Zhang Y, Widmayer M A, Zhang B, Cui J K, Baskin D S
Department of Neurosurgery, Baylor College of Medicine, Suite 944, 6560 Fannin Street, Houston, TX 77030, USA.
Brain Res. 1999 Jun 19;832(1-2):112-7. doi: 10.1016/s0006-8993(99)01459-6.
Activation of c-fos, an immediate early gene, and the subsequent upregulation of Fos protein expression occur following neural injury, including focal cerebral ischemia (fci). Fos and Jun form a heterodimer known as activator protein 1, which regulates the expression of many late effector genes. To study the downstream effects of c-fos expression following ischemia, we suppressed the translation of c-fos by administering an antisense oligonucleotide (AO) to c-fos mRNA. Eighteen hours prior to fci, male, Long Evans (LE) rats received intraventricular injections of AO, mismatched AO (MS) or artificial cerebrospinal fluid (aCSF). Fci was induced by permanent right middle cerebral artery occlusion. At 24-h post-occlusion, neurological function was assessed, and the animals were sacrificed. The brains were removed and stained with triphenyltetrazolium chloride for infarct volume determination. Fos immunohistochemistry was performed in separate animals to determine the effects of treatment on Fos expression number of Fos positive cells. AO administration reduced the number of cells with fci-induced Fos expression by approximately 75%. No differences in neurological scores existed between any of the groups. AO-treated LE developed larger infarcts (40.1+/-1.0%, mean+/-S.D., p<0.001) than MS- or aCSF-treated controls (34.3+/-1.0%, 34.6+/-1.0%, respectively). These results suggest that c-fos activation and subsequent Fos protein expression exerts a neuroprotective effect, which is likely via upregulation of neurotrophins, following focal cerebral ischemia. This response, among others, may contribute to brain adaptation to injury that underlies functional recovery after stroke.
即刻早期基因c-fos的激活以及随后Fos蛋白表达的上调发生在神经损伤后，包括局灶性脑缺血（fci）。Fos和Jun形成一种称为激活蛋白1的异二聚体，它调节许多晚期效应基因的表达。为了研究缺血后c-fos表达的下游效应，我们通过向c-fos mRNA施用反义寡核苷酸（AO）来抑制c-fos的翻译。在fci前18小时，雄性Long Evans（LE）大鼠接受脑室内注射AO、错配AO（MS）或人工脑脊液（aCSF）。通过永久性右侧大脑中动脉闭塞诱导fci。在闭塞后24小时，评估神经功能，并处死动物。取出大脑并用氯化三苯基四氮唑染色以确定梗死体积。在单独的动物中进行Fos免疫组织化学以确定治疗对Fos阳性细胞表达数量的影响。施用AO使fci诱导的Fos表达的细胞数量减少了约75%。各组之间神经评分没有差异。与MS或aCSF处理的对照组（分别为34.3+/-1.0%、34.6+/-1.0%）相比，AO处理的LE大鼠梗死面积更大（40.1+/-1.0%，平均值+/-标准差，p<0.001）。这些结果表明，c-fos激活以及随后的Fos蛋白表达发挥神经保护作用，这可能是通过上调神经营养因子，在局灶性脑缺血后实现的。这种反应等可能有助于大脑适应损伤，这是中风后功能恢复的基础。
