title: The Effects of Methylene Blue on Autophagy and Apoptosis in MRI-Defined Normal Tissue, Ischemic Penumbra and Ischemic Core.
abstract: Methylene blue (MB) USP, which has energy-enhancing and antioxidant properties, is currently used to treat methemoglobinemia and cyanide poisoning in humans. We recently showed that MB administration reduces infarct volume and behavioral deficits in rat models of ischemic stroke and traumatic brain injury. This study reports the underlying molecular mechanisms of MB neuroprotection following transient ischemic stroke in rats. Rats were subjected to transient (60-mins) ischemic stroke. Multimodal MRI during the acute phase and at 24 hrs were used to define three regions of interest (ROIs): i) the perfusion-diffusion mismatch salvaged by reperfusion, ii) the perfusion-diffusion mismatch not salvaged by reperfusion, and iii) the ischemic core. The tissues from these ROIs were extracted for western blot analyses of autophagic and apoptotic markers. The major findings were: 1) MB treatment reduced infarct volume and behavioral deficits, 2) MB improved cerebral blood flow to the perfusion-diffusion mismatch tissue after reperfusion and minimized harmful hyperperfusion 24 hrs after stroke, 3) MB inhibited apoptosis and enhanced autophagy in the perfusion-diffusion mismatch, 4) MB inhibited apoptotic signaling cascades (p53-Bax-Bcl2-Caspase3), and 5) MB enhanced autophagic signaling cascades (p53-AMPK-TSC2-mTOR). MB induced neuroprotection, at least in part, by enhancing autophagy and reducing apoptosis in the perfusion-diffusion mismatch tissue following ischemic stroke.
authors.affiliation: Department of Anatomy and Embryology, Peking University Health Science Center, Beijing, China; Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Lora Talley
authors.initials: LT
authors.lastname: Watts
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Pavel
authors.initials: P
authors.lastname: Rodriguez
authors.affiliation: Department of Anatomy and Embryology, Peking University Health Science Center, Beijing, China; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Anatomy and Embryology, Peking University Health Science Center, Beijing, China.
authors.forename: Changman
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Timothy Q
authors.initials: TQ
authors.lastname: Duong
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D020520:Brain Infarction / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000263:Adenylate Kinase; D008751:Methylene Blue