N-methyl-norsalsolinol, an endogenous neurotoxin, inhibits tyrosine hydroxylase activity in the rat brain nucleus accumbens in vitro.

As a compound of structural analogy with MPTP, N-methyl-norsalsolinol (2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; 2-MDTIQ) was recently identified in the brain and cerebrospinal fluid of patients with Parkinson's disease. As 2-MDTIQ cannot pass the blood-brain barrier, endogenous formation is suggested. Previous studies of the dopamine metabolism in Parkinson's disease have demonstrated an increased dopamine turnover in the presence of 2-MDTIQ. In the present study, we investigated the effect of 2-MDTIQ on tyrosine hydroxylase [L-tyrosine, tetrahydropteridine, oxygen: oxidoreductase (3-hydroxylating). EC 1.14.16.2; TH] activity in vitro using homogenated tissue of the rat nucleus accumbens as enzyme source. Basal TH activity was 20.1 +/- 5.9 pmol L-3,4-dihydroxyphenylalanine (L-DOPA)/min/mg protein. 2-MDTIQ non-competitively inhibited basal TH activity with an IC50 of 10 microM. After addition of 0.1 mM 2-MDTIQ, enzyme activity was nearly completely blocked. These results indicate that the endogenous formation of 2-MDTIQ in consequence of an impaired dopamine metabolism may in turn lead to a decrease in dopamine synthesis. Thus, 2-MDTIQ is suggested not only to represent an endogenous marker of Parkinson's disease, but also to support changes in the transmitter synthesis of dopaminergic neurons. Since previous investigations have moreover demonstrated a cytotoxic potential of 2-MDTIQ, these findings require special attention. 2-MDTIQ may represent an essential factor in the degenerative process of Parkinson's disease.