Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Nigral cell loss produced by infusion of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 891 Sep 5

A series of neurotoxic tetrahydroisoquinoline alkaloids has been detected in certain regions of mammalian brains. One such dopaminergic tetrahydroisoquinoline neurotoxin is salsolinol (SAL), which is suspected of being associated with the etiology of Parkinson's disease and neuropathology of chronic alcoholism. In the present study, we found that SAL in combination with Cu(II) induced strand scission in pBR322 and phiX174 supercoiled DNA, which was inhibited by the copper chelator, reactive oxygen species (ROS) scavengers, reduced glutathione, and catalase. SAL in the presence of Cu(II) caused hydroxylation of salicylic acid to produce 2,3- and 2,5-dihydroxybenzoic acids. Reaction of calf thymus DNA with SAL plus Cu(II) resulted in substantial oxidative DNA damage as determined by 8-hydroxydeoxyguanosine (8-OH-dG) formation. Blockade of the dihydroxy functional group of SAL abolished its capability to yield 8-OH-dG in the presence of Cu(II). The dehydro analog of SAL, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinoline, produced significantly high levels of 8-OH-dG when incubated with calf thymus DNA, even in the absence of Cu(II), which appears to be attributable to the tautomer formation by this compound. In another experiment, SAL exerted cytotoxicity when treated to rat pheochromocytoma (PC12) cells. Based on these findings, it seems likely that SAL undergoes redox cycling in the presence of Cu(II) with concomitant production of ROS, particularly hydroxyl radical, which could contribute to DNA damaging and cytotoxic properties of this neurotoxin.
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PMID:Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid. 1139 Jan 86