Alkaloids in mammalian tissues. 4. Synthesis of (+)- and (-)-salsoline and isosalsoline.
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Alkaloids↗
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Interaction of salsolinol and tetrahydropapaveroline with catecholamines.
Formation of aberrant amine metabolites, tetrahydroisoquinolines (TIQs) has been hypothesized to account for some of the effects of ethanol. These compounds have been shown to interact with catecholamine neurons in a variety of ways by in vitro techniques. The most interesting facet of these alkaloids, however, is the fact that they cause an increase in preference for and voluntary consumption of ethanol when administered into the ventricle of the rat in exceedingly low amounts. Investigation of the neurochemical effects in vivo of two of the TIQs tetrahydropapaveroline (THP) and salsolinol, indicates that they influence several aspects of presynaptic catecholamine function when examined acutely. The mechanism of action responsible for the radical long-lasting behavioral effects of these substances has yet to be defined.
Animals↗
[Competitive inhibition of catechol-O-methyltransferase by the tetrahydroisoquinoline alkaloids salsolidine and 1-carboxysalsoline].
The tetrahydroisoquinoline alkaloids salsolidine (1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) and 1-carboxysalsoline (1-carboxy-1-methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline), which are themselves not substrates for the enzyme catechol-O-methyltransferase, are - contrary to a hitherto existing view - able to inhibit competitively the methylation of the catecholamine metabolite 3,4-dihydroxybenzoic acid by the enzyme enriched from rat liver. The inhibitor constants were determined to be Ki = 0.19 mM for salsolidine and Ki = 0.44 mM for 1-carboxysalsoline.
Animals↗
Assay for the (R)- and (S)-enantiomers of salsolinols in biological samples and foods with ion-pair high-performance liquid chromatography using beta-cyclodextrin as a chiral mobile phase additive.
A chromatographic procedure was devised for the quantitative determination of the enantiomers of salsolinol and N-methylsalsolinol, which are biologically important alkaloids. The enantiomers of salsolinol and N-methylsalsolinol were completely separated using beta-cyclodextrin in a reversed-phase ion-pair system. The HPLC method was sensitive enough to detect the isoquinolines at a concentration less than 0.1 pmol per injection. The presence of (R)- and (S)-salsolinol was confirmed in fermented foods and beverages, while N-methylsalsolinol was not detected. On the other hand, the (R)-enantiomers of both salsolinol and N-methylsalsolinol were found to predominate in the human brain.
Beverages↗
Determination of the (R)- and (S)-enantiomers of salsolinol and N-methylsalsolinol by use of a chiral high-performance liquid chromatographic column.
A new method for the quantitative determination of the enantiomers of salsolinol and N-methylsalsolinol, biologically important alkaloids, is reported. The enantiomers were completely separated without derivatization, using a cyclodextrin-modified silica gel column with an HPLC-electrochemical detection system. The HPLC conditions were examined for the best resolution. The method was sensitive enough to detect salsolinol and N-methylsalsolinol at a concentration of less than 0.1 pmol per injection. In the product of the Pictet-Spengler reaction of acetaldehyde with dopamine or epinine, almost equimolar (R)- and (S)-enantiomers of salsolinol and N-methylsalsolinol were detected. Preliminary results indicate that the (R)-enantiomer of both isoquinoline derivatives predominate in the human brain.
Chromatography, High Pressure Liquid↗
Detection of endogenous salsolinol in neonatal rat tissue by a radioenzymatic--thin-layer chromatographic assay.
A sensitive radioenzymaticc--thin-layer chromatographic assay for the quantitative analysis of the tetrahydroisoquinoline alkaloid, salsolinol, in plasma and neonatal rat tissue is described. The assay involves the enzymatic O-methylation of salsolinol by catechol-O-methyltransferase in presence of [3H]S-adenosylmethionine, and subsequent separation by thin-layer chromatography of the resultant [3H]O-methyl-salsolinol from the O-methylated derivatives of dopamine, epinephrine and norepinephrine. The method allows the detection of as little as 100 pg salsolinol per g tissue, and the accurate quantitation of as little as 100 pg/ml plasma and 500 pg/g tissue. This assay permitted the detection of trace amounts of endogenous salsolinol in neonatal rat tissue (less than 500 pg/g tissue).
Animals↗
Demonstration of highly specific and sensitive antibodies to a naturally occurring tetrahydroisoquinoline alkaloid, salsolidine.
1. We report for the first time on the production and characterization of antibodies against a naturally occurring tetrahydroisoquinoline, namely salsolidine (6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline). 2. Immunogen synthesis was carried out by coupling the hapten salsolidine to bovine serum albumin (BSA) as carrier protein on the basis of reductive amination. 3. By immunization of rabbits with salsolidine-BSA conjugate antisalsolidine antibodies were produced. 4. At a final dilution of 1:1700 the highest-titre antiserum bound 35% of 0.21 pmol [3H]salsolidine. This antiserum was used to develop a radioimmunoassay for salsolidine. 5. Cross-reactivity studies revealed a high specificity of the antiserum to the hapten. 6. The antibodies had a high affinity to salsolidine (Ka = 1.5 x 10(9) M-1). 7. Standard curves covered a measuring range of 0.5-70 pmol/tube and the detection limit was found to be 0.27 pmol/tube.
