Sarabi A, Chang C F, Wang Y, Hoffer B J, Morales M
National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Exp Neurol. 2001 Aug;170(2):283-9. doi: 10.1006/exnr.2001.7714.
Previous studies have shown that intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-mediated cerebral infarction. The biological effects of GDNF are mediated by GDNF-family receptor alpha-1 (GFRalpha-1) and c-Ret. In this study, we examined the levels of expression of GFRalpha-1 and c-Ret in a rat model of stroke. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The right middle cerebral artery was ligated at its distal branch for 90 min. Animals were sacrificed at 0, 6, 12, and 24 h after reperfusion and levels of expression of GFRalpha-1 and c-Ret mRNA were determined by in situ hybridization histochemistry. We found that GFRalpha-1 mRNA was up-regulated in CA3, dentate gyrus (DG), cortex, and striatum. The peak of up-regulation in DG was 6 h after reperfusion. GFRalpha-1 mRNA levels in CA3 were gradually up-regulated over the 24-h reperfusion period. In cortex, GFRalpha-1 mRNA was up-regulated at all time points; however, the peak of up-regulation was observed at 0 and 24 h after reperfusion. In striatum, an initial up-regulation of GFRalpha-1 was found at 0 h after ischemia. In striatum, up-regulation of c-Ret mRNA was detected as early as 0 h after reperfusion. A gradual increase was found at 6, 12, and 24 h after reperfusion. In conclusion, our results indicate that there are both regional and temporal differences in up-regulation of GFRalpha-1 and c-Ret after ischemia. Since GDNF is neuroprotective, up-regulation of GFRalpha-1 and c-Ret could enhance the responsiveness to GDNF and reduce neuronal damage. The selective up-regulation of GFRalpha-1 and c-Ret in different brain areas suggests that there may be regional differences in GDNF-induced neuroprotection in stroke.
先前的研究表明，脑内给予胶质细胞系源性神经营养因子（GDNF）可减少缺血介导的脑梗死。GDNF的生物学效应由GDNF家族受体α-1（GFRα-1）和c-Ret介导。在本研究中，我们检测了中风大鼠模型中GFRα-1和c-Ret的表达水平。成年Sprague-Dawley大鼠用氯水合醛麻醉。右侧大脑中动脉在其远端分支处结扎90分钟。在再灌注后0、6、12和24小时处死动物，通过原位杂交组织化学法测定GFRα-1和c-Ret mRNA的表达水平。我们发现，GFRα-1 mRNA在CA3、齿状回（DG）、皮质和纹状体中上调。DG中上调的峰值出现在再灌注后6小时。CA3中GFRα-1 mRNA水平在24小时再灌注期逐渐上调。在皮质中，GFRα-1 mRNA在所有时间点均上调；然而，上调的峰值出现在再灌注后0和24小时。在纹状体中，缺血后0小时发现GFRα-1最初上调。在纹状体中，再灌注后0小时最早检测到c-Ret mRNA上调。在再灌注后6、12和24小时发现逐渐增加。总之，我们的结果表明，缺血后GFRα-1和c-Ret的上调存在区域和时间差异。由于GDNF具有神经保护作用，GFRα-1和c-Ret的上调可增强对GDNF的反应性并减少神经元损伤。GFRα-1和c-Ret在不同脑区的选择性上调表明，中风中GDNF诱导的神经保护可能存在区域差异。
