Parkinsonism-Preventing Activity of 1-Methyl-1,2,3,4-tetrahydroisoquinoline Derivatives in C57BL Mouse in Vivo

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration of nigro-striatal dopaminergic neurons and reduction in the level of dopamine in this area. Since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could induce parkinsonism in humans, 1) 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been considered as candidate endogenous causative factors of idiopathic Parkinson's disease (PD), because of their structural similarity to MPTP. We have reported that tetrahydroisoquinoline derivatives (Fig. 1), such as TIQ, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ),2) 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), 3) and 1-(3Ј,4Ј-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3Ј,4ЈDHBnTIQ), 4) exist in the brain of mammalians of several species. While the content of 1BnTIQ tends to be increased in cerebrospinal fluid (CSF) of PD patients, 3) 1MeTIQ is significantly decreased in the parkinsonian brain and MPTP-injected mouse brain. 5,6) Bradykinesia, one of the symptoms of PD, was induced by injection of TIQ, 1BnTIQ, or 3Ј,4ЈDHBnTIQ in mice, 2,3) so these TIQ derivatives are considered to be parkinsonism-inducing substances. MPTP and TIQ derivatives have inhibitory activities towards complex I of the mitochondrial respiratory chain and tyrosine hydroxylase. 9) Thus, 1MeTIQ is a possible endogenous PD-preventing substance. Since 1MeTIQ is an endogenous amine, it may be synthesized enzymatically. Indeed, a candidate enzyme was partially purified from mitochondrial-synaptosomal fraction of rat brain, 10) and its regional distribution was examined in monkey brain.11) However, the mechanism of the parkinsonism-preventing activity of 1MeTIQ is still unknown.We have synthesized derivatives of 1MeTIQ ( Fig. 1) and evaluated their in vitro neurotoxicity and protective activity against toxicity due to salsolinol in SH-SY5Y human neuroblastoma cells.12) The introduction of one methoxyl group into 1MeTIQ increased the toxicity, especially in the case of 7-methoxy-1MeTIQ. The introduction of one hydroxyl group, however, reduced the toxicity. 1MeTIQ showed a week (not statistically significant) in vitro protective effect against the toxicity of salsolinol. 6-or 7-Hydroxy-1MeTIQ showed a greater (statistically significant) protective effect at 20 mM concentration against the toxicity of 20 or 40 mM salsolinol.In the present study, we examined whether these hydroxylsubstituted 1MeTIQ derivatives have parkinsonism-preventing activity in C57BL/6N mice by means of the pole test, and measured the brain dopamine content. MATERIALS AND METHODSReagents 1MeTIQ, 5-hydroxy-1MeTIQ, 6-hydroxy1MeTIQ and 7-hydroxy-1MeTIQ were synthesized according to the literature. 6,12,13) Treatment of the Reagents Twenty-four C57BL/6N male mice were divided into six groups (nϭ4) with the aid of a table of random numbers. Saline or a 1MeTIQ derivative Minami-ku, Hiroshima 734-8553, Japan. Received February 28, 2006; accepted April 17, 2006; published online April 21, 2006 1- Methyl-1,2,3,4-tetrah...

A Guide to Neurotoxic Animal Models of Parkinson's Disease

“…Additionally, the effects of 1,2,3,4-tetrahydroisoquinoline in monkeys are not reproduced by other isoquinoline derivatives that have similar properties to 1,2,3,4-tetrahydroisoquinoline (Yoshida et al 1993). Furthermore, some tetrahydroisoquinoline derivatives such as 1-methyl-1,2,3,4-tetrahydroisoquinoline even have neuroprotective effects Abe et al 2005;Okuda et al 2006). Because one isoquinoline derivative can be transformed to another one, for example, 1,2,3,4-tetrahydroisoquinoline (neurotoxic) can be converted by N-methyltransferase in vivo to 1-methyl-1,2,3,4-tetrahydroisoquinoline (neuroprotective), which is then further oxidized by monoamine oxidase to N-methyl-isoquinolinium ion (neurotoxic) (Nagatsu 1997), the overall neurotoxic properties of a particular isoquinoline isoform can be difficult to interpret or predict.…”

A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP

“…A structurally related compound, 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1‐methyl‐TIQ), is present in the brain and exhibits neuroprotective effects both in vitro and in vivo (Tasaki et al ., 1991; Abe et al ., 2005; Kotake et al ., 2005; Antkiewicz‐Michaluk et al ., 2006). Further, some derivatives of 1‐methyl‐TIQ exert even a higher neuroprotective effect (Okuda et al ., 2006; Katagiri et al ., 2010). The effect of TIQ derivatives on microglial system had not been reported thus far to our knowledge.…”

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

“…Tetrahydro-isoquinolines administered intraperitoneally to rats caused rigidity and a decrease in the number of dopaminergic neurons in the SN [58]. By contrast, 1-methyl-1,2,3,4-tetrahydro-isoquinoline and hydroxylated derivatives showed neuroprotective effects against MPTP treatment of dopaminergic neurons in an in vivo model [59]. In fact, a decreased biosynthesis of protective 1-methyl-1,2,3,4-tetrahydro-isoquinoline was discovered after incubation with PD-inducing toxins such as MPTP and norharman [60].…”