- 作者: Daniela Lecca, Shih-Chang Hsueh, Weiming Luo, David Tweedie, Dong Seok Kim, Abdul Mannan Baig, Neil Vargesson, Yu Kyung Kim, Inho Hwang, Sun Kim, Barry J. Hoffer, Yung-Hsiao Chiang & Nigel H. Greig
- 作者服務機構: 1.Aevis Bio Inc., Daejeon, 34141, Republic of Korea 2.Aevisbio Inc., Gaithersburg, MD, 20878, USA 3.Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, 74800, Pakistan 4.Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA 5.Department of Neurosurgery, Taipei Medical University Hospital, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan 6.Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA 7.Neuroscience Research Center, Taipei Medical University, Taipei, 110, Taiwan 8.School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK
- 中文摘要:
- 英文摘要:
Background
Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs.
Methods
TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions.
Results
TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice.
Conclusion
TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component. - 中文關鍵字:
- 英文關鍵字: Neuroinfammation, Thalidomide, Cereblon, Immunomodulatory imide drugs (IMiDs), Neurodegeneration, Microglia, Teratogenicity, Spalt like transcription factor 4 (SALL4)