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Role of GABA(A) receptor depolarization-mediated VGCC activation in sevoflurane-induced cognitive impairment in neonatal mice
BACKGROUND: In neonatal mice, anesthesia with sevoflurane depolarizes the GABA Type A receptor (GABA(A)R), which leads to cognitive impairment. Calcium accumulation in neurons can lead to neurotoxicity. Voltage-gated calcium channels (VGCCs) can increase intracellular calcium concentration under iso...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9514857/ https://www.ncbi.nlm.nih.gov/pubmed/36176629 http://dx.doi.org/10.3389/fncel.2022.964227 |
Sumario: | BACKGROUND: In neonatal mice, anesthesia with sevoflurane depolarizes the GABA Type A receptor (GABA(A)R), which leads to cognitive impairment. Calcium accumulation in neurons can lead to neurotoxicity. Voltage-gated calcium channels (VGCCs) can increase intracellular calcium concentration under isoflurane and hypoxic conditions. The underlying mechanisms remain largely unknown. METHODS: Six-day-old mice were anesthetized with 3% sevoflurane for 2 h/day for 3 days. The Y-Maze, new object recognition (NOR) test, the Barnes maze test, immunoassay, immunoblotting, the TUNEL test, and Golgi–Cox staining were used to assess cognition, calcium concentration, inflammatory response, GABA(A)R activation, VGCC expression, apoptosis, and proliferation of hippocampal nerve cells in mice and HT22 cells. RESULTS: Compared with the control group, mice in the sevoflurane group had impaired cognitive function. In the sevoflurane group, the expression of Gabrb3 and Cav1.2 in the hippocampal neurons increased (p < 0.01), the concentration of calcium ions increased (p < 0.01), inflammatory reaction and apoptosis of neurons increased (p < 0.01), the proliferation of neurons in the DG area decreased (p < 0.01), and dendritic spine density decreased (p < 0.05). However, the inhibition of Gabrb3 and Cav1.2 alleviated cognitive impairment and reduced neurotoxicity. CONCLUSIONS: Sevoflurane activates VGCCs by inducing GABA(A)R depolarization, resulting in cognitive impairment. Activated VGCCs cause an increase in intracellular calcium concentration and an inflammatory response, resulting in neurotoxicity and cognitive impairment. |
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