title: Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia.
abstract: Therapeutic hypothermia (TH) is the most potent therapeutic strategy for global cerebral ischemia (GCI), usually induced by cardiac arrest. TH has been shown both to suppress the delayed neuronal cell death in the vulnerable hippocampal CA1 subregion and to improve neurological outcomes in experimental animals after GCI. However, given the multiple adverse effects resulting from TH, application of such a therapy is typically limited. In recent years, methylene blue (MB) has emerged as a potential therapeutic drug for the treatment of neurodegenerative diseases. In this study, we investigated the beneficial effects of mild TH combined with MB treatment after GCI. We report that both the neuronal survival in the hippocampal CA1 region and the hippocampus-dependent spatial learning and memory in the combined treatment animals were enhanced compared to those in the single treatment animals. Mechanistic studies revealed that combined TH and MB treatment significantly attenuated mitochondrial dysfunction induced by GCI in the hippocampus CA1 region. The combined treatment also markedly suppressed GCI-induced reactive gliosis and inflammation and reduced oxidative stress while enhancing the antioxidant capacity of hippocampal CA1 neurons. Finally, combining TH and MB synergistically attenuated the intrinsic cytochrome c/caspase-3 apoptotic pathway induced by GCI. Our results suggest that TH and MB act synergistically to protect the ischemic brain and suppress cognitive impairment caused by GCI.
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Rongli
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Pingjing
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, 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, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. qzhang@augusta.edu.
authors.forename: Quanguang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D008751:Methylene Blue / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008751:Methylene Blue
keywords: Combination treatment; Global cerebral ischemia; Hypothermia; Learning and memory; Methylene blue; Neuroprotection