1‐Benzyl‐1,2,3,4‐Tetrahydroisoquinoline as a Parkinsonism‐Inducing Agent: A Novel Endogenous Amine in Mouse Brain and Parkinsonian CSF

Abstract

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1 BnTIQ) was detected as a novel endogenous amine in mouse brain and parkinsonian CSF by using the gas chromatography-selected ion-monitoring method . The level of 1 BnTIQ was very high in CSF of some parkinsonian patients compared with that of controls with other neurological diseases, the mean value being three times higher (parkinsonians : 1 .17 ± 0 .35 ng/ml of CSF, n = 18 ; vs . controls : 0.40 -0 .10 ng/ml of CSF, n = 11 ; mean !-SEM, not significantly different) . The pole test, a toxicological examination to evaluate behavior abnormalities related to Parkinson's disease, was used to examine the pharmacological effect of 1 BnTIQ in mice . Repeated administration of 1 BnTIQ induced behavior abnormalities, which pretreatment with 1-methyl-1,2,3,4-tetrahydroisoquinoline could prevent. We suggest that 1 BnTIQ may be related to the idiopathic Parkinson's disease.

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

“…Many TIQ derivatives have been found in animals, including humans, as endogenous amines (Sjoquist and Ljungquist, 1985;Kohno et al, 1986;Kotake et al, 1,995;Nakagawa et al, 1996), and some of them may be related to the pathogenesis of parkinsonism or Parkinson's disease (Ohta et al, 1987;Nagatsu and Yoshida, 1988;Tasaki et al, 1991;Maruyama et al, 1993;Kotake et al, 1995Kotake et al, , 1996. We report here that 3 ',4 'DHBnTIQ and 6,7DHBnTIQ also exist in mouse brain as endogenous parkinsonism-related TIQ derivatives.…”

“…TIQ derivatives are thought to be biosynthesized from /3-phenethylamine derivatives and aldehyde or aldehyde-equivalent compounds by Pictet-Spenglertype condensation, which seems to be at least partially enzymatic in animals (Makino et al, 1990;Tasaki et al, 1993;Yamakawa and Ohta, 1997). 1BnTIQ and tetrahydropapaveroline, which was detected in urine from L-DOPA-treated parkinsonian patients (Sandler et al, 1973), were proposed to be biosynthesized from /3-phenethylamine and phenylacetaldehyde or dopamine and 3,4-dihydroxyphenylacetaldehyde, respectively (Sandler et al, 1973;Rueffer et al, 1981;Kotake et a!., 1995). That is, /3-phenethylamine and dopamine are each oxidized to aldehyde by monoamine oxidase [MAO; amine :oxygen oxidoreductase (deaminating; flavin-containing); EC 1.4.3.4], and condensed with their own metabolite to form 1BnTIQ and THP.…”

“…In previous reports, we showed that various TIQ derivatives exist endogenously in animal brain (Kohno et al, 1986;Kotake et al, 1995;Nakagawa et al, 1996), and some of them seem to be related to parkinsonism. TIQ and 1-benzyl-1 ,2,3,4-tetrahydroisoquinoline (1BnTIQ) could induce parkinsonism in rodents (Tasaki et al, 1991;Kotake et al, 1995) and a primate (Kotake et al, 1996), and 1BnTIQ existed in CSF of parkinsonian patients at about three times higher levels than in disease controls (Kotake et al, 1995).…”

“…TIQ and 1-benzyl-1 ,2,3,4-tetrahydroisoquinoline (1BnTIQ) could induce parkinsonism in rodents (Tasaki et al, 1991;Kotake et al, 1995) and a primate (Kotake et al, 1996), and 1BnTIQ existed in CSF of parkinsonian patients at about three times higher levels than in disease controls (Kotake et al, 1995). Thus, TIQ and 1BnTIQ are plausible candidates as Parkinson's disease-inducing substances, but we speculated that other neurotoxins might also be present in the CNS.…”

Annonamine, a New Aporphine Alkaloid from the Leaves of Annona muricata

“…5) On the other hand, we have previously identified 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) alkaloids as one of the endogenous neurotoxins that could induce PD in an animal model. 6) In this study, we have phytochemically investigated the leaves of the title plant in detail to characterize the chemical constituents especially on alkaloids, because the leaves of A. muricata are used as tea for cardiotonics and it has been known that A. muricata produced benzylisoquinoline type alkaloids. 7,8) The present study describes the isolation and structural elucidation of a new aporphine alkaloid, annonamine (1) together with four known alkaloids (2)(3)(4)(5).…”