Animal model of Parkinson's disease induced by naturally-occurring 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline

A dopamine-derived isoquinoline, 1(R), 2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 2(N)-methyl-(R)-salsolinol [NM(R)Sal], could induce parkinsonism into rats. After injection into the striatum, NM(R)Sal and its oxidation product, 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion (DMDHIQ(+)) caused behavioral changes very similar to Parkinson's disease. Biochemical analysis revealed the reduction of dopamine and noradrenaline in the substantia nigra in addition to the striatum, accompanied with DMDHIQ(+) accumulation. The density of dopamine neurons stained with anti-tyrosine hydroxylase antibody was reduced in the substantia nigra after one week of continuous infusion of NM(R)Sal in the striatum. In addition, only R-enantiomers of Sal and NMSal were identified in the human brain, and an enzyme was isolated, which catalyzes the condensation of dopamine or N-methyldopamine with acetaldehyde to produce the R-enantiomers of Sal or NMSal. The possible involvement of NM(R)Sal in the pathogenesis of Parkinson's disease is discussed.