title: Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia.
abstract: Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a four-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in the hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in the CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, caspase-8, and caspase-9 activities and the increased numbers of TUNEL-positive cells of the CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI was significantly improved in the MB-treatment group compared to the ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regent University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regent University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors.forename: Donovan
authors.initials: D
authors.lastname: Tucker
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regent University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regent University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors.forename: Ningjun
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regent University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA. qzhang@gru.edu.
authors.forename: Quanguang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D008751:Methylene Blue / Q000494:pharmacology / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D003576:Electron Transport Complex IV; D020169:Caspases; D008751:Methylene Blue
keywords: Functional improvement; Global cerebral ischemia; Methylene blue; Mitochondria; Neuroprotection