Journal of Inflammation Research (Sep 2023)
HDAC1 is Involved in Neuroinflammation and Blood-Brain Barrier Damage in Stroke Pathogenesis
Abstract
Hao-Kuang Wang,1– 3 Yu-Ting Su,4 Yu-Cheng Ho,3,5 Yung-Kuo Lee,6 Tian-Huei Chu,6 Kuang-Ti Chen,7 Cheng-Chun Wu3,5 1Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City, Taiwan; 2School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 3Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 4Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, Taiwan; 5School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 6Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan; 7Department of Veterinary Medicine, Nation Chung-Hsing University, Taichung City, TaiwanCorrespondence: Cheng-Chun Wu, School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan, Tel +886-7-6151100-7961, Fax +886-7-6155150, Email [email protected]: 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.Methods: 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.Results: 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.Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.Keywords: HDAC1, stroke, blood-brain barrier, TNF-α, IL-1β, ROS, mNSS, cylinder test
