3,6′- and 1,6′-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation

Pharmaceutics

Eui Jung Jo¹  Inho Hwang¹  Dayeon Gil¹  Yukyung Kim¹  Dong Seok Kim²  Barry J. Hoffer³  Warren R. Selman³  Yi-Syue Tsou⁴  Shih-Chang Hsueh⁵  Nigel H. Greig⁵  David Tweedie⁵  Michael T. Scerba⁵  Daniela Lecca⁵  John Chung-Che Wu⁶  Kai-Yun Chen⁶  Jia-Yi Wang⁶  Yung-Hsiao Chiang⁶  Yan-Rou Tsai⁶  Baek-Soo Han⁷ 

[1] Aevis Bio Inc., Daejeon 34141, Korea;Aevisbio Inc., Gaithersburg, MD 20878, USA;Department of Neurological Surgery, Case Western Reserve University, Cleveland, OH 44106, USA;Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USA;Neuroscience Research Center, Taipei Medical University, Taipei 110, Taiwan;Research Center for Biodefence, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea;

关键词: ischemic stroke;    3,6′-dithiopomalidomide;    1,6′-dithiopomalidomide;    pomalidomide;    cereblon;    inflammation;   

DOI  :  10.3390/pharmaceutics14050950

来源: DOAJ

【 摘 要 】

(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.

【 授权许可】

Unknown