Presence of N-methyl-norsalsolinol in the CSF: correlations with dopamine metabolites of patients with Parkinson's disease

doi:10.1016/0022-510X(95)00110-N

Journal of the Neurological Sciences

Volume 131, Issue 2, August 1995, Pages 183-189

https://doi.org/10.1016/0022-510X(95)00110-N Get rights and content

Abstract

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 3-0-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.

References (33)

A. Ayala et al.
Reduction of 1-methyl-1,2,3,4-tetrahydroisoquinoline level in substantia nigra of the aged rat
Brain Res.
(1994)
G.L. Bernardini et al.
Increased midbrain dopaminergic cell activity following 2CH₃-MPTP-induced dopaminergic cell loss: an in vitro electrophysiological study
Brain Res.
(1990)
T. Fukuda
2-Methyl-1,2,3,4-tetrahydroisoquinoline does dependently reduce the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra and the locus ceruleus of C57BL/6J mice
Brain Res.
(1994)
M. Gerlach et al.
Determination of L-dopa and 3-O-methyl dopa in human plasma by extraction using C₁₈ cartridges followed by high performance liquid chromatographic analysis with electrochemical detection
J. Chromatog.
(1986)
A. Gjerris et al.
CSF dopamine increased in depression: CSF dopamine, noradrenaline and their metabolites in depressed patients and in controls
J. Affect. Disord.
(1987)
Y. Makino et al.
Presence of tetrahydroisoquinoline and 1-methyl-tetrahydroisoquinoline in foods, compounds related to Parkinson's disease
Life Sci.
(1988)
A. Moser et al.
Presence of methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, derivatives of the neurotoxin isoquinoline, in parkinsonian lumbar CSF
Life Sci.
(1992)
T. Nagatsu et al.
An endogenous substance of the brain, tetrahydroisoquinoline, produces parkinsonism in primates with decreased dopamine, tyrosine hydroxytase and biopterin in the nigrostrialal regions
Neurosci. Lett.
(1988)
M. Naoi et al.
A N-methyltransferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline into N-methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin, N-methylisoquinolinium ion
Biochem. Biophys. Res. Commun.
(1989)
T. Niwa et al.
Migration of tetrahydroisoquinoline, a possible parkinsonian neurotoxin, into monkey brain from blood as proved by gas chromatography-mass spectrometry
J. Chromatog.
(1988)

T. Niwa et al.

Presence of 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydro-isoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, novel endogenous amines, in parkinsonian and normal human brains

Biochem. Biophys. Res. Commun.

(1991)

T. Origitano et al.

Rat brain salsolinol and blood-brain barrier

Brain Res.

(1981)

M. Yoshida et al.

Parkinsonism in monkeys produced by chronic administration of an endogenous substance of the brain, tetrahydroisoquinoline: the behavioral and biochemical changes

Neurosci. Lett.

(1990)

R.S. Burns et al.

A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine

C.J. Coscia et al.

Occurrence of a new class of tetrahydroisoquinoline alkaloids in L-dopa-treated parkinsonian patients

Nature

(1977)

P. Dostert et al.

Biosynthesis of salsolinol, a tetrahydroisoquinoline alkaloid, in healthy subjects

J. Neural Transm.

(1990)

Cited by (53)

