FTY720 Protects Against Ischemia–Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model

• DOI: 10.1007/s12975-020-00789-x
• Publication Date: 2020-02-27T05:23:16Z
• Authors: Zifeng Wang; Kei Higashikawa; Hironobu Yasui; Yuji Kuge; Yusuke Ohno; Akio Kihara; Yenari A. Midori; Kiyohiro Houkin; Masahito Kawabori
• Keywords: FTY720; 490; Medical Physiology; Clinical Sciences; 610; Clinical sciences; Apoptosis; Brain Ischemia; Blood–brain barrier; Brain ischemia–reperfusion; Rats, Sprague-Dawley; 03 medical and health sciences; 0302 clinical medicine; Sphingosine; Animals; Sphingosine-1-phosphate receptor; Inflammation; Tight Junction Proteins; Biomedical and Clinical Sciences; Fingolimod Hydrochloride; Neurosciences; Endothelial Cells; Organophosphates; Brain Disorders; Rats; 3. Good health; Stroke; Public Health and Health Services; Original Article; Sprague-Dawley

AbstractInjury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood–brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [18F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.