Oncotarget

Research Papers: Pathology:

Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation

Mustafa C. Beker, Ahmet B. Caglayan, Taha Kelestemur, Berrak Caglayan, Esra Yalcin, Burak Yulug, Ulkan Kilic, Dirk M. Hermann and Ertugrul Kilic _

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Oncotarget. 2015; 6:30604-30614. https://doi.org/10.18632/oncotarget.5773

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Abstract

Mustafa C. Beker1, Ahmet B. Caglayan1, Taha Kelestemur1, Berrak Caglayan1, Esra Yalcin1, Burak Yulug2, Ulkan Kilic1, Dirk M. Hermann3 and Ertugrul Kilic1

1 Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey

2 Department of Neurology, Istanbul Medipol University, Istanbul, Turkey

3 Department of Neurology, University Hospital Essen, Essen, Germany

Correspondence to:

Ertugrul Kilic, email:

Keywords: hyperoxia, reperfusion injury, cerebral microcirculation, BBB permeability, NOS, Pathology Section

Received: August 14, 2015 Accepted: September 13, 2015 Published: September 21, 2015

Abstract

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.


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