抑制组蛋白去乙酰化酶6活性通过调节焦亡和自噬途径减轻脑室内出血后的神经损伤和出血性脑积水。

IF 5.9 1区 医学 Q1 NEUROSCIENCES
Hao-Xiang Wang, Zi-Ang Deng, Yuan-You Li, Jun Li, Ya-Xing Chen, Yan-Jie Zhao, Ke-Ru Huang, Wei-Ning Tian, Ai-Ping Tong, Liang-Xue Zhou
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引用次数: 0

摘要

背景:出血性脑积水(PHH)是影响脑室内出血(IVH)患者预后的一种常见且重要的并发症。然而,潜在的机制是不确定的。神经元焦亡的特征是神经元的溶解和破坏,并伴有炎症因子的释放。已知自噬可以抑制炎症,组蛋白去乙酰酶-6 (HDAC6)参与自噬和NLRP3炎症小体的调节。然而,这些蛋白在IVH模型中调控神经元焦亡的作用尚未确定。方法:采用40 μ L/只的自体血脑室灌注法,建立IVH小鼠(6-8周)模型。手术后,我们在不同时间点监测小鼠,通过MRI评估心室大小。此外,在术后急性期(3天)和慢性期(28天),我们使用HE染色、尼氏染色、扫描电镜和行为实验(如神经功能评分和水迷宫测试)检查神经元细胞损伤和心室纤毛以及神经功能。最后,我们通过免疫印迹和免疫荧光染色检测焦亡和自噬途径的激活情况。结果:自噬诱导能减轻急性期自体血液注射引起的脑神经细胞焦亡。HDAC6通过影响核因子κ b (NF-κB)的转录,参与调控IVH急性期的焦亡。此外,HDAC6调节IVH慢性期神经元过度的自噬激活。立可立他治疗可改善IVH急性期的神经功能缺损和心室损伤。此外,它减轻了IVH慢性期的情绪、记忆和学习缺陷,同时也改善了PHH。结论:在IVH急性期,自噬增强可减弱nod样受体蛋白3 (NLRP3)炎性体的激活,抑制神经元焦亡。HDAC6在调节自噬与焦亡相互作用中起重要作用。立立司他治疗显著减轻IVH急性期炎症因子上调和焦亡引起的神经损伤。此外,立柯碱他能有效地减少神经元在慢慢期过度的自噬和凋亡,减弱PHH的形成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of histone deacetylase 6 activity mitigates neurological impairment and post-hemorrhagic hydrocephalus after intraventricular hemorrhage by modulating pyroptosis and autophagy pathways.

Background: Posthemorrhagic hydrocephalus (PHH) is a frequent and significant complication that impacts the prognosis of patients suffering from intraventricular hemorrhage (IVH). However, the underlying mechanism is uncertain. Neuronal pyroptosis is characterized by neuronal lysis and destruction, along with the release of inflammatory factors. Autophagy is known to inhibit inflammation, and histone deacetylase-6 (HDAC6) is implicated in the regulation of both autophagy and the NLRP3 inflammasome. However, the role of these proteins in the regulation of neuronal pyroptosis in an IVH model has not been determined.

Methods: In this study, an IVH mouse (6-8 weeks) model was generated via the intracerebroventricular administration of autologous blood at a volume of 40 µL/animal. After the surgical operation, we monitored the mice at various time points, assessing ventricle size via MRI. Additionally, during both the acute (3 days) and chronic (28 days) phases post-surgery, we examined neuronal cell damage and ventricular cilia, as well as neurological function, using HE staining, Nissl staining, scanning electron microscopy, and behavioral experiments such as neurological function scoring and water maze tests. Finally, we detected activation of the pyroptosis and autophagy pathway through western blotting and immunofluorescence staining.

Results: Autophagy induction attenuated cerebral neuronal pyroptosis caused by acute-phase autologous blood injection. HDAC6 was implicated in regulating pyroptosis in the acute phase IVH through its influence on the transcription of nuclear factor kappa-B (NF-κB). Furthermore, HDAC6 regulates excessive autophagic activation in neurons in the chronic phase of IVH. Treatment with ricolinostat improved neurological deficits and ventricular damage during the acute phase of IVH. Moreover, it alleviated mood, memory, and learning deficits in the chronic phase of IVH while also improving PHH.

Conclusions: Enhanced autophagy attenuates activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and inhibits neuronal pyroptosis in the acute phase of IVH. HDAC6 plays an important role in regulating the interaction between autophagy and pyroptosis. Ricolinostat treatment significantly attenuated the upregulation of inflammatory factors and neurological impairments induced by pyroptosis in the acute phase of IVH. In addition, ricolinostat effectively reduced excessive autophagy and apoptosis in neurons in the chronic phase and attenuated the formation of PHH.

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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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