In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia.
The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)
Unit on Neurotoxicology and Neuroprotection, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
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Chiueh
R M
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Wu
K P
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Mohanakumar
L M
LM
Sternberger
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Krishna
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Obata
D L
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Murphy
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D016166:Free Radical Scavengers; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000032:analysis / Q000378:metabolism*; D020267:MPTP Poisoning; D008543:Melanins / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D012459:Salicylates; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D008543:Melanins; D012459:Salicylates; D012642:Selegiline; D017665:Hydroxyl Radical; D004298:Dopamine