2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke

Sounds useful, which stroke associations are going to fail by not pursuing human clinical trials?
http://www.sciencedirect.com/science/article/pii/S0006295213007491

acute ischemic stroke

• Chang-Ming Chern^{d, 1},
• Yea-Hwey Wang^{e, 1},
• Kuo-Tong Liou^{f, 1},
• Yu-Chang Hou^{g, h, 1},
• Chien-Chih Chen^{c, 1},
• Yuh-Chiang Shen^{a, b, e, 1, ,}

• ^a Institute of Biomedical Sciences, College of Life Science, National Chung-hsing University, Taichung, Taiwan
• ^b National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan
• ^c Departments of Biotechnology, College of Medicine and Nursing, Hung-kuang University, Taichung, Taiwan
• ^d Stroke and Neurovascular Disease Center, Section of Cerebrovascular Disease, Department of Neurology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan
• ^e National Taipei University of Nursing and Health Science
• ^f Department of Martial Arts, Chinese Culture University, Taipei, Taiwan
• ^g Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan
• ^h Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan

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Abstract

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischaemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10∼100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.