DOPAMINE TURNOVER AND METABOLISM IN THE STRIATUM OF PARKINSONIAN RATSGRAFTED WITH GENETICALLY-MODIFIED HUMAN ASTROCYTES

The potential of a novel therapeutic approach for treating Parkinson's disease, which involves the transplantation of a transfected human as trocyte cell line SVG-TH, that stably expresses the rate-limiting enzy me for dopamine production, tyrosine hydroxylase, was examined. SVG-TH and untransfected parent cells were grafted into the diseased striatu m of rats in which Parkinson's disease had been induced by the adminis tration of 6-hydroxydapamine. The in situ production and spillover of 3,4-dihydroxyphenylalanine (the precursor of dopamine), dopamine and t heir metabolites in the striatal extracellular fluid of the grafted ra ts was determined in conscious animals using the microdialysis techniq ue and a high pressure liquid chromatography apparatus. Alleviation of symptoms of Parkinson's disease (abnormal movements) was evaluated by rotation tests. Upon transplantation of the SVG-TH cells into the str iatum of the parkinsonian rats, the levels of dopamine in extracellula r fluid of the striatum reached those of the normal rats, and correlat ed well with the improvement (74%) in their rotating behaviour (behavi oural deficit). The levels of the two main dopamine metabolites, dihyd roxyphenylacetic acid and homovanillic acid, were low in the lesioned rats, even after SVG-TH transplantation. An alternative route of metab olism of dopamine may occur in the transplanted striatum, since the do pamine metabolite, 3-O-methoxy-4-hydroxy-phenylethylamine, appeared, w hich indicates activity of catechol-O-methyl transferase. Upon blockad e of L-aromatic-amino acid decarboxylase, 3,4-dihydroxyphenylalanine a ccumulated in extracellular fluid of the 6-hydroxydopamine-lesioned an d SVG-TH-grafted rats, which indicated that these cells produced activ e tyrosine hydroxylase in vivo. These findings indicate the potential of treating Parkinson's disease by the intrabrain grafting of human as trocyte cells transfected with the rate limiting enzyme for dopamine p roduction. (C) 1998 IBRO. Published by Elsevier Science Ltd.