Exogenous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-induced cerebral infarction. Cerebral ischemia induces gene expression of GDNF, GDNF-receptor α-1 (GFRα-1) and c-Ret, suggesting that a GDNF signaling cascade mechanism may be involved in endogenous neuroprotection during ischemia. In the present study, we examined if this endogenous neuroprotective pathway was altered in Gfrα-1 deficient mice. Since mice homozygous for the Gfrα-1 deletion (-/-) die within 24 h of birth, stroke-induced changes in the levels of Gfrα-1 mRNA were studied in Gfrα-1 heterozygous (+/-) mice and their wild-type (+/+) littermates. The right middle cerebral artery was transiently ligated for 45 min in anesthetized mice. Animals were killed at 0, 6, 12 and 24 h after the onset of reperfusion and levels of Gfrα-1 mRNA were measured by in situ hybridization histochemistry. Previously, we showed that Gfrα-1 (+/-) mice are more vulnerable to focal cerebral ischemia. In the present study, we found that basal levels of GFRα-1 mRNA were at similar low levels in cortex and striatum in adult Gfrα-1 (+/+) and Gfrα-1 (+/-) mice and that ischemia/reperfusion induced up-regulation of Gfrα-1 mRNA in the lesioned and contralateral sides of cortex and striatum in both Gfrα-1 (+/+) and GFRα-1 (+/-) mice. However, the ischemia/reperfusion induction of Gfrα-1 mRNA was significantly higher in the cortex of wild type mice, as compared to Gfrα-1 (+/-) mice. Moreover, the increased expression of Gfrα-1 in striatum after reperfusion occurred earlier in the GFRα-1 (+/+) than in the Gfrα-1 (+/-) mice. These results indicate that after ischemia, there is a differential up-regulation of Gfrα-1 expression in Gfrα-1 (+/+) and Gfrα-1 (+/-) mice. Since GDNF has neuroprotective effects, the reduced up-regulation of Gfrα-1 in Gfrα-1 (+/-) mice at early time points after ischemia suggests that the responsiveness to GDNF and GDNF receptor mediated neuroprotection is attenuated in these genetically modified animals and may underlie their greater vulnerability.
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