Preventative Effects of 1-Methyl-1,2,3,4-Tetrahydroisoquinoline Derivatives (N-Functional Group Loading) On MPTP-Induced Parkinsonism In Mice

Abstract

1,2,3,4-Tetrahydroisoquinoline (TIQ) is endogenously present in human brain, and some of its derivatives are thought to contribute to the induction of Parkinson’s disease (PD)-like symptoms 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-MeTIQ derivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms 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-MeTIQ and 1-Me-N-propyl-TIQ did not. Induction of thiobarbituric acid reactive substances (TBARS) by MPTP in the substantia nigra was significantly suppressed by not only 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ, but also by 1-Me-N-propyl-TIQ; in contrast, 1-Me-N-propenyl-TIQ had no effect. These results suggest that although loading an N-propargyl group on 1-MeTIQ clearly 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.