Division of Immunopathology of the Nervous System, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany.
J Neuropathol Exp Neurol. 2013 Mar;72(3):178-85. doi: 10.1097/NEN.0b013e318283114a.
Alzheimer disease is the most common neurodegenerative disease and the major cause of dementia. In addition to β-amyloid aggregation and hyperphosphorylated tau, neuroinflammation also plays important roles in the pathophysiology of this multifactorial disorder. Histone deacetylase catalyzes deacetylation of histones and has important roles in the regulation of gene expression. Histone deacetylase inhibitors have been reported to exhibit neuroprotective and anti-neuroinflammatory activities and have therapeutic effects in several animal models of neurodegenerative diseases. Here, an efficient benzamide histone deacetylase inhibitor, MS-275, was orally administered by gavage to transgenic APP/PS1 mice, an animal model of cerebral amyloidosis for Alzheimer disease. After 10 days of treatment, MS-275 significantly ameliorated microglial activation and β-amyloid deposition in cerebral cortex and/or hippocampus. This was associated with improved nesting behavior, an important affiliative/social behavior. MS-275 also attenuated inflammatory activation of a mouse macrophage cell line in vitro. These results suggest that MS-275 may be a therapeutic option for Alzheimer disease and other neuroinflammatory diseases.
阿尔茨海默病是最常见的神经退行性疾病，也是痴呆症的主要病因。除了β-淀粉样蛋白聚集和过度磷酸化的 tau 外，神经炎症在这种多因素疾病的病理生理学中也起着重要作用。组蛋白去乙酰化酶催化组蛋白的去乙酰化，在基因表达的调控中具有重要作用。组蛋白去乙酰化酶抑制剂已被报道具有神经保护和抗神经炎症活性，并在几种神经退行性疾病的动物模型中具有治疗效果。在这里，一种有效的苯甲酰胺组蛋白去乙酰化酶抑制剂 MS-275 通过灌胃给予阿尔茨海默病的脑淀粉样变性动物模型 APP/PS1 转基因小鼠。经过 10 天的治疗，MS-275 显著改善了大脑皮层和/或海马中的小胶质细胞激活和β-淀粉样蛋白沉积。这与改善筑巢行为有关，筑巢行为是一种重要的亲和/社交行为。MS-275 还减弱了体外小鼠巨噬细胞系的炎症激活。这些结果表明，MS-275 可能是治疗阿尔茨海默病和其他神经炎症性疾病的一种选择。
