Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
J Neurosurg. 2010 Sep;113(3):591-7. doi: 10.3171/2009.9.JNS09859.
The authors' previous studies have demonstrated that simvastatin treatment promotes neuronal survival and reduces inflammatory cytokine release from astrocytes after traumatic brain injury (TBI) in rats. Since reactive astrocytes produce inflammation mediators, in the current study the authors investigated the effect of simvastatin on astrocyte activation after TBI and its underlying signaling mechanisms.
Saline or simvastatin (1 mg/kg) was orally administered to rats starting at Day 1 after TBI and then daily for 14 days. Rats were killed at 1, 3, 7, and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining and Western blot analysis, respectively. Cultured astrocytes were subjected to oxygen-glucose deprivation (OGD) and followed by immunocytochemical staining with glial fibrillary acidic protein/caveolin-1 and Western blot analysis. Lipid rafts were isolated from the cell lysate and Western blotting was carried out to detect the changes in epidermal growth factor receptor (EGFR) expression and phosphorylation in the lipid rafts.
Simvastatin significantly promoted neuronal survival after TBI and attenuated activation of astrocytes. Simvastatin modified the caveolin-1 expression in lipid rafts in astrocyte cell membrane, suppressed the phosphorylation of EGFR in lipid rafts of astrocytes after OGD, and inhibited the OGD-induced interleukin-1 production.
These data suggest that simvastatin reduces reactive astrogliosis and rescues neuronal cells after TBI. These beneficial effects of simvastatin may be mediated by inhibiting astrocyte activation after TBI through modifying the caveolin-1 expression in lipid rafts and the subsequent modulation of EGFR phosphorylation in lipid rafts.
作者先前的研究表明，辛伐他汀治疗可促进创伤性脑损伤（TBI）后大鼠神经元的存活，并减少星形胶质细胞中炎性细胞因子的释放。由于反应性星形胶质细胞产生炎症介质，因此在本研究中，作者研究了辛伐他汀对 TBI 后星形胶质细胞激活的影响及其潜在的信号机制。
在 TBI 后第 1 天开始，用盐水或辛伐他汀（1mg/kg）经口给予大鼠，并在接下来的 14 天内每天给予一次。在治疗后 1、3、7 和 14 天处死大鼠。制备脑切片和组织，分别用于免疫组织化学染色和 Western blot 分析。将培养的星形胶质细胞进行氧葡萄糖剥夺（OGD），并用胶质纤维酸性蛋白/窖蛋白-1免疫细胞化学染色和 Western blot 分析进行后续处理。从细胞裂解物中分离脂质筏，并进行 Western blot 分析，以检测表皮生长因子受体（EGFR）在脂质筏中的表达和磷酸化变化。
辛伐他汀显著促进 TBI 后神经元的存活，并减轻星形胶质细胞的激活。辛伐他汀改变了星形胶质细胞膜中脂质筏中窖蛋白-1的表达，抑制了 OGD 后星形胶质细胞脂质筏中 EGFR 的磷酸化，并抑制了 OGD 诱导的白细胞介素-1的产生。
这些数据表明，辛伐他汀可减少 TBI 后反应性星形胶质细胞增生并挽救神经元细胞。辛伐他汀的这些有益作用可能是通过调节脂质筏中窖蛋白-1的表达并随后调节 EGFR 在脂质筏中的磷酸化来抑制 TBI 后星形胶质细胞的激活而介导的。