Animals↗
Simultaneous gas chromatographic-mass spectrometric determination of dopamine, norsalsolinol and salsolinol enantiomers in brain samples of a large human collective.
Using a solid-phase extraction procedure, an enantioselective derivatization and a gas chromatographic-mass spectrometric method, the levels of dopamine (DA) and of the dopamine-derived tetrahydroisoquinoline alkaloids (R)/(S)-salsolinol (SAL) and norsalsolinol (NorSAL) were determined in human brain samples. A complex pre-analytical synthesis of reference substances as well as deuterated internal standards allowed the standardized and reproducible analysis. In this study, to our best knowledge for the first time, the regional distribution of (R)-SAL and (S)-SAL, as well as NorSAL is examined systematically in a large collective of human brain samples obtained by autopsy. The material comprises 91 brains and 8 standardized specimens in each case. Anatomical concentration differences and no ubiquitous occurence were encountered. Significant amounts of (R)-SAL, (S)-SAL and NorSAL were only found in dopamine-rich areas of the basal ganglia, whereas in other regions of the brain no tetrahydroisoquinolines were detected. These findings suggest that the concentration of the substrate dopamine may determine the alkaloid level during in vivo formation. In our opinion, non-enzymatic formation of SAL via the Pictet-Spengler reaction reveals both the SAL enantiomers. An additional enzymatic synthesis of only (R)-SAL could explain the predominant occurrence of this enantiomer. Especially in the nucleus caudatus, the concentrations of DA, SAL and NorSAL decreased significantly with rising age, which may be consistent with apoptotic effects of ageing. Our data can serve as reference for other studies in humans concerning the etiology of alcoholism or other neurodegenerative diseases with the involvement of tetrahydroisoquinolines.
Adult↗
Dopamine-derived endogenous N-methyl-(R)-salsolinol: its role in Parkinson's disease.
A dopamine-derived alkaloid, N-methyl-(R)-salsolinol [NM(R)Sal], enantioselectively occurs in human brains and accumulates in the nigrostriatal system. It increases in the cerebrospinal fluid (CSF) of parkinsonian patients and the activity of a neutral (R)-salsolinol [(R)Sal] N-methyltransferase, a key enzyme in the biosynthesis of this toxin, increases in the lymphocytes from parkinsonian patients, suggesting its involvement in the pathogenesis of Parkinson's disease (PD). The studies of animal and cellular models of PD proved that this isoquinoline is selectively cytotoxic to dopamine neurons. Using human dopaminergic SH-SY5Y cells, NM(R)Sal induces apoptosis by the activation of the apoptotic cascade initiated in mitochondria. In this article, we review the recent advance in proving our hypothesis that the dopamine-derived neurotoxin causes the selective depletion of dopamine neurons in PD.
Animals↗
Absence of a role for salsolinol in the mechanism of ethanol teratogenicity.
Alcohol and its primary metabolite, acetaldehyde, are central nervous system teratogens. Acetaldehyde can further interact with endogenous biogenic amines under certain conditions to generate tetrahydroisoquinoline (TIQ) alkaloidal metabolites, some of which interfere with adrenergic neuronal function and structural integrity. The possible role of salsolinol (the TIQ derived from the condensation of acetaldehyde with dopamine) in the mechanism of alcohol teratogenicity was investigated in rats. Administration of 2 mg/kg of salsolinol to rats on the 15th day of gestation did not result in the recovery of this TIQ in the fetuses. Furthermore, acute oral administration of alcohol (3 g/kg x 3 doses) to rats on different days of gestation did not result in the synthesis of salsolinol by the fetuses despite the high maternal blood ethanol levels (124 +/- 22 mg%). These findings argue against a role for salsolinol in the mechanism of alcohol teratogenicity. Small amounts of endogenous salsolinol (3.6 ng/g) were detected in fetuses from control rats, in agreement with previous findings in neonatal rats. The physiological role (if any) of endogenous salsolinol in the fetal and neonatal rat is not known.
Abnormalities, Drug-Induced↗
Oxidation chemistry of the endogenous central nervous system alkaloid salsolinol-1-carboxylic acid.
The oxidation chemistry of salsolinol-1-carboxylic acid (1), an alkaloid endogenous to the central nervous system which is elevated as a result of ethanol consumption, has been studied by electrochemical approaches at pH 7.0 in aqueous solution. The first voltammetric oxidation peak of Ia of 1 at pH 7.0 occurs at Ep = +0.116 V, indicating that this alkaloid is a very easily oxidized compound. The peak Ia reaction is a 2e-2H+ oxidation of 1 to 1,2,3,4-tetrahydro-1-methyl-1-carboxy-6,7-isoquinolinedione (8), which rapidly decarboxylates (k > 10(3) s-1) to give predominantly the quinone methide tautomer of 3,4-dihydro-1-methyl-6,7-isoquinolinediol (2). The latter compound is responsible for the second observed oxidation peak IIa observed with 1. This peak is a 2e oxidation of 2 to a quinoid intermediate (9) which can either be attacked by water to yield 3,4-dihydro-1-methyl-5,7-dihydroxyisoquinolin-6-one (13b) (which is readily further oxidized to 3,4-dihydro-1-methyl-5-hydroxyisoquinoline-6,7-dione (3)) or aromatizes to yield 1-methyl-6,7-isoquinolinediol (4). Preliminary in vivo experiments have revealed that 2 and 13b are behavioral toxins when injected into the brains of laboratory mice. The in vitro oxidation reactions of 1 and 2 reported here might be of relevance to the neurodegenerative, behavioral, and addictive consequences of chronic alcoholism.
