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Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia

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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.

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Acknowledgment

This study was supported by Research Grant NS086929 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA; an American Heart Association Grant-in-Aid 15GRNT25240004; and a science and technology project of Xuzhou city, Jiangsu (KC15SH093).

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Authors and Affiliations

  1. Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People’s Republic of China

    Lei Li, Rongli Yang, Pingjing Li, Hailong Lu, Jingbo Hao & Liyan Li

  2. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Donovan Tucker & Quanguang Zhang

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  1. Lei Li
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  2. Rongli Yang
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Correspondence to Quanguang Zhang.

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All animal procedures were approved by the institutional animal use committee and conformed to the local and international guidelines on the ethical use of animals.

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Lei Li and Rongli Yang contributed equally to this work.

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Li, L., Yang, R., Li, P. et al. Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia. Mol Neurobiol 55, 2042–2055 (2018). https://doi.org/10.1007/s12035-017-0470-1

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