Complexities in the neurotoxic actions of 6-hydroxydopamine in relation to the cytoprotective properties of taurine.
The neurotoxin 6-hydroxydopamine was shown to cause an imbalance between the direct and indirect pathways of the striato-nigral system as evidenced by a decreased release of gamma-aminobutyric acid and taurine in the substantia nigra but not in the globus pallidus following neostriatal stimulation with kainate (100 microM). The neurotoxicity of 6-hydroxydopamine is generally believed to result from reactive-oxygen radical formation, although it is also known to inhibit mitochondrial NADH dehydrogenase. The release of Fe(II) from the unactivated form [3Fe(III)-4S] of cytoplasmic aconitase (EC(50) < 8 microM) was shown to be followed by the slower oxidation of thiol groups in the protein. Complete loss of -SH groups, and enzyme activity, was seen after incubation of glyceraldenyde-3-phosphate dehydrogenase with 200 microM 6-hydroxydopamine for 75 min at 37 degrees C (IC(50) = 70.8 +/- 0.3 microM). Thus the cellular effects of 6-hydroxydopamine are complex, involving impairment of mitochondrial function, iron- release, sulphydryl-group oxidation, and enzyme inhibition in addition to direct generation of reactive oxygen radicals. Taurine, which is known to be neuroprotective in some other systems, only affords protection against some of these effects, thereby explaining its reported ineffectiveness against 6-hydroxydopamine toxicity.
Hayes
J
J
Department of Biochemistry, Trinity College, Dublin, Ireland.
Tipton
K F
KF
Bianchi
L
L
Corte
L D
LD
D000154:Aconitate Hydratase / Q000187:drug effects / Q000378:metabolism; D018663:Adrenergic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009498:Neurotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D016627:Oxidopamine / Q000493:pharmacokinetics / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018663:Adrenergic Agents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013438:Sulfhydryl Compounds; D013654:Taurine; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D007501:Iron; D000154:Aconitate Hydratase; D007608:Kainic Acid; D004298:Dopamine