Wang Hao-Kuang, Su Yu-Ting, Ho Yu-Cheng, Lee Yung-Kuo, Chu Tian-Huei, Chen Kuang-Ti, Wu Cheng-Chun
Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City, Taiwan.
School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, Taiwan.
J Inflamm Res. 2023 Sep 18;16:4103-4116. doi: 10.2147/JIR.S416239. eCollection 2023.
Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood-brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown.
The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury.
The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia.
HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.
中风是全球致残和致死的常见原因；然而，有效的治疗方法仍然有限。在中风发病机制中，缺血/再灌注损伤引发胶质细胞增生和神经炎症，进而激活基质金属蛋白酶（MMPs），从而破坏血脑屏障（BBB）。血脑屏障通透性增加会促进巨噬细胞浸润和脑水肿，进而恶化行为结果和预后。组蛋白去乙酰化酶1（HDAC1）是表观基因组基因转录的抑制因子，参与DNA损伤和细胞周期调控。尽管中风后HDAC1失调并参与神经元丢失和DNA修复，但其在神经炎症和血脑屏障损伤中的作用仍不清楚。
通过使用内皮素-1诱导的大鼠脑缺血/再灌注损伤模型，评估脑缺血大鼠的行为结果、胶质细胞增生中的炎症水平和细胞因子，以及血脑屏障损伤情况。
结果显示，HDAC1功能障碍可通过破坏紧密连接蛋白（如ZO-1和闭合蛋白）促进大鼠中风后血脑屏障损伤。抑制HDAC1还会增加星形胶质细胞和小胶质细胞胶质增生、肿瘤坏死因子-α、白细胞介素-1β、乳酸脱氢酶和活性氧的水平，进一步触发MMP-2和MMP-9的活性。此外，圆柱体试验的改良神经功能严重程度评分显示，抑制HDAC1会使脑缺血大鼠的行为结果恶化。
HDAC1在缺血/再灌注诱导的神经炎症和血脑屏障损伤中起关键作用，因此表明其作为治疗靶点的潜力。
