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首页> 外文期刊>Neurobiology of Aging: Experimental and Clinical Research >Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging
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Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging

机译：新型铁螯合剂-大脑选择性单胺氧化酶-A /单胺氧化酶-B抑制剂在帕金森氏病和衰老动物模型中的神经保护和神经修复活性

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Recently, we have designed and synthesized a novel multipotent, brain-permeable iron-chelating drug, VAR10303 (VAR), possessing both propargyl and monoamine oxidase (MAO) inhibitory moieties. The present study was undertaken to determine the multiple pharmacological activities of VAR in neurodegenerative preclinical models. We demonstrate that VAR affords iron chelating/iron-induced lipid-peroxidation inhibitory potency and brain selective MAO-A and MAO-B inhibitory effects, with only limited tyramine-cardiovascular potentiation of blood pressure. The results show that in 6-hydroxydopamine rat (neuroprotection) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse (neurorescue) Parkinson's disease models, VAR significantly attenuated the loss of striatal dopamine levels, markedly reduced dopamine turnover, and increased tyrosine-hydroxylase levels. Furthermore, chronic systemic treatment of aged rats with VAR improved cognitive behavior deficits and enhanced the expression levels of neurotrophic factors (e.g., brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor), Bcl-2 family members and synaptic plasticity in the hippocampus. Our study indicates that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinson's disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders. (C) 2015 Elsevier Inc. All rights reserved.
机译：最近，我们已经设计并合成了一种新型的，能渗透脑的铁螯合药物VAR10303（VAR），该药物同时具有炔丙基和单胺氧化酶（MAO）抑制部分。进行本研究以确定在神经变性临床前模型中VAR的多种药理活性。我们证明，VAR提供了铁螯合/铁诱导的脂质过氧化抑制潜能以及对脑的选择性MAO-A和MAO-B抑制作用，而酪胺-心血管对血压的增强作用有限。结果表明，在6-羟基多巴胺大鼠（神经保护）和1-甲基-4-苯基-1,2,3,6-四氢吡啶小鼠（神经挽救）帕金森氏病模型中，VAR显着减弱了纹状体多巴胺水平的降低。减少多巴胺周转，并增加酪氨酸羟化酶水平。此外，对VAR的老年大鼠进行长期全身治疗可改善认知行为缺陷，并增强神经营养因子（例如，脑源性神经营养因子，神经胶质细胞源性神经营养因子和神经生长因子），Bcl-2家族成员和神经营养因子的表达水平。海马突触可塑性。我们的研究表明，多目标化合物VAR在帕金森氏病和衰老的动物模型中发挥神经保护和神经修复作用，进一步表明，可以调节多个脑靶标的药物可能是与年龄相关的神经退行性疾病的理想治疗策略。 （C）2015 Elsevier Inc.保留所有权利。

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