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

Abstract

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...

Salsolinol: a potential modulator of the activity of the hypothalamic–pituitary–adrenal axis in nursing and postweaning sheep

“…One such biologically active compound is salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a putative dopaminederived prolactin releasing factor [16]. Salsolinol was found in many brain regions of rodents and humans [17,18] and in the extracellular matrix of the infundibular nucleus/ median eminence (IN/ME) in lactating sheep [19]. In this hypothalamic area, its higher concentration is correlated with the presence of the suckling stimulus [16].…”

A Guide to Neurotoxic Animal Models of Parkinson's Disease

“…Isoquinoline and its derivatives can be found in the environment (Rommelspacher and Susilo 1985), in plants (Rommelspacher and Susilo 1985), in foodstuffs (Niwa et al 1989), and in mammalian organs, including the brain (Nagatsu 1997;DeCuypere et al 2008). In the brain, these molecules can be formed endogenously either enzymatically or nonenzymatically from dopamine and its metabolites (Nagatsu 1997;Naoi et al 2002).…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Recently, Deng's group confirmed the existence of Sal synthetase, that is a thermostable enzyme, and the higher enzymatic condensation reaction of DA and acetaldehyde was detected in the striatum and substantia nigra of rat brains [22,23]. Of CTIQs, Sal is a representative neurotoxin, which presents a high level in brains of PD patients and has been shown to increase ROS, inhibit mitochondrial function and cell injury [24][25][26]. Therefore, we have a hypothesis of CTIQs induced PD that when oxidative stress occurs, the aldehydic product of lipid peroxidation condenses with DA to form a series of CTIQs such as Sal in DA neurons.…”

“…Among the CTIQs, 1-methyl-6,7-phenyl-1,2,3,4 -tetrahydroisoquinoline (Salsolinol, Sal) and its derivatives can cause the prominent toxic effect on the nervous system [24] Sal derivatives were the first isoquinoline compounds found in the urine and brain of PD patients who received the treatment of L-DOPA [13]. Sal is known to be synthesized from DA and acetaldehyde (AcH) and has two enantiomers, (S)-Sal and (R)-Sal.…”