Time course study of GFR alpha-1 expression in an animal model of stroke

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 rec eptor alpha -1 (GFR alpha -1) and c-Ret. In this study, we examined the lev els of expression of GFR alpha -1 and c-Pet in a rat model of stroke. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The right midd le cerebral artery was ligated at its distal branch for 90 min. Animals wer e sacrificed at 0, 6,12, and 24 h after reperfusion and levels of expressio n of GFR alpha -1 and c-Ret mRNA were determined by in situ hybridization h istochemistry. We found that GFR alpha -1 mRNA was up-regulated in CAS, den tate gyrus (DG), cortex, and striatum. The peak of up-regulation in DG was 6 h after reperfusion. GFR alpha -1 mRNA levels in CA3 were gradually up-re gulated over the 24-h reperfusion period. In cortex, GFR alpha -1 mRNA was up-regulated at all time points; however, the peak of up-regulation was obs erved at 0 and 24 h after reperfusion. In striatum, an initial up-regulatio n of GFR alpha -1 was found at 0 h after ischemia. In striatum., up-regulat ion 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, ou r results indicate that there are both regional and temporal differences in up-regulation of GFR alpha -1 and c-Ret after ischemia. Since GDNF is neur oprotective, up-regulation of GFR alpha -1 and c-Ret could enhance the resp onsiveness to GDNF and reduce neuronal damage. The selective up-regulation of GFR alpha -1 and c-Ret in different brain areas suggests that there may be regional differences in GDNF-induced neuroprotection in stroke. (C) 2001 Academic Press.