抑制HDAC6增强过氧化物还蛋白1乙酰化以减轻局灶性皮质发育不良的氧化应激和癫痫发作活动。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2025-06-30 DOI:10.1016/j.expneurol.2025.115367

Sonali Kumar , Ozasvi R. Shanker , Sreestha Dinesh Parambath , Jyotirmoy Banerjee , Manjari Tripathi , P. Sarat Chandra , M.C. Sharma , Sanjeev Lalwani , Fouzia Siraj , Aparna Banerjee Dixit

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引用次数: 0

摘要

背景：局灶性皮质发育不良（FCD）是耐药癫痫（DRE）最常见的病因之一，其特征是皮质畸形和分子失调。尽管在分类和手术干预方面取得了进展，但其背后的病理生理学仍不清楚，非手术治疗选择仍然有限。由活性氧（ROS）和抗氧化防御失衡引起的氧化应激参与了FCD的病理生理过程。本研究评估了组蛋白去乙酰化酶6 （HDAC6）通过过氧化氧还蛋白-1 （Prdx1）的乙酰化状态来调节氧化应激和癫痫发作活动的作用，Prdx1是一种关键的抗氧化酶。方法：采用qRT-PCR、免疫印迹和免疫共沉淀法对FCD II型患者和BCNU模型大鼠皮质样品进行分析，评估HDAC6的表达和Prdx1的乙酰化状态。采用双醋酸二氯荧光素（DCFDA）法测定ROS水平。研究了Tubastatin A （TubA）对氧化应激、Prdx1乙酰化和匹罗卡平诱导的癫痫发作活性的药理抑制作用。结果：hdac - 6在FCDⅱ型组织和BCNU大鼠皮质样品中表达显著上调。HDAC6活性的增加降低了Prdx1乙酰化，导致ROS水平升高和氧化应激。在BCNU模型中，TubA治疗恢复Prdx1乙酰化，降低氧化应激，并显著降低癫痫发作频率和增加癫痫发作潜伏期。结论：本研究确定HDAC6通过Prdx1去乙酰化在FCD中作为氧化应激和癫痫发生的关键调节因子。通过恢复抗氧化防御和减轻癫痫发作活动，药物抑制HDAC6为fcd相关癫痫的治疗提供了一种很有前景的治疗策略。需要进一步的研究来探索其临床潜力。

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HDAC6 inhibition enhances peroxiredoxin 1 acetylation to mitigate oxidative stress and seizure activity in focal cortical dysplasia

Background

Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy (DRE) which is characterized by malformations of the cortex and molecular dysregulation. Despite advancements in classification and surgical interventions the pathophysiology behind it remains unclear and non-surgical treatment options remain limited. Oxidative stress, induced by imbalances of reactive oxygen species (ROS) and antioxidant defences, has been involved in the pathophysiology of FCD. This study evaluates the role of histone deacetylase 6 (HDAC6) in modulating oxidative stress and seizure activity through the acetylation status of peroxiredoxin-1 (Prdx1), a key antioxidant enzyme.

Methods

Cortical samples from FCD Type II patients and BCNU rat model were analysed using qRT-PCR, immunoblotting, and co-immunoprecipitation to assess the expression of HDAC6, and acetylation status of Prdx1. ROS levels were measured using dichlorofluorescin diacetate (DCFDA) assay. Pharmacological inhibition of HDAC6 using Tubastatin A (TubA) was evaluated for its effects on oxidative stress, Prdx1 acetylation, and seizure activity induced by pilocarpine.

Results

HDAC6 was found to be significantly upregulated in the cortical samples from FCD Type II tissues and BCNU rats. Increased HDAC6 activity reduced Prdx1 acetylation, leading to elevated ROS levels and oxidative stress. TubA treatment restored Prdx1 acetylation, reduced oxidative stress, and significantly decreased seizure frequency and increased seizure latency in the BCNU model.

Conclusion

This study identifies HDAC6 as a key regulator of oxidative stress and epileptogenesis in FCD through Prdx1 deacetylation. Pharmacological inhibition of HDAC6 offers a promising therapeutic strategy for managing FCD-associated epilepsy by restoring antioxidant defences and mitigating seizure activity. Further studies are warranted to explore its clinical potential.

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.