Catecholamine‐Derived Tetrahydroisoquinolines: <i>O‐</i>Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Several members of the tetrahydroisoquinoline (TIQ) family of monoamine alkaloids can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell death in Parkinson's disease (PD). Using enantiomeric-selective high-performance liquid chromatography with electrochemical detection and liquid chromatography with tandem mass spectroscopy, the regional concentrations of several TIQ derivatives, including salsolinols, were determined in mouse, rat, normal human, and PD brain. TIQ derivatives were detected in all regions subjected to analysis. In general, salsolinols were present at higher concentrations than TIQ and its benzyl and methyl derivatives, especially in human brain. Moreover, salsolinols were concentrated in areas with increased dopamine synthesis and turnover such as the ventral midbrain and striatum, respectively. A possible consequence of nigrostriatal dopaminergic cell death, significantly lower levels of (R)salsolinol, (S)salsolinol, N-methyl-(R)salsolinol and N-methyl-(S)salsolinol were found in the caudate nuclei of PD in comparison with normal human brain. Our data support the hypothesis of endogenous synthesis of salsolinols and provide evidence for their accumulation in catecholaminergic neurons. Keywords: N-methyl-salsolinol, Parkinson's disease, salsolinol, substantia nigra pars compacta, tetrahydroisoquinoline. Bayerle 1934;Cohen and Collins 1970). Other derivatives can then be generated from SAL via the addition and/or subtraction of methyl groups via transferases . As a result, SAL and a number of its derivatives have been detected in brain tissue (Sjöquist et al. 1982a,b;Musshoff et al. 1999Musshoff et al. , 2000Musshoff et al. , 2003Musshoff et al. , 2005 Tóth et al. 2001;Naoi et al. 2002Naoi et al. , 2004. In addition to endogenous synthesis, TIQ derivatives may also derive from exogenous sources. For example, TIQ and many of its derivatives are natural substances in plants (Rommelspacher and Susilo 1985) and have been detected in certain foods and beverages consumed by humans Duncan and Smythe 1982;Duncan et al. 1984;Makino et al. 1988;Niwa et al. 1989;Collins et al. 1990). Several TIQ derivates have also demonstrated blood-brain permeability (Makino et al. 1988;Thumen et al. 2002;Song et al. 2006). These results, taken together, suggest that, in conjunction with endogenous synthesis, environmental sources may contribute to accumulation of TIQ derivatives in the nervous system.To elucidate the potential role of TIQ neurotoxins in the pathogenesis of idiopathic PD, the tissue concentration of these compounds must be rigorously characterized. Brain distribution studies of TIQ derivatives to date have been largely incomplete, focusing on only a few regions of the brain in a single species and/or involving only a subset of TIQ derivatives, often ignoring enantiomeric considerations. Moreover, stability of TIQ derivatives has been neglected, raising concerns about the validity of previous experimental studies and questions regardin...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Regional distribution of tetrahydroisoquinoline derivatives in rodent, human, and parkinson’s disease brain

DeCuypere

Lü

Miller

et al. 2008

“…As MPTP is metabolized to MPP~and MPP~exerts toxicity, similar bioactivation may be considered in the case of DHBnTIQs. Based on known metabolic pathways of TIQ derivatives (Collins and Origitano, 1983;Kikuchi et al, 1991), hydroxylation, N-methylation, 0-methyl-ation, and oxidation to isoquinoline or 3,4-dihydroisoquinoline may occur. Aromatization and N-methylation of DHBnTIQ may lead to an N-methylisoquinolinium cation compound analogous to MPP~and this cation may enter mitochondria easily across the mitochondrial membrane (Ramsay and Singer, 1986;Ramsay et al, 1986a).…”

mentioning

confidence: 99%

Novel Endogenous 1,2,3,4‐Tetrahydroisoquinoline Derivatives: Uptake by Dopamine Transporter and Activity to Induce Parkinsonism

Kawai

Makino

Hirobe

et al. 1998

“…In vivo studies DSAL (hydrobromide salt), dissolved in sterile isotonic saline, was injected bilaterally (25 pg/2 pl per cerebral ventricle) with the aid of a stereotaxic apparatus into anesthetized young adult male rats (Collins and Origitano, 1983). Experimental and saline-injected control rats were killed by decapitation 40 rnin after injections.…”

Section: In Vitro Comt Studiesmentioning

confidence: 99%

Inhibition of Catechol‐O‐Methyltransferase by 6,7‐Dihydroxy‐3,4‐Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O‐Methylation

Cheng

Origitano

Collins

1987

Self Cite

We report that 6,7-dihydroxy-3,4-dihydroisoquinolines related to dopamine are potent inhibitors of catechol-O-methyltransferase (COMT), but are not apparent substrates for the enzyme in vitro or in vivo. Three dihydroxy (catecholic) dihydroisoquinolines, including the 1-benzyl (DesDHP) and the 1-methyl (DSAL) analogs, were found to inhibit COMT activity in rat liver supernatant more effectively than the well-known inhibitor, tropolone. Inhibition of O-methylation was uncompetitive with substrate, and O-methylated products of the catecholic dihydroisoquinolines were undetectable. For these in vitro studies, a facile liquid chromatographic assay was developed utilizing as a site-specific substrate, 1-methyl-6,7-dihydroxy-tetrahydroisoquinoline-1-carboxylate (salsolinol-1-carboxylate). This catechol produces only one phenolic product isomer when incubated with liver supernatant and S-adenosylmethionine. Following central injection of DSAL in rats, inhibition of brain COMT in vivo was indicated by the reduced brain levels of homovanillic acid, but not of 3,4-dihydroxyphenylacetic acid. Furthermore, O-methylated DSAL metabolites could not be detected in brain by liquid or gas chromatography. We suggest that 6,7-dihydroxy-dihydroisoquinolines are "nonmethylatable" COMT inhibitors because they exist as quinoidal tautomers resembling pyridones or tropolones rather than as catechols. Quinoid formation is supported by the fluorescence and ultraviolet spectra for DSAL and its O-methyl derivatives. The experiments reveal a new class of COMT inhibitors that may be of pharmacological and mechanistic value. Additionally, 3,4-dihydroisoquinolines could arise endogenously via oxidation of the 1,2,3,4-tetrahydroisoquinolines which are ingested or produced from cellular catecholamine condensations. However, it is unlikely that dihydroisoquinoline (e.g., DSAL) concentrations necessary to inhibit COMT significantly would be attained via endogenous pathways.