title: Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation.
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.
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Mustafa C
authors.initials: MC
authors.lastname: Beker
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Ahmet B
authors.initials: AB
authors.lastname: Caglayan
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Taha
authors.initials: T
authors.lastname: Kelestemur
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Berrak
authors.initials: B
authors.lastname: Caglayan
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Yalcin
authors.affiliation: Department of Neurology, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Yulug
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.affiliation: Department of Neurology, University Hospital Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Department of Physiology and Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000628:therapy*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000097:blood; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020521:Stroke / Q000628:therapy*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D016166:Free Radical Scavengers; D007074:Immunoglobulin G; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin; D010100:Oxygen
keywords: BBB permeability; NOS; Pathology Section; cerebral microcirculation; hyperoxia; reperfusion injury