Novel free radical spin traps protect against malonate and MPTP neurotoxicity.
Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are neurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydrogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I. We examined the effects of pretreatment with the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MPTP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection against malonate-induced striatal lesions. MDL 101, 002 produced significant protection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3-nitrotyrosine concentrations. The free radical spin trap tempol also produced significant protection against MPTP neurotoxicity. These findings provide further evidence that free radical spin traps produce neuroprotective effects in vivo and suggest that they may be useful in the treatment of neurodegenerative diseases.
Matthews
R T
RT
Neurology Service, Massachusetts General Hospital, Harvard Medical School, 32 Fruit Street, Boston, Massachusetts 02114, USA.
Klivenyi
P
P
Mueller
G
G
Yang
L
L
Wermer
M
M
Thomas
C E
CE
Beal
M F
MF
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000506:poisoning*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D020267:MPTP Poisoning; D008297:Male; D008314:Malonates / Q000506:poisoning*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D013113:Spin Labels; D014443:Tyrosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism
C091566:3,4-dihydro-3,3-dimethylisoquinoline-N-oxide; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D005609:Free Radicals; D007546:Isoquinolines; D008314:Malonates; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D013113:Spin Labels; C002744:3-nitrotyrosine; D014443:Tyrosine; C030290:malonic acid; D004298:Dopamine