Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6-Dithiothalidomide on Traumatic Brain Injury
Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6-Dithiothalidomide on Traumatic Brain Injury
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DOI：
10.3390/ijms20030502
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Wang, Jia-Yi
中科院分区：
文献类型：
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作者：
Batsaikhan, Buyandelger;Wang, Jing-Ya;Wang, Jia-Yi
外伤性脑损伤（TBI）是世界范围内导致死亡和残疾的主要原因。创伤性脑损伤后的长期功能缺陷不仅源于损伤的直接影响，还与神经元兴奋性毒性、炎症、氧化应激和细胞凋亡等持续过程有关。已知肿瘤坏死因子- (TNF-)参与这些过程。我们之前的研究表明，3,6-二硫代沙利度胺（3,6- dt）是一种沙利度胺类似物，比沙利度胺更有效，具有相似的脑穿透性，可以选择性地抑制培养细胞中TNF-的合成，逆转小鼠轻度TBI引起的行为障碍。在本研究中，我们进一步探讨了3,6- dt在Sprague-Dawley大鼠中度脑外伤动物模型中的治疗潜力。TBI后5小时单剂量3,6- dt （28 mg/kg, i.p）可显著减少损伤后24小时的挫伤体积、神经元变性、神经元凋亡和神经功能缺损。在转录和翻译水平上，3,6- dt也抑制了挫伤区促炎细胞因子的表达。值得注意的是，3,6- dt也抑制了神经元的氧化应激。我们得出结论，3,6- dt可能是一种潜在的治疗方法，可以改善tbi诱导的功能缺陷。
Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor- (TNF-) is known to contribute to these processes. We have previously shown that 3,6-dithiothalidomide (3,6-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF- in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6-DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6-DT. Notably, neuronal oxidative stress was also suppressed by 3,6-DT. We conclude that 3,6-DT may represent a potential therapy to ameliorate TBI-induced functional deficits.