Hypoxia-induced long-term increase of dopamine and tyrosine hydroxylase mRNA levels.

The aim of the present study was to determine hypoxia-induced changes in the long-term expression of tyrosine hydroxylase (TH) mRNA and the steady-state dopamine (DA) levels in rat mesencephalic cell cultures. The cultures were exposed to hypoxia during the early developmental period, and DA content and TH mRNA expression were determined on day in vitro (DIV) 14. Hypoxic exposure of 5-day-old cultures resulted in increased DA (control 89.9+/-8.9, hypoxia 135.8+/-23.7 pg/microg protein) and TH mRNA (control 37.3+/-4.7, hypoxia 143.1+/-49.4 pg/microg RNA) levels. To analyze the involvement of hypoxia-inducible factor-1 (HIF-1) in these changes, we studied its activation using reporter gene. Hypoxia caused a 3-fold increase in HIF-1 activity. Our data suggest that hypoxia/ischemia during the putative critical developmental period of neurons may determine the tyrosine hydroxylase gene expression and, consequently, the development of the dopaminergic system.