Preventative effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives ( N -functional group loading) on MPTP-induced parkinsonism in mice

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ(1-MeTIQ) is reported to...

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Bibliographic Details
Published in:Canadian journal of physiology and pharmacology 2022-07, Vol.100 (7), p.594-611
Main Authors: Munakata, Hiroko, Ishikawa, Risa, Saitoh, Toshiaki, Kambe, Toshie, Chiba, Terumasa, Taguchi, Kyoji, Abe, Kenji
Format: Article
Language:English
Subjects:
Analysis
Basal ganglia
Brain
Brain diseases
Care and treatment
Central nervous system diseases
Dopamine
Dopamine transporter
Hydroxylase
Movement disorders
MPTP
Neostriatum
Neurodegenerative diseases
Neuroprotection
Parkinson's disease
Properties
Quinoline
Substantia nigra
Tetrahydroisoquinoline
Tyrosine 3-monooxygenase
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Summary:1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ(1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQderivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl- 1,2,3,6tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me-N-propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQand 1-Me-N-propyl-TIQdid not. These results suggest that although loading an N-propargyl group on 1-MeTIQclearly enhanced neuroprotective effects, other N-functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N-functional group may contribute to the observed differences in effect.
ISSN:0008-4212
1205-7541
DOI:10.1139/cjpp-2021-0659