Striatal damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice.
Intrastriatal administration of the succinate dehydrogenase (SDH) inhibitor malonate produces neuronal injury by a "secondary excitotoxic" mechanism involving the generation of reactive oxygen species (ROS). Recent evidence indicates dopamine may contribute to malonate-induced striatal neurodegeneration; infusion of malonate causes a pronounced increase in extracellular dopamine and dopamine deafferentation attenuates malonate toxicity. Inhibition of the catabolic enzyme monoamine oxidase (MAO) also attenuates striatal lesions induced by malonate. In addition to forming 3,4-dihydroxyphenylacetic acid, metabolism of dopamine by MAO generates H2O2, suggesting that dopamine metabolism may be a source of ROS in malonate toxicity. There are two isoforms of MAO, MAO-A and MAO-B. In this study, we have investigated the role of each isozyme in malonate-induced striatal injury using both pharmacological and genetic approaches. In rats treated with either of the specific MAO-A or -B inhibitors, clorgyline or deprenyl, respectively, malonate lesion volumes were reduced by 30% compared to controls. In knock-out mice lacking the MAO-A isoform, malonate-induced lesions were reduced by 50% and protein carbonyls, an index ROS formation, were reduced by 11%, compared to wild-type animals. In contrast, mice deficient in MAO-B showed highly variable susceptibility to malonate toxicity precluding us from determining the precise role of MAO-B in this form of brain damage. These findings indicate that normal levels of MAO-A participate in expression of malonate toxicity by a mechanism involving oxidative stress.
Maragos
William F
WF
University of Kentucky, Department of Neurology, USA. maragos@uky.edu
Young
Kristie L
KL
Altman
Chris S
CS
Pocernich
Chava B
CB
Drake
Jennifer
J
Butterfield
D Allan
DA
Seif
Isabelle
I
Holschneider
Daniel P
DP
Chen
Kevin
K
Shih
Jean C
JC
D000818:Animals; D001483:Base Sequence; D003010:Clorgyline / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D005260:Female; D008297:Male; D008314:Malonates / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000187:drug effects*; D008995:Monoamine Oxidase / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D008314:Malonates; C030290:malonic acid; D008995:Monoamine Oxidase; D003010:Clorgyline