Metabolic Bioactivation of Endogenous Isoquinolines as Dopaminergic Neurotoxins to Elicit Parkinson’s Disease

Abstract

After the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), endogenous and exogenous compounds have been intensively studied as pathogenic neurotoxins to elicit Parkinson’s disease (PD). The studies on animal PD models with MPTP reveal common and basic characteristics of the dopaminergic neurotoxins. MPTP is transported into the brain through the blood-brain-barrier and is oxidized into a more potent neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP⁺) by type B monoamine oxidase [monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4, MAO]. The oxidation of MPTP is essential for the selective uptake and accumulation in dopamine neurons. The inhibition of oxidative phosphorylation and formation of active oxygen species are considered to cause the cell death of dopamine neurons in the nigro-striatum. Using such characteristics as markers, neurotoxin candidates have been screened among the dopamine metabolites and the related compounds. In the human brain, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (DHTIQs) and 1,2,3,4-tetrahydroisoquinolines (TIQs) have been identified as monoamine-derived isoquinolines. One of them, 1-methyl-DHTIQ (salsolinol, Sal) is well known to occur in humans (Sandler et al., 1973; Barker et al., 1981), and it is thought to result from condensation of dopamine with pyruvic acid, followed by decarboxylation and reduction (Dostert et al., 1990). The last reaction is probably enzymatic, but has not been well characterized, while there is evidence that the decarboxylation can occur non-enzymatically. This biosynthesis pathway produces (R)salsolinol [(R)Sal], which is detected in healthy subjects (Strolin Benedetti et al., 1989). Another pathway is the non-enzymatic Pictet-Spengler reaction of dopamine with an aldehyde, yielding both (R)- and (S)Sal. In addition, (S)Sal is found in the urine (Strolin Benedette et al., 1989), and of patients treated with L-DOPA (Dostert et al., 1989). On the one hand, TIQs without catechol structure are found in food and transported into the brain, or they are synthesized from β-phenethylamine. On the other hand, 1,2,3,4-tetrahydroiso-quinoline (TIQ) and 2-methyl-tetrahydroquinoline (Niwa et al., 1987) and 1-methyl-TIQ (Ohta et al., 1987) were found to occur in the human brain. TIQ was reported to induce parkinsonism in monkeys (Nagatsu and Yoshida, 1988), but the effects on dopamine neurons are transitory. The search continues for more potent neurotoxins.