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首页> 美国卫生研究院文献>NeuroRx >The Copper bis(thiosemicarbazone) Complex CuII(atsm) Is Protective Against Cerebral Ischemia Through Modulation of the Inflammatory Milieu
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The Copper bis(thiosemicarbazone) Complex CuII(atsm) Is Protective Against Cerebral Ischemia Through Modulation of the Inflammatory Milieu

机译：铜双（硫代半碳酮）配合物CuII（atsm）通过调节炎症环境来预防脑缺血

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Developing new therapies for stroke is urgently needed, as this disease is the leading cause of death and disability worldwide, and the existing treatment is only available for a small subset of patients. The interruption of blood flow to the brain during ischemic stroke launches multiple immune responses, characterized by infiltration of peripheral immune cells, the activation of brain microglial cells, and the accumulation of immune mediators. Copper is an essential trace element that is required for many critical processes in the brain. Copper homeostasis is disturbed in chronic neurodegenerative diseases and altered in stroke patients, and targeted copper delivery has been shown to be protective against chronic neurodegeneration. This study was undertaken to assess whether the copper bis(thiosemicarbazone) complex, CuII(atsm), is beneficial in acute brain injury, in preclinical mouse models of ischemic stroke. We demonstrate that the copper complex CuII(atsm) protects neurons from excitotoxicity and N2a cells from OGD in vitro, and is protective in permanent and transient ischemia models in mice as measured by functional outcome and lesion size. Copper delivery in the ischemic brains modulates the inflammatory response, specifically affecting the myeloid cells. It reduces CD45 and Iba1 immunoreactivity, and alters the morphology of Iba1 positive cells in the ischemic brain. CuII(atsm) also protects endogenous microglia against ischemic insult and reduces the proportion of invading monocytes. These results demonstrate that the copper complex CuII(atsm) is an inflammation-modulating compound with high therapeutic potential in stroke and is a strong candidate for the development of therapies for acute brain injury.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0504-9) contains supplementary material, which is available to authorized users.
机译：迫切需要开发针对中风的新疗法，因为该疾病是全球范围内死亡和残疾的主要原因，并且现有的治疗方法仅适用于一小部分患者。缺血性中风期间流向大脑的血液中断会启动多种免疫反应，其特征是周围免疫细胞的浸润，脑小胶质细胞的活化以及免疫介质的积累。铜是大脑许多关键过程必需的微量元素。铜稳态在慢性神经退行性疾病中会受到干扰并在中风患者中发生改变，并且铜的靶向递送已显示出对慢性神经变性的保护作用。这项研究旨在评估在缺血性脑卒中的临床前小鼠模型中，双（硫代半脲）铜复合物Cu II （atsm）是否对急性脑损伤有益。我们证明铜复合物Cu II （atsm）可以保护神经元免受OGD的兴奋性毒性和N2a细胞的侵害，并且通过功能性结果和病变大小在小鼠的永久性和短暂性缺血模型中具有保护作用。铜在缺血性大脑中的传递调节炎症反应，特别影响髓样细胞。它降低了CD45和Iba1的免疫反应性，并改变了缺血性脑中Iba1阳性细胞的形态。 Cu II （atsm）还可以保护内源性小胶质细胞免受缺血性损伤，并减少侵入的单核细胞的比例。这些结果表明铜络合物Cu II （atsm）是一种调节炎症的化合物，在中风中具有很高的治疗潜力，并且是开发急性脑损伤疗法的有力候选者。本文的版本（doi：10.1007 / s13311-016-0504-9）包含补充材料，可供授权用户使用。

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