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 dela yed neuronal death in the hippocampal CA1 region induced by transient foreb rain ischemia, In the present study, we examined the role of GDNF in the ex pression of tyrosine hydroxylase (TH) mRNA induced by transient forebrain i schemia in rats. The expression of TH mRNA was increased in a time-dependen t manner, with a significant increase in 24 h to 7 days, in the hippocampus after induction of transient forebrain ischemia, as determined using the r everse transcription and polymerase chain reaction method. Although it has been suggested that the increase of dopamine beta-hydroxylase mRNA expressi on correlates with the activation of noradrenergic neurons, no increase of dopamine beta-hydroxylase mRNA in the hippocampus was observed in our syste m. Western blot analysis revealed that TH protein, but not dopamine beta-hy droxylase protein, was produced in a time-dependent manner in the hippocamp us during the ischemia. Interestingly, the induction level of TH mRNA was r educed by intrahippocampal microinjection of GDNF (1.0 mu g), and this loca l 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 sug gest that GDNF protects against neuronal degeneration including delayed neu ronal death in the hippocampal CA1 region by modulating the expression leve ls of TH mRNA and protein.