ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , Neurotoxins/pharmacology , Nucleus Accumbens/drug effects , Tetrahydroisoquinolines , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Analysis of Variance , Animals , Female , Nucleus Accumbens/enzymology , Rats , Rats, WistarABSTRACT
The effects of N-methyl-norsalsolinol on basal and inhibited activity of monoamine oxidase (MAO) in membrane preparations from the caudate nucleus of the rat have been studied. For the first time, the physiological step of dopamine oxidation to 3, 4 dihydroxyphenylacetic aldehyde (DPAA) was examined. N-methyl-norsalsolinol (2-MDTIQ) dose-dependently inhibited MAO activity with a IC50 of 33 microM. The MAO inhibitors clorgyline and deprenyl were also found to inhibit formation of DPAA. In this case, the inhibition of these antagonists, clorgyline and deprenyl, was additive. N-methyl-norsalsolinol modified neither the enzyme inhibition induced by clorgyline nor by deprenyl. These results suggest that 2-MDTIQ, the naturally occurring compound found in parkinsonian brain and cerebrospinal fluid, perturbs dopamine metabolism in basal ganglia.
Subject(s)
Caudate Nucleus/enzymology , Isoquinolines/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Tetrahydroisoquinolines , 3,4-Dihydroxyphenylacetic Acid/analogs & derivatives , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Caudate Nucleus/drug effects , Dopamine/metabolism , Female , In Vitro Techniques , Isoenzymes/metabolism , Oxidation-Reduction , Rats , Rats, WistarABSTRACT
We could identify the MPTP-like compound and isoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) in cerebrospinal fluid (CSF) of patients with Parkinson's disease. The presence of 2-MDTIQ negatively correlated with the disease duration. In order to study the relationship between presence of 2-MDTIQ and dopamine metabolism, we examined 3-O-methyl-dopa (MDOPA) and homovanillic acid (HVA) levels in CSF of 15 normal control subjects and 34 patients with Parkinson's disease (PD). In the PD group in which 2-MDTIQ was detected, the HVA/MDOPA ratio was also negatively correlated with the duration of the disease and was increased when compared to patients without 2-MDTIQ. Since in both PD groups the daily L-dopa dose, the mean MDOPA levels, and the daily L-dopa dose/MDOPA ratio were nearly identical the results are not related to different L-dopa medications. In vitro experiments demonstrated 2-MDTIQ to inhibit monoamine oxidase activity in the caudate-putamen. These results suggest that 2-MDTIQ indicates an increased dopamine turnover in patients with PD. The enhanced metabolism at the beginning of the disease is not due to the presence of 2-MDTIQ since it inhibits dopamine metabolism. Thus, 2-MDTIQ, probably endogenously synthesized from dopamine, appears as a result of a compensatively activated dopaminergic system.
