Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.
Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.
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DOI：
10.1186/s12929-023-00907-5
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发表时间：
2023-03-06
影响因子：
11
通讯作者：
Greig, Nigel H.
中科院分区：
文献类型：
--
作者：
Lecca, Daniela;Hsueh, Shih-Chang;Luo, Weiming;Tweedie, David;Kim, Dong Seok;Baig, Abdul Mannan;Vargesson, Neil;Kim, Yu Kyung;Hwang, Inho;Kim, Sun;Hoffer, Barry J.;Chiang, Yung-Hsiao;Greig, Nigel H.
关键词：
抑制小胶质细胞诱导的过度神经炎症是神经系统疾病（包括创伤性脑损伤（TBI））的潜在治疗策略，可以通过沙利度胺类药物实现，尽管这种批准的药物类别受到潜在致畸性的影响。生成四氟冰片基邻苯二甲酰亚胺（TFBP）和四氟冰片基邻苯二甲酰亚胺（TFNBP）以保留沙利度胺免疫调节酰亚胺药物（IMiD）类别的核心邻苯二甲酰亚胺结构。然而，经典的戊二酰亚胺环被桥环结构取代。因此，TFBP/TFNBP被设计为保留IMiD的有益抗炎特性，但重要的是，阻碍作为沙利度胺样药物不良作用基础的cereblon结合。合成TFBP/TFNBP并在人和啮齿动物细胞培养物中评价cereblon结合和抗炎作用。在鸡胚中评估致畸潜力，并在用脂多糖（LPS）或受控皮质撞击（CCI）中度创伤性脑损伤（TBI）挑战的啮齿动物中评估体内抗炎作用。进行分子建模以提供对药物/cereblon结合相互作用的了解。TFBP/TFNBP减少了小鼠巨噬细胞样RAW264.7细胞培养物和用LPS攻击的啮齿动物中的炎症标志物，降低了促炎细胞因子。结合研究表明，与cereblon的相互作用最小，没有导致致畸性相关的转录因子SALL 4或致畸性在鸡胚试验中的降解。为了评估其抗炎作用的生物学相关性，在CCI TBI后损伤后1和24小时向小鼠施用两种剂量的TFBP。与载体治疗相比，TFBP减少了TBI损伤大小以及TBI诱导的活化小胶质细胞表型，如通过损伤后2周的免疫组织化学所评估的。在损伤后1周和2周的行为评估表明，与媒介物处理的小鼠相比，TFBP提供了TBI诱导的运动协调和平衡障碍的更快恢复。TFBP和TFNBP代表一类新的沙利度胺样IMiD，其降低促炎细胞因子的产生，但缺乏与cereblon的结合，cereblon是主要的致畸相关机制。这使得TFBP和TFNBP在临床使用中可能比经典IMiD更安全。TFBP提供了一种减轻与中度TBI相关的过度神经炎症的策略，从而改善行为结局指标，并保证进一步研究涉及神经炎症成分的神经系统疾病。
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. 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. 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. 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.
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