Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic.
Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic.
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DOI：
10.1186/s12974-015-0289-5
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发表时间：
2015-04-10
影响因子：
9.3
通讯作者：
Van Eldik LJ
中科院分区：
文献类型：
--
作者：
Bachstetter AD;Webster SJ;Goulding DS;Morton JE;Watterson DM;Van Eldik LJ
来自临床研究和临床前动物模型的证据表明，促炎细胞因子过度产生是创伤性脑损伤（TBI）病理进展的潜在驱动力。这就提出了一种可能性，即选择性靶向过度活跃的细胞因子反应（神经炎症的一个组成部分，导致神经元功能障碍）可能是一种有用的治疗方法。MW151是一种CNS渗透性小分子实验性治疗剂，可选择性恢复损伤或疾病诱导的促炎细胞因子过度产生，以达到体内平衡。我们以前报道过，MW151在损伤后（p.i.）在小鼠弥漫性TBI的闭合性头部损伤（CHI）模型中有效。在这里，我们测试了MW151抑制靶机制（促炎细胞因子上调）的剂量依赖性，并探索了MW151疗效的治疗窗口。我们研究了在损伤后不同时间给予MW151时对急性细胞因子激增的抑制以及细胞因子抑制的剂量依赖性。我们还测试了在损伤后的前7天内使用MW151进行更长时间的治疗，并测量了对认知障碍和神经胶质激活的影响。MW151给药后6小时损伤抑制急性细胞因子激增，在剂量依赖性的方式。在损伤后的前7天内施用MW151挽救了CHI诱导的认知障碍并减少了CHI的焦点区域中的神经胶质活化。我们的研究结果确定了CHI后的临床相关时间窗，在此期间MW151有效地将细胞因子产生恢复到正常水平，从而减轻下游认知障碍。
Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test dose dependence of MW151 to suppress the target mechanism (proinflammatory cytokine up-regulation), and explore the therapeutic window for MW151 efficacy. We examined suppression of the acute cytokine surge when MW151 was administered at different times post-injury and the dose-dependence of cytokine suppression. We also tested a more prolonged treatment with MW151 over the first 7 days post-injury and measured the effects on cognitive impairment and glial activation. MW151 administered up to 6 h post-injury suppressed the acute cytokine surge, in a dose-dependent manner. Administration of MW151 over the first 7 days post-injury rescues the CHI-induced cognitive impairment and reduces glial activation in the focus area of the CHI. Our results identify a clinically relevant time window post-CHI during which MW151 effectively restores cytokine production back towards normal, with a resultant attenuation of downstream cognitive impairment.
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影响因子：
2.9
作者：
Somera-Molina KC;Nair S;Van Eldik LJ;Watterson DM;Wainwright MS
通讯作者：
Wainwright MS
影响因子：
5.8
作者：
Mosher, Kira Irving;Wyss-Coray, Tony
通讯作者：
Wyss-Coray, Tony
DOI：
10.1186/alzrt182
发表时间：
2013
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Webster SJ;Bachstetter AD;Van Eldik LJ
通讯作者：
Van Eldik LJ
DOI：
10.1523/jneurosci.5399-12.2013
发表时间：
2013-04-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bachstetter AD;Rowe RK;Kaneko M;Goulding D;Lifshitz J;Van Eldik LJ
通讯作者：
Van Eldik LJ
影响因子：
11.2
作者：
Ramlackhansingh, Anil F.;Brooks, David J.;Sharp, David J.
通讯作者：
Sharp, David J.