Sevoflurane suppresses ALG13 transcription in a CREBBP-dependent manner to induce hippocampal damage and cognitive impairment

Abstract

BackgroundSevoflurane (Sev) is a common clinical anesthetic but may lead to cognitive impairment. This study aims to deconstruct the underpinning molecular mechanism involved in Sev-induced neurological damage. MethodsBioinformatics analyses was conducted to investigate candidate cognitive impairment-related physiological targets of Sev. C57BL/6 mice and SH-SY5Y cells were exposed to Sev to generate animal and cellular models, respectively. Neurological impairment in mice was evaluated by Morris water maze test, modified Longa scoring, and pathological changes and cell apoptosis in the hippocampal tissues. In vitro, viability, apoptosis, and inflammatory cytokine concentration in SH-SY5Y cells were measured. Gain- or loss-of-function studies of CREB binding protein (CREBBP) and its predicted target asparagine-linked glycosylation 13 (ALG13) were performed in mice and in SH-SY5Y cells to investigate their roles in neural damage. ResultsSev treatment induced neurological deficit in mice and damage on SH-SY5Y cells, and it reduced protein level of CREBBP in both models. CREBBP overexpression restored learning and memory ability of mice, reduced neurological deficit score, and reduced cell apoptosis while enhancing neuronal viability in the hippocampus. In vitro, the CREBBP overexpression increased viability while suppressing apoptosis and inflammation in SH-SY5Y cells. CREBBP bound to the ALG13 promoter to increase its transcription. Further knockdown of ALG13 negated the neuro-protective functions of CREBBP in vivo and in vitro. ConclusionThis study demonstrates that Sev targets CREBBP to inhibit ALG13 transcription to induce hippocampal damage and cognitive impairment.