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 potential endogenous neurotoxins causing nigral cell death from Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (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/24h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24h) did not show spontaneous or drug-induced motor changes. Infusion of MPP+ decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N-Me-diOme-IQ+ and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP+ markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ+ and THIQ also reduced the DA content of the ipsilateral 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 isoquinoline 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 substrates 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 to cell death in Parkinson's disease.
Neurodegenerative Diseases Research Centre, King's College, London.
K S
KS
McNaught
U
U
Thull
P A
PA
Carrupt
C
C
Altomare
S
S
Cellamare
A
A
Carotti
B
B
Testa
P
P
Jenner
C D
CD
Marsden
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives*; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death; D007260:Infusion Pumps; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D007546:Isoquinolines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium