Differential effects of hypoxia on untreated and NGF treated PC12 cells

Perinatal hypoxia is known to induce long-lasting changes in the central do paminergic system. In order to understand the cellular mechanism of these c hanges, we studied the effects of hypoxia on the levels of dopamine (DA) an d tyrosine hydroxylase (TH) mRNA in untreated and NGF treated PC12 cells. O n the second day after plating (DAP), cells were exposed to a hypoxic episo de (pO(2) = 10-20 mm Hg, 24 h), and the levels of DA and TH mRNA were exami ned on DAP 4 and DAP 8. In untreated cells, hypoxia induced a two fold incr ease both in DA and TH mRNA levels on DAP 4 which normalized up to DAP 8. T his increase correlated with an activation of the hypoxia inducible factor (HIF-1alpha), measured with a reporter gene. In contrast, NGF treated cells responded to hypoxia with an increase of DA level on DAP 8. In these cells neither an increase of the HIF-1 alpha activity measured immediately after hypoxia nor a significant increase of the TH mRNA level on DAP 8 were foun d. The findings indicate that NGF shifts the hypoxia induced changes of DA levels from a short-term to a long-term mode. The long-term increase of dop amine levels is the most likely result of changes connected with cell growt h and differentiation and not the result of a long-term TH mRNA level incre ase. (C) 2000 Elsevier Science Inc. All rights reserved.