Parallel induction of the formation of dopamine and its metabolites with induction of tyrosine hydroxylase expression in foetal rat and human cerebral cortical cells by brain-derived neurotrophic factor and glial-cell derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF; 50 ng/ml), dopamine (DA; 10 muM) a nd forskolin (Fsk; 10 muM) have previously been shown by this and other lab oratories to induce the tyrosine hydroxylase (TH) enzyme in foetal human an d rat cerebral cortex during specified sensitive developmental periods. In the present study, these findings were extended for human and rat cells by showing that the induced TH+ cells also produce dopamine and its metabolite 3,3-dihydroxyphenylacetic acid (DOPAC). In addition to this, TH induction and DA plus DOPAC production was observed in foetal human and rat cerebral cortex by using glial-cell derived neurotrophic factor (GDNF) in place of B DNF. The degree of induction by GDNF (1-10 ng/ml) was similar to that produ ced by BDNF and did not increase further when the two neurotrophic factors were used together. The time-course of induction in human cultures was foll owed: GDNF was found to cause a mon rapid induction process than BDNF durin g the first 2 weeks. However the degree of induction after 3 weeks was the same for both neurotrophic factors. Inhibitors of transcription (actinomyci n D) or of translation (cycloheximide) eliminated all the increase in DA+DO PAC contents elicited by these compounds, indicating that de novo transcrip tion and translation were required for increased expression of the TH and o ther related enzymes. The intracellular pathways by which these molecules e xert this dopaminergic phenotype induction effect are discussed. This study indicates a new source of dopaminergic brain tissue for use as transplants to neurosurgically treat Parkinson's disease patients. (C) 2001 Elsevier S cience B.V. All rights reserved.