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In spite of the enormous scientific interest raised by its widespread use, ethanol still remains, from the pharmacological and toxicological standpoints, an elusive molecule. Accordingly, its effects cannot be attributed only to actions onto specific targets (receptors, enzymes, channels, etc.) nor to the unique involvement of neurotransmitter systems (glutamate, GABA, dopamine, opioid peptides, etc.). Both the pharmacological and toxicological effects of ethanol, in fact, have also been related to its metabolic conversion into acetaldehyde, a highly reactive molecule that, besides other properties, shows the ability to condensate, spontaneously or enzymatically, with nucleophilic compounds to form tetrahydroisoquinolines. Among the latter, salsolinol has recently received a great deal of attention both for its neurobiological properties potentially related to alcoholism development and for its neurotoxicity. Accordingly, although detected at very low concentrations in ethanol-naïve subjects, salsolinol appears particularly enriched in the brain, in dopamine-containing nuclei where its main metabolites, N-methyl-salsolinol and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, may exert cytotoxic effects. This chapter recapitulates the most compelling evidence that relates ethanol-derived salsolinol to the neurobiological basis of alcoholism and to the suggested emergence of neurological disorders associated, in particular, to dopamine neurodegeneration.
N-methyltetrahydropyridines and pyridinium cations as toxins and comparison with naturally-occurring alkaloids
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In general, the concentrations detected of TIQs in human brain are in the low pmol/g tissue. TIQs derived from dopamine (i.e those with two ortho-hydroxyl substituents) were found in higher levels than other TIQs, and accumulated in the nigrostriatal region (DeCuypere et al., 2008; Moser et al., 1995; Naoi et al., 1996c, 2004). In some studies, the level of dopamine-derived TIQs (e.g. salsolinol, 2-methyl-R-salsolinol) in the CSF of PD patients was significantly higher than in controls but it was not confirmed in other studies (Muller et al., 1999; Naoi et al., 2002).
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium cation (MPP⁺) are selective dopaminergic neurotoxins producing Parkinsonism. MPTP is activated by monoamine oxidase-B (MAO-B) to MPP⁺ that inhibits mitochondrial function. Molecules resembling MPTP which afford pyridinium cations are also neurotoxins. The herbicide paraquat (a bipyridinium dication) and the naturally-occurring β-carboline and isoquinoline alkaloids are structural analogues of MPTP/MPP⁺. Paraquat generates reactive oxygen species (ROS) producing neurotoxicity by a mechanism that differs from MPTP/MPP⁺. Human exposure to PQ is increasingly associated with neurodegeneration. Tetrahydro-β-carbolines (THβCs), β-carbolines (βCs) and tetrahydroisoquinolines (TIQ_s) are bioactive compounds occurring in foods and the human body. They are not MPTP-like toxins and do not appear to induce neurotoxicity at normal levels of exposure. Among TIQs, endogenous dopamine-derived TIQs (i.e. salsolinol) and 1-benzyl-TIQ are toxic through ROS generation. In contrast, β-carbolinium (βC⁺s) and isoquinolinium cations (IQ⁺s) are neurotoxicants resembling MPP⁺ although they are less potent and selective. βC⁺s and IQ⁺s have been detected in the human brain but their toxicological significance remains unknown. THβCs/βCs and TIQs are activated to toxic cations by N-methyltransferases (NMT) and/or heme peroxidases and are metabolized by cytochrome P450 enzymes. Remarkably, recent findings suggest, instead, that βCs and TIQs are neuroprotectants and neurorestorative, raising the interest of these molecules.
Neuromodulation in Tourette syndrome: Dopamine and beyond
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Citation Excerpt :
Furthermore, exogenously administered TIQ are known to produce changes of motor activity in rodents (Hipólito et al., 2010). In humans, TIQ are found at low concentrations in post-mortem brains (Niwa et al., 1991), cerebrospinal fluid (Moser et al., 1995) and urine (Scholz et al., 2004). In the human brain concentration of the TIQ derivative salsolinol and its metabolites are highest in the basal ganglia (Musshoff et al., 1999).
Almost since the beginning of research on Tourette syndrome (TS), tics have been linked to a dysfunction of the dopamine (DA) system. At first, this assumption was mainly based on clinical findings of DA antagonists being the most effective drug in treating tics, but in recent years nuclear imaging has enabled a much deeper understanding of DA neurotransmission in TS. Based on the findings of various PET and SPECT studies the first part of the review discusses four hypotheses on DA dysfunctions in TS: (i) DA hyperinnervation, (ii) supersensitive DA receptors, (iii) pre-synaptic DA abnormality and (iv) DA tonic-phasic dysfunction. According to the latter hypothesis, reduced levels of tonic DA in the extracellular space lead to higher concentrations of DA in the axon terminal and an increase of stimulus-dependent DA release. The second part of the review addresses the modulating role of DA in some major clinical features of TS, like the exacerbation with stress or infection and the association with deficient sensorimotor gating.
