Yasunaga Miho, Takata Fuyuko, Iwao Takuro, Mizoguchi Junko, Tajima Nanako, Dohgu Shinya
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Int J Mol Sci. 2025 Mar 25;26(7):3002. doi: 10.3390/ijms26073002.
Traumatic brain injury (TBI) causes neurovascular unit (NVU) dysfunction, including hyperpermeability of the blood-brain barrier to fibrinogen, glial activation, and neuronal damage, possibly leading to secondary brain damage. However, no known substance can inhibit its pathogenesis. In this study, we investigated noggin, a bone morphogenetic protein (BMP) 4 inhibitor, as a TBI pathogenesis-inhibiting substance. We induced acute TBI in C57BL/6J mice through a controlled cortical impact (CCI) and evaluated the effects of noggin on fibrinogen leakage into the brain and NVU-constituting cells, including pericytes, microglia, astrocytes, and neurons. CCI mice showed increased BMP4 levels and extravascular fibrinogen in the hippocampus. Noggin treatment significantly suppressed fibrinogen leakage four days post-CCI in a dose-dependent manner. Immunofluorescence staining revealed that noggin administration did not inhibit the activation of NVU cells such as pericytes, microglia, and astrocytes, which were characterized by increased PDGFRβ, Iba1, and GFAP expression levels, respectively. On postoperative day 4, CCI mice showed neuronal cell and myelinated neuronal fiber loss, which were not significantly affected by noggin administration. In conclusion, noggin administration suppresses fibrinogen leakage into the brain in the acute phase after TBI. However, the suppression of fibrinogen leakage through noggin administration did not alleviate neuronal damage and activation of NVU cells during the acute phase of TBI.
创伤性脑损伤（TBI）会导致神经血管单元（NVU）功能障碍，包括血脑屏障对纤维蛋白原的通透性增加、神经胶质激活和神经元损伤，这可能会导致继发性脑损伤。然而，目前尚无已知物质能够抑制其发病机制。在本研究中，我们研究了骨形态发生蛋白（BMP）4抑制剂头蛋白（noggin）作为一种抑制TBI发病机制的物质。我们通过控制性皮质撞击（CCI）在C57BL/6J小鼠中诱导急性TBI，并评估了头蛋白对纤维蛋白原渗入大脑以及构成NVU的细胞（包括周细胞、小胶质细胞、星形胶质细胞和神经元）的影响。CCI小鼠海马中的BMP4水平和血管外纤维蛋白原增加。头蛋白治疗在CCI后四天以剂量依赖的方式显著抑制了纤维蛋白原渗漏。免疫荧光染色显示，给予头蛋白并没有抑制NVU细胞如周细胞、小胶质细胞和星形胶质细胞的激活，这些细胞分别以PDGFRβ、Iba1和GFAP表达水平增加为特征。在术后第4天，CCI小鼠出现神经元细胞和有髓神经纤维丢失，给予头蛋白对此没有显著影响。总之，给予头蛋白可抑制TBI急性期纤维蛋白原渗入大脑。然而，通过给予头蛋白抑制纤维蛋白原渗漏并不能减轻TBI急性期的神经元损伤和NVU细胞的激活。
