Baicalein Alleviates Lithium-Pilocarpine-Induced Status Epilepticus by Regulating DNMT1/GABRD Pathway in Rats.

IF 1.6 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Organogenesis Pub Date : 2025-12-01 Epub Date: 2025-06-26 DOI:10.1080/15476278.2025.2519607

Zhenggang Wu, Jing Liu, Deju Yin, Jing Huang, Yujing Huang, Pengfei Wang

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引用次数: 0

Abstract

Background: Epilepsy is a common disease of the nervous system. Recent advances in epigenetics have revealed DNA methylation as a key mechanism in epilepsy pathogenesis, particularly through dysregulation of GABAergic signaling. Baicalein has been shown to have anticonvulsant and neuroprotective effects. However, its epigenetic regulatory effects on GABA receptor function remain unexplored.

Methods: The status epilepticus (SE) model was induced by lithium chloride-pilocarpine (LiCl-PILO) in Sprague-Dawley (SD) rats. The rats were divided into control group, epileptic SE group and baicalein intervention group. Morris water maze (MWM) test, Nissl staining, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) were used to detect cognitive functions and neuronal damage. Online sites, chromatin immunoprecipitation (ChIP) and western blotting were used to identify DNA methyltransferase 1 (DNMT1)-mediated methylation of gamma-aminobutyric acid type A receptor subunit delta (GABRD) promoter region.

Results: Baicalein treatment significantly prolonged the latency of SE onset and seizure onset, and improved the development of epilepsy. Meanwhile, baicalein improved the cognitive impairment in rats induced by LiCl-PILO. After treatment with baicalein, a sustained elevation in the number of neurons and NeuN levels was observed, along with a decrease in the contents of tumor necrosis factor -alpha (TNF-α), interleukin-1β (IL-1β), and ionized calcium-binding adapter molecule 1 (Iba-1) in the hippocampus. Mechanistically, baicalein interacted with DNMT1 to suppress GABRD promoter region methylation, thus increasing GABRD protein level in the hippocampus of rats induced by LiCl-PILO.

Conclusion: This study identifies DNMT1/GABRD axis as a novel epigenetic target for epilepsy intervention. Baicalein's ability to enhance tonic inhibition through demethylation of GABRD provides a groundbreaking strategy for drug-resistant epilepsy.

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黄芩苷通过调节DNMT1/GABRD通路减轻锂-匹罗卡平诱导的大鼠癫痫持续状态

背景：癫痫是一种常见的神经系统疾病。表观遗传学的最新进展表明，DNA甲基化是癫痫发病的关键机制，特别是通过gaba能信号的失调。黄芩素已被证明具有抗惊厥和神经保护作用。然而，其对GABA受体功能的表观遗传调控作用尚不清楚。方法：采用氯化锂-匹罗卡品（LiCl-PILO）诱导SD大鼠癫痫持续状态（SE）模型。将大鼠分为对照组、癫痫SE组和黄芩素干预组。Morris水迷宫（MWM）法、尼氏染色法、免疫荧光法和酶联免疫吸附法（ELISA）检测大鼠认知功能和神经元损伤。利用在线网站、染色质免疫沉淀（ChIP）和western blotting鉴定DNA甲基转移酶1 （DNMT1）介导的γ -氨基丁酸A型受体亚单位三角洲（GABRD）启动子区域甲基化。结果：黄芩苷治疗可显著延长SE发作潜伏期和癫痫发作时间，改善癫痫的发展。黄芩素对lcl - pilo所致大鼠认知功能障碍有改善作用。在黄芩素治疗后，观察到神经元数量和NeuN水平持续升高，同时海马中肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)和离子钙结合适配分子1 （Iba-1）含量降低。机制上，黄芩素与DNMT1相互作用抑制GABRD启动子区甲基化，从而增加LiCl-PILO诱导大鼠海马GABRD蛋白水平。结论：本研究确定DNMT1/GABRD轴是癫痫干预的一个新的表观遗传靶点。黄芩素通过GABRD去甲基化增强强直性抑制的能力为治疗耐药癫痫提供了一种突破性的策略。

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来源期刊

Organogenesis BIOCHEMISTRY & MOLECULAR BIOLOGY-DEVELOPMENTAL BIOLOGY

CiteScore

4.10

自引率

4.30%

发文量

审稿时长

>12 weeks

期刊介绍： Organogenesis is a peer-reviewed journal, available in print and online, that publishes significant advances on all aspects of organ development. The journal covers organogenesis in all multi-cellular organisms and also includes research into tissue engineering, artificial organs and organ substitutes. The overriding criteria for publication in Organogenesis are originality, scientific merit and general interest. The audience of the journal consists primarily of researchers and advanced students of anatomy, developmental biology and tissue engineering. The emphasis of the journal is on experimental papers (full-length and brief communications), but it will also publish reviews, hypotheses and commentaries. The Editors encourage the submission of addenda, which are essentially auto-commentaries on significant research recently published elsewhere with additional insights, new interpretations or speculations on a relevant topic. If you have interesting data or an original hypothesis about organ development or artificial organs, please send a pre-submission inquiry to the Editor-in-Chief. You will normally receive a reply within days. All manuscripts will be subjected to peer review, and accepted manuscripts will be posted to the electronic site of the journal immediately and will appear in print at the earliest opportunity thereafter.