Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid.
The mechanisms of delayed onset and cell death in Huntington's disease (HD) are unknown. One possibility is that a genetic defect in energy metabolism may result in slow excitotoxic neuronal death. Therefore, we examined the effects of age on striatal lesions produced by local administration of the mitochondrial toxin 3-nitropropionic acid in rats. In vivo chemical shift magnetic resonance imaging showed marked increases in striatal lactate concentrations that significantly correlated with increasing age. Histologic and neurochemical studies showed a striking age dependence of the lesions, with 4- and 12-month-old animals being much more susceptible than 1-month-old animals. Continuous systemic administration of low doses of 3-nitropropionic acid for 1 month resulted in striatal lesions showing growth-related changes in dendrites of striatal spiny neurons using the Golgi technique. These results show that a known mitochondrial toxin can produce selective axon-sparing striatal lesions showing both the age dependence and striatal spiny neuron dendritic changes that characterize HD.
Brouillet
E
E
Department of Pathology, Massachusetts General Hospital, Boston 02114.
Jenkins
B G
BG
Hyman
B T
BT
Ferrante
R J
RJ
Kowall
N W
NW
Srivastava
R
R
Roy
D S
DS
Rosen
B R
BR
Beal
M F
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008928:Mitochondria / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*
D007773:Lactates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C015392:3-nitropropionic acid