Mitochondrial impairment reduces the threshold for in vivo NMDA-mediated neuronal death in the striatum.
There may be important relationships between glutamate receptor activation and neurotoxicity in neurodegenerative diseases. Previous experiments using cultured neurons have demonstrated a correlation between the metabolic status of neurons and their sensitivity to glutamate receptor-mediated cytotoxicity (Novelli et al. Brain Res. 451, 205, 1988). To examine such a relationship in vivo, we first established a dose-response curve for N-methyl-D-aspartate (NMDA)-induced neuronal death in the rat striatum. We then examined the interaction between metabolic impairment and infusion of NMDA at a dose below the threshold for neurotoxicity. Metabolic impairment was induced by intraperitoneal delivery of 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II (succinic dehydrogenase). Twelve hours after 3-NP delivery we performed stereotactic infusion of NMDA or vehicle into the striatum. During mitochondrial impairment, a relatively nonneurotoxic dose of NMDA (15 nmol) produced a lesion that was significantly larger than that caused by this dose under normal metabolic conditions. At a dose normally below the threshold for neurotoxicity, metabolic impairment significantly increased the likelihood of neuronal death in the striatum by a factor of 5. Lesions were characterized by neuronal loss with gliosis and sparing of traversing fiber bundles. These results demonstrate that metabolic impairment reduces the threshold for glutamate receptor-mediated neurotoxicity in vivo. This potentiation may have implications for understanding the role of "neuronal stress" produced by glutamate receptor activation in neurodegenerative diseases and normal aging.
Simpson
J R
JR
Neuroregeneration Laboratory, McLean Hospital, Belmont, Massachusetts 02178.
Isacson
O
O
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D016202:N-Methylaspartate; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid