Beker Mustafa C, Caglayan Ahmet B, Kelestemur Taha, Caglayan Berrak, Yalcin Esra, Yulug Burak, Kilic Ulkan, Hermann Dirk M, Kilic Ertugrul
Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
Department of Neurology, Istanbul Medipol University, Istanbul, Turkey.
Oncotarget. 2015 Oct 13;6(31):30604-14. doi: 10.18632/oncotarget.5773.
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.
为了在不可逆损伤发生前保护大脑，半暗带氧合是当前急性缺血性脑卒中治疗的首要目标。然而，由于存在自由基生成和血管收缩的风险，高氧治疗仍存在争议。褪黑素是一种高效的自由基清除剂，可预防缺血性脑卒中。考虑到其抗氧化活性，我们推测褪黑素可能增强常压氧（NBO）的促存活作用并预防脑梗死。在此，我们将小鼠暴露于管腔内大脑中动脉闭塞（MCAo）30或90分钟，并评估单独或与褪黑素（4mg/kg，腹腔注射）联合给予NBO（90分钟内70%或100%）对弥漫性神经元损伤、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尤其是单独的褪黑素均可减少神经元损伤、神经功能缺损、梗死体积和BBB通透性，并增加缺血后CBF。它们还显著改善了缺血核心区和半暗带的CBF，这与IgG外渗减少、DNA片段化、梗死体积、脑肿胀和神经评分降低相关。联合给予氧气和褪黑素后，磷酸化Akt、抗凋亡蛋白Bcl-xL、促凋亡蛋白Bax和内皮型一氧化氮合酶（NOS）的水平得到重新调节，而经氧气治疗后升高的神经元型和诱导型NOS不受褪黑素影响。我们目前的数据表明，褪黑素和NBO是治疗急性缺血性脑卒中的有前景的方法，这鼓励在人类脑卒中患者中进行概念验证研究。
