Tumor necrosis factor-α synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice.
Tumor necrosis factor-α synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice.
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DOI：
10.1111/j.1471-4159.2011.07377.x
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Pick CG
中科院分区：
文献类型：
--
作者：
Baratz R;Tweedie D;Rubovitch V;Luo W;Yoon JS;Hoffer BJ;Greig NH;Pick CG
轻度创伤性脑损伤（mTBI）患者没有明显的脑结构性缺陷，一般不需要住院治疗，但经常出现长期的认知、行为和情感困难。尽管目前尚无有效的mTBI治疗方法或治愈方法，但肿瘤坏死因子-α (TNF-α)是一种潜在的药物靶点。TNF-α是全身性炎症过程中的一种基本细胞因子。mTBI后TNF-α水平升高，可能诱发或加重脑组织继发性损伤。本研究评估了实验性TNF-α合成抑制剂3,6'-双硫沙利度胺对mTBI小鼠恢复的疗效，该模型在损伤后72小时和7天通过y迷宫、新物体识别和被动回避范式评估，诱导脑TNF-α急性升高和认知功能障碍。在损伤前1小时或损伤后1或12小时接受3,6′-双硫沙利度胺低剂量（28 mg/kg）或高剂量（56 mg/kg）一次性给药的小鼠，这些损伤得到了完全改善。总之，这些结果暗示TNF-α是mTBI的药物靶点，并表明3,6'-双硫代沙利度胺可能作为神经保护药物来减少损伤。
Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-α), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-α levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-α and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 hr and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 hr prior to injury, or at 1 or 12 hr post injury. Together, these results implicate TNF-α as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment.
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