6-Hydroxydopamine injections into the nigrostriatal pathway attenuate striatal malonate and 3-nitropropionic acid lesions.
The mitochondrial inhibitors malonate and 3-nitropropionic (3NP) acid are potent neurotoxins in vivo. Administration of these compounds results in neuronal loss similar to that seen in Huntington's disease. Although the mechanism of cell death produced by these compounds likely involves activation of N-methyl-D-aspartate receptors, it remains unclear why the striatum demonstrates regional susceptibility to the toxicity of these and other mitochondrial poisons. We hypothesized that dopamine, a weak neurotoxin that occurs in high concentrations in the striatum, may contribute to the neuronal damage caused by mitochondrial inhibition. We investigated whether depletion of striatal dopamine using the catecholaminergic toxin 6-hydroxydopamine would attenuate lesions induced by mitochondrial inhibition. We found that dopamine depletion reduced significantly the extent of histological damage in the striatum elicited by both intraparenchymal injections of 0.8 micromol malonate and 20 mg/kg systemic administration of 3NP. These data suggest that dopamine or one of its metabolites may contribute to mitochondrial toxin-induced cell death.
Maragos
W F
WF
Department of Neurology, University of Kentucky Medical Center, Lexington, Kentucky, 40536-0284, USA.
Jakel
R J
RJ
Pang
Z
Z
Geddes
J W
JW
D000818:Animals; D000959:Antihypertensive Agents; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism*; D003714:Denervation; D008297:Male; D008314:Malonates; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology; D009434:Neural Pathways; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000502:physiology; D016627:Oxidopamine; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology* / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013565:Sympatholytics
D000959:Antihypertensive Agents; D008314:Malonates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D013565:Sympatholytics; D016627:Oxidopamine; C030290:malonic acid; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid