Soluble epoxide hydrolase inhibition enhances anti-inflammatory and antioxidative processes, modulates microglia polarization, and promotes recovery after ischemic stroke

Abstract

Chien-Fu Yeh,1–3,* Tung‐Yueh Chuang,4,* Yu-Wen Hung,5 Ming-Ying Lan,2,3 Ching-Han Tsai,4 Hao-Xiang Huang,4 Yung-Yang Lin1,4,6–8 1Institute of Brain Science, National Yang-Ming University, Taipei 11221, Taiwan; 2Department of Otorhinolaryngology, National Yang-Ming University, Taipei 11221, Taiwan; 3Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan; 4Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; 5Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; 6Institute of Physiology, National Yang-Ming University, Taipei 11221, Taiwan; 7Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan; 8Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan*These authors contributed equally to this workCorrespondence: Yung-Yang LinDepartment of Critical Care Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei 11217, TaiwanTel [phone]Fax [phone]Email [email protected]: Ischemic stroke triggers inflammatory responses and oxidative stress in the brain, and microglia polarization affects the degree of neuroinflammation. It has been reported that the inhibition of soluble epoxide hydrolase (sEH) activity protects brain tissue. However, the anti-inflammatory and antioxidative effects of sEH inhibition in the ischemic brain are not fully understood. This study aimed to investigate the effects of a selective sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), after ischemic stroke.Methods: Adult male rats with middle cerebral artery occlusion (MCAO) were administered with AUDA or a vehicle. Behavioral outcome, infarct volume, microglia polarization, and gene expression were assessed.Results: Rats treated with AUDA showed better behavioral outcomes and smaller infarct volumes after MCAO. After AUDA treatment, a reduction of M1 microglia and an increase of M2 microglia occurred at the ischemic cortex of rats. Additionally, there was an increase in the mRNA expressions of antioxidant enzymes and anti-inflammatory interleukin-10, and pro-inflammatory mediators were decreased after AUDA administration. Heme oxygenase-1 was mainly expressed by neurons, and AUDA was found to improve the survival of neurons.Conclusion: The results of this study provided novel and significant insights into how AUDA can improve outcomes and modulate inflammation and oxidative stress after ischemic stroke.Keywords: ischemic stroke, microglia polarization, middle cerebral artery occlusion, soluble epoxide hydrolase, anti-inflammation, antioxidant

Keywords

• ischemic stroke
• microglia polarization
• middle cerebral artery occlusion
• soluble epoxide hydrolase
• anti-inflammation
• antioxidant