Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India; Ellen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
Eur J Med Chem. 2023 Nov 5;259:115718. doi: 10.1016/j.ejmech.2023.115718. Epub 2023 Aug 9.
Traumatic brain injury (TBI) is a debilitating mental condition which causes physical disability and morbidity worldwide. TBI may damage the brain by direct injury that subsequently triggers a series of neuroinflammatory events. The activation of NLRP3 inflammasome and dysregulated host immune system has been documented in various neurological disorders such as TBI, ischemic stroke and multiple sclerosis. The activation of NLRP3 post-TBI increases the production of pro-inflammatory cytokines and caspase-1, which are major drivers of neuroinflammation and apoptosis. Similarly, GSK-3β regulates apoptosis through tyrosine kinase and canonical Wnt signalling pathways. Thus, therapeutic targeting of NLRP3 inflammasome and GSK-3β has emerged as promising strategies for regulating the post-TBI neuroinflammation and neurobehavioral disturbances. In this review, we discuss the identification & development of several structurally diverse and pharmacologically interesting small molecule inhibitors for targeting the NLRP3 inflammasome and GSK-3β in the management of TBI.
创伤性脑损伤（TBI）是一种使人虚弱的精神疾病，会在全球范围内导致身体残疾和发病率上升。TBI 可能通过直接损伤大脑，进而引发一系列神经炎症事件。NLRP3 炎性小体的激活和失调的宿主免疫系统已在各种神经疾病中得到证实，如 TBI、缺血性中风和多发性硬化症。TBI 后 NLRP3 的激活会增加促炎细胞因子和半胱天冬酶-1 的产生，这是神经炎症和细胞凋亡的主要驱动因素。同样，GSK-3β 通过酪氨酸激酶和经典 Wnt 信号通路调节细胞凋亡。因此，针对 NLRP3 炎性小体和 GSK-3β 的治疗靶向已成为调节 TBI 后神经炎症和神经行为障碍的有前途的策略。在这篇综述中，我们讨论了几种结构多样且具有药理学意义的小分子抑制剂的鉴定和开发，这些抑制剂可用于针对 NLRP3 炎性小体和 GSK-3β 来管理 TBI。
