title: Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice.
abstract: We have recently shown that melatonin decreases the late (24 hr) increase in blood-brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.
authors.affiliation: Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery and Institute of Biomedical Engineering, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan.
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lee
authors.forename: Shur-Tzu
authors.initials: ST
authors.lastname: Chen
authors.forename: Yun-Shang
authors.initials: YS
authors.lastname: Hsu
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Kuo
authors.forename: Guan-Liang
authors.initials: GL
authors.lastname: Chang
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: E-Jian
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply; D005070:Evans Blue / Q000493:pharmacokinetics; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D005070:Evans Blue; D008550:Melatonin