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)