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.