Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains.

Salsolinol, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, is an endogenous catechol isoquinoline detected in humans by M. Sandler. In human brain, a series of catechol isoquinolines were identified as the condensation products of dopamine or other monoamines with aldehydes or keto-acids. Recently selective occurrence of the (R)enantiomers of salsolinol derivatives was confirmed in human brain, and they are synthesized by enzymes in situ, but not by the non-enzymatic Pictet-Spengler reaction. A (R)salsolinol synthase catalyzes the enantio-specific synthesis of (R)salsolinol from dopamine and acetaldehyde, and (R)salsolinol N-methyltransferase synthesizes N-methyl(R)salsolinol, which is further oxidized into 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion by non-enzymatic and enzymatic oxidation. The step-wise reactions, N-methylation and oxidation, induce the specified distribution of the N-methylated and oxidized derivatives in the human nigro-striatum, suggesting that these derivatives may be involved in the function of dopamine neurons under physiological and pathological conditions. As shown by in vivo and in vitro experiments, salsolinol derivatives affect the levels of monoamine neurotransmitters though the inhibition of enzymes related in the metabolism of catechol- and indoleamines. In addition, the selective neurotoxicity of N-methyl(R)salsolinol to dopamine neurons was confirmed by preparation of an animal model of Parkinson's disease in rats. The involvement of N-methyl(R)salsolinol in the pathogenesis of Parkinson's disease was further indicated by the increase in the N-methyl(R)salsolinol levels in the cerebrospinal fluid and that in the activity of its synthesizing enzyme, a neural (R)salsolinol N-methyltransferase, in the lymphocytes prepared from parkinsonian patients. N-methyl(R)salsolinol induces apoptosis in dopamine neurons, which is mediated by death signal transduction in mitochondria. In addition, salsolinol was found to function as a signal transmitter for the prolactin release in the neuro-intermediate lobe of the brain. These results are discussed in relation to role of dopamine-derived endogenous salsolinol derivatives as the regulators of neurotransmission, dopaminergic neurotoxins and neuro-hormonal transmitters in the human brain.