Sevoflurane-induced cognitive dysfunction in aged mice mediated by HDAC8-dependent suppression of adult hippocampal neurogenesis via the pCREB/BDNF pathway

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-08-05 DOI:10.1016/j.brainresbull.2025.111497

Yingxue He , Yanjing Guo , Xiaowei Li , Jiangnan Wu , Zunsai Feng , Gongming Wang , Mengyuan Zhang

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引用次数: 0

Abstract

Sevoflurane is a widely used anesthetic in elderly patients and has been linked to postoperative cognitive dysfunction; however, its molecular mechanisms remain unclear. Inhibition of adult hippocampal neurogenesis (AHN) and epigenetic alterations, particularly via histone deacetylase 8 (HDAC8), have emerged as potential contributors to these deficits. Using young and aged C57BL/6 J male mice exposed to varying sevoflurane concentrations, we evaluated cognitive function and AHN. High-concentration (3 %) sevoflurane impaired both cognition and AHN in aged mice, correlating with reduced histone acetylation, increased HDAC8 expression, and diminished pCREB/BDNF signaling. Notably, HDAC8 inhibition with PCI-34051 or direct BDNF administration reversed these effects, while HDAC8 overexpression recapitulated the deficits. These findings suggest that HDAC8 upregulation is a key mediator of sevoflurane-induced cognitive decline via AHN suppression, highlighting a promising therapeutic target for anesthesia-related neurotoxicity.

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通过pCREB/BDNF通路抑制hdac8依赖性成年海马神经发生介导的七氟醚诱导的老年小鼠认知功能障碍

七氟醚是一种广泛用于老年患者的麻醉剂，与术后认知功能障碍有关；然而，其分子机制尚不清楚。抑制成年海马神经发生（AHN）和表观遗传改变，特别是通过组蛋白去乙酰化酶8 (HDAC8)，已经成为这些缺陷的潜在因素。使用暴露于不同七氟醚浓度的年轻和老年C57BL/6J雄性小鼠，我们评估了认知功能和AHN。高浓度（3%）七氟醚损害老年小鼠的认知和AHN，与组蛋白乙酰化降低、HDAC8表达增加和pCREB/BDNF信号传导减少相关。值得注意的是，用PCI-34051抑制HDAC8或直接给药BDNF逆转了这些作用，而HDAC8过表达再现了缺陷。这些研究结果表明，HDAC8上调是七氟醚通过AHN抑制诱导的认知能力下降的关键介质，突出了麻醉相关神经毒性的有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.