3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.
3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.
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DOI：
10.3390/pharmaceutics14050950
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发表时间：
2022-04-27
期刊：
影响因子：
5.4
通讯作者：
Chiang, Yung-Hsiao
中科院分区：
文献类型：
--
作者：
Tsai, Yan-Rou;Kim, Dong Seok;Hsueh, Shih-Chang;Chen, Kai-Yun;Wu, John Chung-Che;Wang, Jia-Yi;Tsou, Yi-Syue;Hwang, Inho;Kim, Yukyung;Gil, Dayeon;Jo, Eui Jung;Han, Baek-Soo;Tweedie, David;Lecca, Daniela;Scerba, Michael T.;Selman, Warren R.;Hoffer, Barry J.;Greig, Nigel H.;Chiang, Yung-Hsiao
关键词：
(1)背景：脑卒中的一个重要并发症是神经炎症。泊马度胺是一种临床上可用的免疫调节酰亚胺药物（IMiD），用于癌症治疗，可降低TNF-α的产生，因此具有强效的抗炎作用。耐受性良好的类似物可以提供中风治疗，并允许评估缺血性脑中神经炎症的作用。(2)研究方法：在大鼠大脑中动脉闭塞（MCAo）脑卒中模型中，评价了两种新型泊马度胺衍生物3，6 ′-二硫代泊马度胺（3，6 ′-DP）和1，6 ′-二硫代泊马度胺（1，6 ′-DP）与泊马度胺合用的抗炎作用。(3)结果如下：MCAo后给予所有药物均降低了促炎性TNF-α和IL 1-β水平，并减少了卒中诱导的姿势不对称和梗死面积。尽管3，6 ′-和1，6 ′-DP与泊马度胺一样，在细胞研究中与cereblon有效结合，但3，6 ′-DP不会降低Ikaros、Aiolos或SALL 4水平-介导泊马度胺和IMiD抗癌/致畸作用的关键中间体。3，6 ′-DP和1，6 ′-DP在哺乳动物染色体畸变、艾姆斯和hERG通道试验（关键FDA监管试验）中缺乏活性。最后，3，6 ′-和1，6 ′-DP减轻了α-突触核蛋白激发的大鼠原代多巴胺能神经元和小胶质细胞混合培养物和小鼠LPS激发的RAW 264.7细胞的炎症。(4)结论：通过TNF-α介导的神经炎症在中风结局中发挥关键作用，3，6 '-DP和1，6'-DP可能被证明作为中风治疗有价值，因此需要进一步的临床前开发。
(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′-dithiopomalidomide (3,6′-DP) and 1,6′-dithiopomalidomide (1,6′-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-β levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6′- and 1,6′-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6′-DP did not lower Ikaros, Aiolos or SALL4 levels—critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6′-DP and 1,6′-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays –critical FDA regulatory tests. Finally, 3,6′- and 1,6′-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6′-DP and 1,6′-DP may prove valuable as stroke therapies and thus warrant further preclinical development.
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影响因子：
7.9
作者：
El-Hakim Y;Mani KK;Eldouh A;Pandey S;Grimaldo MT;Dabney A;Pilla R;Sohrabji F
通讯作者：
Sohrabji F
影响因子：
5.6
作者：
Huang PS;Tsai PY;Yang LY;Lecca D;Luo W;Kim DS;Hoffer BJ;Chiang YH;Greig NH;Wang JY
通讯作者：
Wang JY
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
影响因子：
13.3
作者：
Jiang J;Yu Y
通讯作者：
Yu Y
DOI：
10.1097/01.wcb.0000112322.75217.fd
发表时间：
2004-03-01
影响因子：
6.3
作者：
Carswell, HV;Bingham, D;Macrae, IM
通讯作者：
Macrae, IM