Iodoacetate produces striatal excitotoxic lesions.
Impairment of energy production may play a role in the pathogenesis of Huntington's disease (HD). It was recently shown that huntingtin can bind to and possibly inhibit the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We found that intrastriatal administration of the GAPDH inhibitor iodoacetate produces striatal lesions that are significantly attenuated by removal of the corticostriatal glutamatergic input, consistent with an excitotoxic mechanism. The lesions are accompanied by increased production of hydroxyl free radicals as assessed by conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid. In vivo magnetic resonance imaging showed lesions on T2-weighted scans, but there was only a small increase in lactate content. These results show that inhibition of GAPDH produces striatal lesions in vivo and suggest that inhibition of GAPDH could contribute to neuronal degeneration in HD.
Matthews
R T
RT
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, U.S.A.
Ferrante
R J
RJ
Jenkins
B G
BG
Browne
S E
SE
Goetz
K
K
Berger
S
S
Chen
I Y
IY
Beal
M F
MF
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D018698:Glutamic Acid / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors; D007461:Iodoacetates / Q000633:toxicity*; D019807:Iodoacetic Acid; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009410:Nerve Degeneration / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007461:Iodoacetates; D009498:Neurotoxins; D018698:Glutamic Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D009252:NADPH Dehydrogenase; D019807:Iodoacetic Acid