Opioid-salsolinol relationship in the control of prolactin release during lactation
2010, Neuroscience
Endogenous opioid peptides (EOP) and dopamine (DA)-derived salsolinol are implicated in the suckling-induced prolactin surge. The aim of this study was to investigate the relationship between the opioidergic and salsolinergic activity in the mediobasal hypothalamus of nursing sheep. The sheep were infused intracerebroventricularly with opioid receptors antagonists: naloxone (all types of receptors, n=6); naloxonazine (μ receptor, n=6) or the vehicle (control, n=6) in a series of five 30-min infusions (60 μg/60 μl) from 10:00 to 15:00, at 30-min intervals. The period of the experiment included the non-suckling (10:00–12:30) and suckling (12:30–15:00) periods. Simultaneously, a push–pull perfusion of the infundibular nucleus/median eminence was performed in every sheep to study the dopaminergic system activity. Blood samples were also collected at 10-minute intervals to determine plasma prolactin concentration. Both the mean perfusate salsolinol and plasma prolactin concentrations were higher during the suckling vs. non-suckling (P<0.001) period in the control. The perfusate DA concentration was below the detection limit in this group. Treatment with either naloxone or naloxonazine significantly (P<0.01) diminished plasma prolactin concentration, as compared with the controls and blocked the prolactin surge during suckling. In drug-infused sheep, the perfusate salsolinol concentration was below the detection limit but the increased DA and its metabolite 3,4-dihydroxyphenylacetic acid concentrations were observed. In conclusion, the stimulatory action of EOP on prolactin secretion in nursing females is mediated, at least in part, by salsolinol, and the ligands for μ opioid receptor may be the primary factors of this relationship, especially with respect to the suckling-induced prolactin surge.
Ferritin enhances salsolinol-mediated DNA strand breakage: Protection by carnosine and related compounds
2009, Toxicology Letters
Salsolinol is an endogenous neurotoxin, known to be involved in the pathogenesis of neurodegenerative disorders. In this present study, we have attempted to characterize the oxidative damage of DNA induced by the reaction of salsolinol with ferritin. When DNA was incubated with salsolinol and ferritin, DNA strand breakage occurred. Hydroxyl radical scavengers and catalase reduced salsolinol/ferritin system-mediated DNA cleavage, whereas Cu,Zn-superoxide dismutase did not inhibit DNA cleavage. The reaction of salsolinol with ferritin resulted in a time-dependent increase in the release of free iron ions. A strong iron chelator, ferrozine, effectively inhibited the salsolinol/ferritin system-mediated DNA cleavage. Ferritin enhanced a mutation of the lacZ′ gene in the presence of salsolinol when measured as a loss of α-complementation. These results indicate that salsolinol/ferritin system-mediated DNA cleavage and mutation may be attributable to hydroxyl radical generation via the Fenton-like reaction of free iron ions released from oxidatively damaged ferritin. The endogenous dipeptides, carnosine and related compounds, are naturally occurring compounds with a multiplicity of neuroprotective properties. Carnosine, homocarnosine and anserine significantly inhibited salsolinol/ferritin system-mediated DNA strand breakage and mutation. These results indicate that carnosine and related compounds effectively suppressed the salsolinol/ferritin system-mediated DNA strand breakage via hydroxyl radical scavenging.
Quantitative Determination of Endogenous Tetrahydroisoquinolines, Potential Parkinson's Disease Biomarkers, in Mammals
2022, ACS Chemical Neuroscience

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Research articlePresence of N-methyl-norsalsolinol in the CSF: correlations with dopamine metabolites of patients with Parkinson's disease

Abstract

Brain Res.

Brain Res.

Brain Res.

J. Chromatog.

J. Affect. Disord.

Life Sci.

Life Sci.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

J. Chromatog.

Biochem. Biophys. Res. Commun.

Brain Res.

Neurosci. Lett.

A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine

Occurrence of a new class of tetrahydroisoquinoline alkaloids in L-dopa-treated parkinsonian patients

Nature

Biosynthesis of salsolinol, a tetrahydroisoquinoline alkaloid, in healthy subjects

J. Neural Transm.

Research article
Presence of N-methyl-norsalsolinol in the CSF: correlations with dopamine metabolites of patients with Parkinson's disease