Animals↗
Tetrahydroisoquinoline derivatives of enkephalins: synthesis and properties.
Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds deriving from the non-enzymatic Pictet-Spengler condensation of catecholamines with aldehydes. These compounds are able to unsettle catecholamines uptake and release from synaptosomes and have been detected in urine and in post-mortem Parkinsonian brains. We have obtained in vitro, by the reaction of dopa-enkephalin (dopa-Gly-Gly-Phe-Leu) with acetaldehyde in the presence of rameic ions, a TIQ derivative of Leu-enkephalin. The isolation and the recovery of the peptide was obtained by HPLC. The acid hydrolysis and the subsequent analysis of the peptide lysate by the Amino acid analyser clearly revealed the absence of dopa, while the electrospray ionisation mass spectrometry showed that the sequence of the enkephalin derivative was the following: 3-carboxy-salsolinol-Gly-Gly-Phe-Leu (TIQ-enkephalin). This compound was not a good substrate for microsomal aminopeptidase and pronase with respect to Leu-enkephalin. Tested in the binding assay, the TIQ-enkephalin exhibited a very poor affinity toward the enkephalin receptors. When the TIQ-enkephalin was incubated with tyrosinase or peroxidase/H(2)O(2), the formation of TIQ-opio-melanins occurred.
Binding Sites↗
No increase of synthesis of (R)salsolinol in Parkinson's disease.
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Adult↗
A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in Parkinsonian cerebrospinal fluid.
The concentration of (R)-N-methylsalsolinol, which is a dopamine-derived neurotoxin selective to dopamine neurons and induces parkinsonism in rats, was found to be increased significantly in the cerebrospinal fluid of untreated patients with Parkinson's disease. The enantio-specific occurrence of (R)-N-methylsalsolinol in cerebrospinal fluid suggests its enzymatic synthesis in the human brain. The individual differences in the activities of the enzymes determining the metabolism of (R)-N-methylsalsolinol in the brain might be involved in the pathogenesis of Parkinson's disease.
Aged↗
A new rapid method for the analysis of catecholic tetrahydroisoquinolines from biological samples by gas chromatography/mass spectrometry.
A new method for the analysis of tetrahydroisoquinolines (TIQ) from biological materials is described. The method combines extraction and acylation of the TIQs from urine in a one-step procedure followed by analysis by gas chromatography/mass spectrometry. By this extractive derivatization method, a decrease of the extraction time, to speed up sample preparation in order to minimize oxidative side reaction, has been achieved. The detection limits for the analysis of salsolinol and salsolin in urine were 10 fmol/ml sample volume. Tetrahydropapaveroline could only be detected in spiked urine samples with a detection limit of 1 pmol/ml urine. The method is not only restricted to urine samples, but can also be applied to a variety of tissue types, including blood components.
Gas Chromatography-Mass Spectrometry↗
Half-lives and actions of intracerebrally injected isoquinolines.
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Animals↗
Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (-)deprenyl.
An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson's disease. In Parkinson's disease, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid and the high activity of a synthesizing enzyme, (R)salsolinol N-methyltransferase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol isoquinolines, only N-methylsalsolinol induced apoptosis in the cells, and the scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, suggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson's disease apoptosis may be induced in dopamine neurons by this endogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.
Apoptosis↗
Oxidation of N-methyl(R)salsolinol: involvement to neurotoxicity and neuroprotection by endogenous catechol isoquinolines.
1(R), 2(N)-Dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl(R)salsolinol, is a potent dopaminergic neurotoxin to induce parkinsonism in rats. The cytotoxicity of N-methyl(R)salsolinol proved to be ascribed to its oxidation into cytotoxic 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion with generation of hydroxyl radical. The isoquinolinium ion caused massive necrosis in the striatum, whereas N-methyl(R)salsolinol depleted selectively dopaminergic neurons in the substantia nigra without necrotic tissue reaction. N-Methyl(R)salsolinol induced DNA damage to human neuroblastoma SH-SY5Y cells, which could be prevented by anti-oxidants and cycloheximide. These results suggest that oxidative stress through oxidation of N-methyl(R)salsolinol induces apoptotic cell death. On the other hand, (R)salsolinol proved to scavenge hydroxyl radical produced by oxidation of dopamine. The neurotoxicity and neuroprotection of catechol isoquinolines may be ascribed to their oxidation and scavenging of radicals.
3,4-Dihydroxyphenylacetic Acid↗