CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR IN STROKE

神经胶质细胞系来源的神经营养因子（GDNF）在体外和体内促进神经元的存活。先前的研究表明，脑内给药GDNF可减少大脑中动脉闭塞（MCA-O）和随后的再灌注引起的皮层梗死（Wang et al. 1997）。northern blot分析表明，内源性GDNF参与卒中过程，GDNF转录本在再灌注后1小时被诱导（Abe et al. 1997）。GDNF通过与其受体GFR a-1结合并通过c-ret传递其信号来发挥其生物活性。因此，我们评估了MCA-O引起的大鼠中风模型中GFR a-1和c-ret表达的可能变化。通过原位杂交，我们检测到GFR a-1在皮质、齿状回和海马中的表达上调。再灌注后6 ~ 12小时为表达高峰。有趣的是，在再灌注后12-24小时，c-ret在皮质和海马中的表达也上调。在正常成年大鼠脑中，海马中GFR a-1的表达与小白蛋白免疫反应神经元有关。我们目前正在研究MCA-O后GFR a-1和c-ret优先上调的细胞表型群体。这一信息将有助于更好地理解脑卒中中参与GDNF作用的细胞成分。

Glial cell line derived neurotrophic factor (GDNF) promotes neuronal survival in vitro and in vivo. Previous studies have shown that intracerebral administration of GDNF reduces infarction in the cortex (Wang et al. 1997) induced by middle cerebral artery occlusion (MCA-O) and subsequent reperfusion. The participation of endogenous GDNF during stroke has been suggested from northern blot analysis showing that GDNF transcripts are induced one hour after reperfusion (Abe et al. 1997). GDNF exerts its biological activity by binding to its receptor GFR a-1 and transferring its signal through c-ret. Thus, we evaluate possible changes in GFR a-1 and c-ret expression in a rat model of stroke produced by MCA-O. Using in situ hybridization, we detected upregulation of GFR a-1 expression in cortex, dentate gyrus and hippocampus. The peak of expression was 6-12 hrs after reperfusion. Interestingly, c-ret expression was also upregulated in cortex and hippocampus but 12-24 hrs after reperfusion. In normal adult rat brain, GFR a-1 expression in hippocampus is associated with parvalbumin immunoreactive neurons. We are currently investigating the phenotypic population of the cells that undergo preferential upregulation of GFR a-1 and c-ret after MCA-O. This information will permit better understanding the cellular components that participate in the effects of GDNF during stroke.