Mišir Mihael, Renić Marija, Novak Sanja, Mihalj Martina, Ćosić Anita, Vesel Monika, Drenjančević Ines
Clinical Hospital Center Osijek, Neurology Clinic, Osijek, Croatia.
University Josip Juraj Strossmayer Osijek, Faculty of Medicine Osijek, Department of Physiology and Immunology, Laboratory for Circulatory Physiology, Osijek, Croatia.
Exp Physiol. 2017 Dec 1;102(12):1596-1606. doi: 10.1113/EP086402. Epub 2017 Nov 2.
What is the central question of this study? Is there a beneficial effect and what are the mechanisms of acute and multiple hyperbaric oxygenation (HBO ) exposures on the outcome of cerebral tissue injury induced by a transient middle cerebral artery occlusion model in diabetic female rats? Are 20-hydroxyeicosatetreanoic acid and epoxyeicosatrienoic acids involved? What is the main finding and its importance? Equal reduction of cortical and total infarct size in rats treated with HBO and HET0016 (20-hydroxyeicosatetreanoic acid production inhibitor) and significant mRNA upregulation of epoxyeicosatrienoic acid-producing enzymes (Cyp2J3 and Cyp2C11) in treated groups suggest that HBO and HET0016 are highly effective stroke treatments and that cytochrome P450 metabolites are involved in this therapeutic effect. We evaluated the effects of acute and repetitive hyperbaric oxygenation (HBO ), 20-hydroxyeicosatetreanoic acid (20-HETE) inhibition by N-hydroxy-N'-(4-butyl-2methylphenyl)-formamidine (HET0016) and their combination on experimental stroke outcomes. Streptozotocin-induced type 1 diabetic Sprague-Dawley female rats (n = 42; n = 7 per group), were subjected to 30 min of transient middle cerebral artery occlusion (t-MCAO)-reperfusion and divided into the following groups: (1) control group, without treatment; and groups exposed to: (2) HBO ; (3) multiple HBO (HBO immediately and second exposure 12 h after t-MCAO); (4) HET0016 pretreatment (1 mg kg , 3 days before t-MCAO) combined with HBO after t-MCAO; (5) HET0016 treatment (1 h before, during and for 6 h after t-MCAO); and (6) HET0016 treatment followed by HBO after t-MCAO. Messenger RNA expression of CYP2J3, CYP2C11, CYP4A1, endothelial nitric oxide synthase and epoxide hydrolase 2 was determined by real-time qPCR. Cortical infarct size and total infarct size were equally and significantly reduced in HBO - and HET0016-treated rats. Combined treatment with HET0016 and HBO provided no significant additive effect compared with HET0016 treatment only. Messenger RNA of Cyp2J3 was significantly increased in all study groups, and mRNA of Cyp2C11 was significantly increased in the multiple HBO group and the HET0016 treatment followed by HBO group, compared with the control group. Expression of endothelial nitric oxide synthase was significantly increased after HBO treatments, and expression of epoxide hydrolase 2 was increased in all groups compared with the control group. In diabetic female Sprague-Dawley rats, HBO and HET0016 are highly effective stroke treatments, suggesting the involvement of cytochrome P450 metabolites and the NO pathway in this therapeutic effect.
本研究的核心问题是什么？急性和多次高压氧（HBO）暴露对糖尿病雌性大鼠大脑中动脉短暂闭塞模型所致脑组织损伤的结果是否有有益作用及作用机制是什么？20-羟基二十碳四烯酸和环氧二十碳三烯酸是否参与其中？主要发现及其重要性是什么？用HBO和HET0016（20-羟基二十碳四烯酸生成抑制剂）治疗的大鼠皮质梗死灶大小和总梗死灶大小均等量减少，且治疗组中环氧二十碳三烯酸生成酶（Cyp2J3和Cyp2C11）的mRNA显著上调，这表明HBO和HET0016是非常有效的中风治疗方法，且细胞色素P450代谢产物参与了这种治疗作用。我们评估了急性和重复性高压氧（HBO）、用N-羟基-N'-（4-丁基-2-甲基苯基）甲脒（HET0016）抑制20-羟基二十碳四烯酸（20-HETE）及其联合应用对实验性中风结果的影响。用链脲佐菌素诱导1型糖尿病的斯普拉格-道利雌性大鼠（n = 42；每组n = 7），进行30分钟大脑中动脉短暂闭塞（t-MCAO）-再灌注，并分为以下几组：（1）对照组，未治疗；以及暴露于以下情况的组：（2）HBO；（3）多次HBO（t-MCAO后立即进行HBO，第二次暴露在t-MCAO后12小时）；（4）HET0016预处理（1mg/kg，在t-MCAO前3天）联合t-MCAO后的HBO；（5）HET0016治疗（t-MCAO前1小时、期间及t-MCAO后6小时）；以及（6）t-MCAO后先进行HET0016治疗然后进行HBO。通过实时定量PCR测定CYP2J3、CYP2C11、CYP4A1、内皮型一氧化氮合酶和环氧水解酶2的信使核糖核酸表达。HBO和HET0016治疗的大鼠皮质梗死灶大小和总梗死灶大小均等量且显著减少。与仅用HET0016治疗相比，HET0016和HBO联合治疗未提供显著的相加效应。与对照组相比，所有研究组中Cyp2J3的信使核糖核酸均显著增加，多次HBO组以及t-MCAO后先进行HET0016治疗然后进行HBO组中Cyp2C11的信使核糖核酸显著增加。HBO治疗后内皮型一氧化氮合酶的表达显著增加，与对照组相比，所有组中环氧水解酶2的表达均增加。在糖尿病雌性斯普拉格-道利大鼠中，HBO和HET0016是非常有效的中风治疗方法，这表明细胞色素P450代谢产物和NO途径参与了这种治疗作用。
