Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons.
Glutamate-induced excitotoxicity is implicated as playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS), and mitochondrial dysfunction is also found in ALS patients. We investigated the relationship between glutamate excitotoxicity and mitochondrial dysfunction elicited by rotenone (a complex I inhibitor), malonate (a complex II inhibitor), or antimycin (a complex III inhibitor), in primary cultures of the embryonic rat spinal cord. Rotenone and malonate induced relatively selective toxicity against motor neurons as compared to non-motor neurons, whereas antimycin caused non-selective toxicity. The toxicity of rotenone was prevented by a non-N-methyl-D-aspartate (NMDA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not by an NMDA receptor antagonist, 5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801). The toxicity of malonate was blocked by both CNQX and MK-801. The toxicity of antimycin was affected by neither CNQX nor MK-801. When mitochondrial complex I was mildly inhibited by a sub-lethal concentration of rotenone, AMPA-induced motor neuron death was significantly exacerbated. A sub-lethal concentration of malonate exacerbated both NMDA- and AMPA-induced motor neuron death. These data suggest that mitochondrial dysfunction predisposes motor neurons to ionotropic glutamate receptor-mediated excitotoxicity.
Kanki
Rie
R
Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.
Nakamizo
Tomoki
T
Yamashita
Hirofumi
H
Kihara
Takeshi
T
Sawada
Hideyuki
H
Uemura
Kengo
K
Kawamata
Jun
J
Shibasaki
Hiroshi
H
Akaike
Akinori
A
Shimohama
Shun
S
D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives* / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D004357:Drug Synergism; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid / Q000633:toxicity; D008314:Malonates; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009046:Motor Neurons / Q000201:enzymology*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism*; D012402:Rotenone / Q000633:toxicity; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008314:Malonates; D009498:Neurotoxins; D017470:Receptors, Glutamate; D012402:Rotenone; C032456:antimycin; D018698:Glutamic Acid; D000968:Antimycin A; C030290:malonic acid