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Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons.
Brain Res. 2004 Jul 23; 1015(1-2):73-81.BR

Abstract

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.

Authors+Show Affiliations

Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15223368

Citation

Kanki, Rie, et al. "Effects of Mitochondrial Dysfunction On Glutamate Receptor-mediated Neurotoxicity in Cultured Rat Spinal Motor Neurons." Brain Research, vol. 1015, no. 1-2, 2004, pp. 73-81.
Kanki R, Nakamizo T, Yamashita H, et al. Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. Brain Res. 2004;1015(1-2):73-81.
Kanki, R., Nakamizo, T., Yamashita, H., Kihara, T., Sawada, H., Uemura, K., Kawamata, J., Shibasaki, H., Akaike, A., & Shimohama, S. (2004). Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. Brain Research, 1015(1-2), 73-81.
Kanki R, et al. Effects of Mitochondrial Dysfunction On Glutamate Receptor-mediated Neurotoxicity in Cultured Rat Spinal Motor Neurons. Brain Res. 2004 Jul 23;1015(1-2):73-81. PubMed PMID: 15223368.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. AU - Kanki,Rie, AU - Nakamizo,Tomoki, AU - Yamashita,Hirofumi, AU - Kihara,Takeshi, AU - Sawada,Hideyuki, AU - Uemura,Kengo, AU - Kawamata,Jun, AU - Shibasaki,Hiroshi, AU - Akaike,Akinori, AU - Shimohama,Shun, PY - 2004/04/19/accepted PY - 2004/6/30/pubmed PY - 2004/10/16/medline PY - 2004/6/30/entrez SP - 73 EP - 81 JF - Brain research JO - Brain Res VL - 1015 IS - 1-2 N2 - 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. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/15223368/Effects_of_mitochondrial_dysfunction_on_glutamate_receptor_mediated_neurotoxicity_in_cultured_rat_spinal_motor_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006899304006559 DB - PRIME DP - Unbound Medicine ER -