells, thereby affecting their maturation process. Electron microscopy revealed that Sevo exposure reduced myelin sheath thickness. The behavioral tests showed that multiple Sevo exposures induced cognitive impairment. GABAAR and NKCC1 inhibition provided protection against Sevo-induced neurotoxicity and cognitive dysfunction. Thus, bicuculline and bumetanide can protect against Sevo-induced neuronal injury, myelination impairment, and cognitive dysfunction in neonatal mice. Furthermore, GABAAR and NKCC1 may be mediators of Sevo-induced myelination impairment and cognitive dysfunction.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.2c00764