| Co-Investigator(Kenkyū-buntansha) |
NAGAHIRO Shinji The University of Tokushima, Institute of Health Biosciences, Professor, 大学院ヘルスバイオサイエンス研究部, 教授 (60145315)
NISHI Kyoko Tokushima University Hospital, Tokushima University Hospital, Instructor, 医学部・歯学部附属病院, 助手 (60335817)
ITABE Hiroyuki Showa University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30203079)
SUZUE Atsuhiko The University of Tokushima, Tokushima University Hospital, Instructor, 医学部・歯学部附属病院, 助手 (60346608)
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| Research Abstract |
1) We assess the availability of plasma biomarkers to monitor the brain damage and the therapeutic efficacy of edaravone. The study consisted of 51 patients with ischemic cerebral infarcts. They were divided into 2 groups; GI (n=24) had cortical lesions, GII (n=27) had lesions in the basal ganglia or brain stem. Edaravone was administered to 27 randomly selected patients (GIa, n =13; GIIa, n =14) and its efficacy was studied by comparing their plasma OxLDL-, S-100B-, and MnSOD levels to those in patients without edaravone (GIb, n=11, GII, n=13). Three days after the start of edaravone, plasma OxLDL was significantly lower in GIa-than GIb patients (0.177±0.024 ng/μg apoB vs. 0.219±0.026, p<0.05). In GII patients, pre-and post-treatment plasma OxLDL was not significantly different (0.156±0.013 vs. 0.152±0.020). In GIa patients, S-100B and MnSOD were significantly lower than in GIb patients (p<0.05). The neurological condition at the time of discharge had recovered in GIa but not GIb pati
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ents. Ours is the first evidence to confirm the efficacy of edaravone by plasma biomarkers. In patients with cortical infarcts, edaravone reduced oxidative damage, thereby limiting the degree of brain damage.
2) Candesartan, an angiotensin II (Ang II) AT1 receptor blocker (ARB), is protective against cerebral ischemia in hypertensive rats. To elucidate the blood pressure-independent mechanisms underlying this protection we used normotensive rats in our in vivo-and human umbilical endothelial cells (HUVEC) in our in vitro experiments. Wistar rats were subjected to 2-hr middle cerebral artery (MCA) occlusion-reperfusion after 2-week pretreatment with ARB (0.5 or 1 mg/kg/day). HUVEC were stimulated with an optimal concentration of candesartan with or without Ang II. In ARB-treated normotensive rats, the cortical infarct volume was decreased. This was associated with a decrease in oxidative damage and hypoxia, and an increase in the expression of eNOS protein in the cortical penumbra and of eNOS mRNA in the MCA. In HUVEC, both ARB and Ang II increased eNOS protein expression. Ang II increased intracellular ROS and NO production and led to eNOS "uncoupling" to form superoxide. While ARB inhibited these increases, it increased the extracellular NO release and the protein expression of heme oxygenase-1 in the absence and presence of Ang II, suggesting that ARB directly enhanced NO availability and anti-oxidative effects. Ours is the first documentation that ARB increases endothelial function and anti-oxidative defense system, thereby contributing to the protection of the cortical penumbra against cerebral ischemia. The improvement by ARB of post-ischemic endothelial dysfunction via blood pressure-and Ang II-independent mechanisms may represent a therapeutic means of protecting against the consequences of cerebral ischemia. Less
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