title: Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice.
abstract: Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood-brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P < 0.001). Additionally, we found that at 6 hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction (P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation (P < 0.05), and the event was effectively reversed by co-treatment with melatonin (P < 0.05). Thus, melatonin improved postischemic preservation of the BBB permeability and a decreased risk of adverse hemorrhagic transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients.
authors.affiliation: Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan.
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lee
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Kuo
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
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 / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D020300:Intracranial Hemorrhages / Q000517:prevention & control*; D002546:Ischemic Attack, Transient / Q000188:drug therapy; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010539:Permeability / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D010959:Tissue Plasminogen Activator; D008550:Melatonin