Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation.
Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation.
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DOI：
10.18632/oncotarget.5773
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Kilic E
中科院分区：
文献类型：
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作者：
Beker MC;Caglayan AB;Kelestemur T;Caglayan B;Yalcin E;Yulug B;Kilic U;Hermann DM;Kilic E
为了在不可逆损伤发生前保护大脑，半脑氧合是目前急性缺血性脑卒中治疗的首要目标。然而，由于自由基生成和血管收缩的风险，高氧治疗仍然存在争议。褪黑素是一种非常有效的自由基清除剂，可以防止缺血性中风。考虑到其抗氧化活性，我们假设褪黑素可能增强正压氧（NBO）的促生存作用并预防脑梗死。在此，我们将小鼠暴露于腔内大脑中动脉闭塞（MCAo） 30或90分钟，并评估NBO（在90分钟内70%或100%）单独或与褪黑素（4 mg/kg, i.p）联合使用对播散性神经元损伤、神经功能缺损、梗死体积、血脑屏障（BBB）通透性、脑血流量（CBF）和细胞信号传导的影响。通过激光散斑成像（LSI）评估，NBO和褪黑素单独治疗均可减少神经元损伤、神经功能缺损、梗死体积和血脑屏障通透性，并增加缺血后脑血流。它们还显著改善了缺血核心和半暗带的CBF，这与IgG外渗、DNA碎片、梗死体积、脑肿胀和神经学评分降低有关。磷酸化Akt、抗凋亡Bcl-xL、促凋亡Bax和内皮型一氧化氮合酶（NOS）的水平在氧和褪黑激素联合递送后被重新调节，而神经元和诱导型一氧化氮合酶（NOS）在氧处理后升高，不受褪黑激素的影响。我们目前的数据表明，褪黑素和NBO是治疗急性缺血性卒中的有希望的方法，这鼓励在人类卒中患者中进行概念验证研究。
In order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti-oxidant activity, we hypothesized that melatonin may augment the survival-promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic- core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients.