title: Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.
abstract: The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yan
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Shaowu
authors.initials: S
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. florayuan@vip.sina.com.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. florayuan@vip.sina.com.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. florayuan@vip.sina.com.|Department of Pathophysiology, Beijing Neurosurgical Institute, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China. florayuan@vip.sina.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. shaohua.yang@unthsc.edu.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. shaohua.yang@unthsc.edu.|China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. shaohua.yang@unthsc.edu.|Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. shaohua.yang@unthsc.edu.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000648:ultrastructure; D001929:Brain Edema / Q000000981:diagnostic imaging* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000000981:diagnostic imaging*; D002546:Ischemic Attack, Transient / Q000000981:diagnostic imaging*; D008279:Magnetic Resonance Imaging; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000000981:diagnostic imaging*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D008751:Methylene Blue
keywords: Brain edema; Ischemia; Magnetic resonance imaging; Methylene blue; Stroke; Transmission electron microscopy