Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology.
Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology.
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DOI：
10.1523/jneurosci.1496-12.2012
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发表时间：
2012-07-25
期刊：
影响因子：
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通讯作者：
Van Eldik LJ
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文献类型：
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作者：
Bachstetter AD;Norris CM;Sompol P;Wilcock DM;Goulding D;Neltner JH;St Clair D;Watterson DM;Van Eldik LJ
CNS中促炎细胞因子的过度产生已被认为是阿尔茨海默病（AD）病理生理学进展的关键因素，并且对动物模型的广泛研究表明，选择性抑制过量的胶质促炎细胞因子可以改善神经学结果。因此，现有技术提出了逻辑假设，即如果在适当的生物时间窗中使用，则用靶向失调的神经胶质促炎细胞因子产生的药物进行干预可能是有效的疾病修饰治疗剂。为了检验用这些药物进行早期干预可能在治疗上有益的假设，我们检查了用MW 01 -2- 151 SRM（MW-151）进行干预的影响，MW 01 -2- 151 SRM是一种在低剂量下选择性地减弱促炎细胞因子产生的实验性治疗剂。MW-151在APP/PS1基因敲入小鼠模型中进行了检测，该模型显示AD相关病理学进展随年龄增加而增加，包括促炎细胞因子水平增加。在早期病理发展的两个不同但重叠的治疗时间窗内给药。MW-151治疗减弱了皮质中小胶质细胞和星形胶质细胞活化和促炎细胞因子产生的增加，并改善了神经学结局，如防止突触蛋白丢失和突触可塑性损伤。结果还表明，治疗时间窗是一个重要的考虑因素，在药物的疗效研究，调节神经胶质细胞的生物反应参与病理进展，并建议这种范例应考虑在开发新的治疗方案，寻求延迟发病或减缓AD的进展。
Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer’s disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex, and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression, and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.