NIGRAL CELL LOSS PRODUCED BY INFUSION OF ISOQUINOLINE DERIVATIVES STRUCTURALLY RELATED TO 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2 ,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP(+)) are po tential endogenous neurotoxins causing nigral cell death in Parkinson' s disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylis oquinolinium (N-Pr-IQ(+)), N-methyl-6,7-dimethoxyisoquinolinium (N-Me- 6,7-diOMe-IQ(+)), 6,7-dimethoxy-1-styryl-3,4-dihydroisoquinoline (6,7- diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP(+). MPP(+) (33 nmol/24 h)-infused rats showed a marked reducti on in motor activity and displayed ipsilateral postural asymmetry. Adm inistration of apomorphine or (+)-amphetamine to these animals produce d robust contralateral and ipsilateral rotations, respectively. Ln con trast, rats infused with the isoquinoline derivatives (150 nmol/24 h) did not show spontaneous or drug-induced motor changes. Infusion of MP P(+) decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia ni,ora pars compacta (SNc) by approximat ely 90%. Infusion of N-Me-diOMe-IQ(+) and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ(+) an d 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP(+) marked ly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DO PAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ(+) and THIQ also reduced the DA content of the ipsilater al striatum by approximately 39% and 20% respectively, but N-Pr-IQ(+) and 6,7-diOMe-1-S-3,4-DHIQ did not deplete striatal DA content. The is oquinoline derivatives slightly reduced (N-Me-diOMe-IQ(+) and THIQ) or had no effect (N-Pr-IQ(+) and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substra tes for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute t o cell death in Parkinson's disease. (C) 1996 Academic Press Limited