Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate.
Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age-dependent striatal lesions, which were significantly greater in 4- and 12-month-old animals than in 1-month-old animals. Both histologic and neurochemical studies showed that the lesions were significantly attenuated by administration of the noncompetitive NMDA receptor antagonist MK-801. Water-suppressed chemical shift magnetic resonance imaging showed that malonate produces increased striatal lactate concentrations and striatal lesions on T2-weighted scans that were attenuated by MK-801. Neurochemical characterization of the lesions showed significant decreases in markers of medium-sized spiny neurons (GABA and substance P), whereas a marker of medium-sized aspiny neurons (somatostatin) was not different from control values, consistent with an NMDA receptor-mediated mechanism. The effects of intrastriatal injections of malonate on ATP concentrations were compared with those of the irreversible SDH inhibitor 3-nitropropionic acid (3-NP). The ATP depletions following an equimolar injection of malonate were less marked and more transient than those of 3-NP. These results show that the competitive SDH inhibitor malonate produces more transient and milder bioenergetic defects than 3-NP, which are associated with selective activation of NMDA receptors. The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.
Beal
M F
MF
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
Brouillet
E
E
Jenkins
B
B
Henshaw
R
R
Rosen
B
B
Hyman
B T
BT
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D007773:Lactates; D008314:Malonates; D009498:Neurotoxins; D013373:Substance P; D019344:Lactic Acid; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; C030290:malonic acid