Glial cell line-derived neurotrophic factor modulates ischemia-induced tyrosine hydroxylase expression in rat hippocampus.

Recently, we have reported that glial cell line-derived neurotrophic factor (GDNF), which supports the survival of dopaminergic neurons, prevents delayed neuronal death in the hippocampal CA1 region induced by transient forebrain ischemia. In the present study, we examined the role of GDNF in the expression of tyrosine hydroxylase (TH) mRNA induced by transient forebrain ischemia in rats. The expression of TH mRNA was increased in a time-dependent manner, with a significant increase in 24 h to 7 days, in the hippocampus after induction of transient forebrain ischemia, as determined using the reverse transcription and polymerase chain reaction method. Although it has been suggested that the increase of dopamine beta-hydroxylase mRNA expression correlates with the activation of noradrenergic neurons, no increase of dopamine beta-hydroxylase mRNA in the hippocampus was observed in our system. Western blot analysis revealed that TH protein, but not dopamine beta-hydroxylase protein, was produced in a time-dependent manner in the hippocampus during the ischemia. Interestingly, the induction level of TH mRNA was reduced by intrahippocampal microinjection of GDNF (1.0 microg), and this local GDNF treatment also reduced the increase of TH-like immunohistochemistry-positive terminals in the hippocampus. In contrast, local GDNF treatment of normal rats increased the TH mRNA expression at 6-12 h. These findings suggest that GDNF protects against neuronal degeneration including delayed neuronal death in the hippocampal CA1 region by modulating the expression levels of TH mRNA and protein.