Wang Haiquan, Liao Zhengbu, Sun Xiaochuan, Shi Quanhong, Huo Gang, Xie Yanfeng, Tang Xiaolan, Zhi Xinggang, Tang Zhaohua
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China.
Laboratory of Medical Molecular Biology, Medical College of Qinghai University, No.16 Kunlun Road, Xining 810000, Qinghai Province, China; Department of Cardiology, Medical College of Qinghai University, No.16 Kunlun Road, Xining 810000, Qinghai Province, China.
Neuropharmacology. 2014 Nov;86:9-21. doi: 10.1016/j.neuropharm.2014.06.018. Epub 2014 Jun 25.
Recently, increasing evidence has shown that cell cycle activation is a key factor of neuronal death and neurological dysfunction after traumatic brain injury (TBI). This study aims to investigate the effects of Honokiol, a cell cycle inhibitor, on attenuating the neuronal damage and facilitating functional recovery after TBI in rats, in an attempt to unveil its underlying molecular mechanisms in TBI. This study suggested that delayed intravenous administration of Honokiol could effectively ameliorate TBI-induced sensorimotor and cognitive dysfunctions. Meanwhile, Honokiol treatment could also reduce the lesion volume and increase the neuronal survival in the cortex and hippocampus. The neuronal degeneration and apoptosis in the cortex and hippocampus were further significantly attenuated by Honokiol treatment. In addition, the expression of cell cycle-related proteins, including cyclin D1, CDK4, pRb and E2F1, was significantly increased and endogenous cell cycle inhibitor p27 was markedly decreased at different time points after TBI. And these changes were significantly reversed by post-injury Honokiol treatment. Furthermore, the expression of some of the key cell cycle proteins such as cyclin D1 and E2F1 and the associated apoptosis in neurons were both remarkably attenuated by Honokiol treatment. These results show that delayed intravenous administration of Honokiol could effectively improve the functional recovery and attenuate the neuronal cell death, which is probably, at least in part, attributed to its role as a cell cycle inhibitior. This might give clues to developing attractive therapies for future clinical trials.
最近，越来越多的证据表明，细胞周期激活是创伤性脑损伤（TBI）后神经元死亡和神经功能障碍的关键因素。本研究旨在探讨细胞周期抑制剂厚朴酚对减轻大鼠TBI后神经元损伤和促进功能恢复的影响，试图揭示其在TBI中的潜在分子机制。本研究表明，延迟静脉注射厚朴酚可有效改善TBI诱导的感觉运动和认知功能障碍。同时，厚朴酚治疗还可减少损伤体积，增加皮质和海马区的神经元存活。厚朴酚治疗进一步显著减轻了皮质和海马区的神经元变性和凋亡。此外，TBI后不同时间点，细胞周期相关蛋白（包括细胞周期蛋白D1、细胞周期蛋白依赖性激酶4、磷酸化视网膜母细胞瘤蛋白和E2F1）的表达显著增加，内源性细胞周期抑制剂p27明显减少。损伤后厚朴酚治疗可显著逆转这些变化。此外，厚朴酚治疗显著减弱了一些关键细胞周期蛋白（如细胞周期蛋白D1和E2F1）的表达以及神经元中的相关凋亡。这些结果表明，延迟静脉注射厚朴酚可有效改善功能恢复并减轻神经元细胞死亡，这可能至少部分归因于其作为细胞周期抑制剂的作用。这可能为未来临床试验开发有吸引力的治疗方法提供线索。
