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N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx.
J Neurosci Res. 2001 Mar 01; 63(5):377-87.JN

Abstract

Mitochondrial uptake of Ca(2+) has recently been found to play an important role in glutamate-induced neurotoxicity (GNT) as well as in the activation of Ca(2+)-dependent molecules, such as calmodulin and neuronal nitric oxide synthase (nNOS), in the cytoplasm. Prolonged exposure to glutamate injures motor neurons predominantly through the activation of Ca(2+)/calmodulin-nNOS, as previously reported, and is, in part, associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated how mitochondrial uptake of Ca(2+) is involved in GNT in spinal motor neurons. Acute excitotoxicity induced by exposure to 0.5 mM glutamate for 5 min was found in both motor and nonmotor neurons in cultured spinal cords from rat embryos and was dependent on extracellular Ca(2+) and on N-methyl-D-aspartate (NMDA) receptor activation. Mitochondrial uncouplers markedly blocked acute excitotoxicity, and membrane-permeable superoxide dismutase mimics attenuated acute excitotoxicity induced by glutamate and NMDA but not by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate. Fluorimetric analysis showed that mitochondrial Ca(2+) was elevated promptly with subsequent accumulation of reactive oxygen species (ROS) in the mitochondria. An NMDA receptor antagonist and a mitochondrial uncoupler eliminated the increase in fluorescence of mitochondrial Ca(2+) and ROS indicators. These data indicate that acute excitotoxicity in spinal neurons is mediated by mitochondrial Ca(2+) overload and ROS generation through the activation of NMDA receptors. This mechanism is different from that of chronic GNT.

Authors+Show Affiliations

Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyoku, Kyoto, Japan.No 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

11223912

Citation

Urushitani, M, et al. "N-methyl-D-aspartate Receptor-mediated Mitochondrial Ca(2+) Overload in Acute Excitotoxic Motor Neuron Death: a Mechanism Distinct From Chronic Neurotoxicity After Ca(2+) Influx." Journal of Neuroscience Research, vol. 63, no. 5, 2001, pp. 377-87.
Urushitani M, Nakamizo T, Inoue R, et al. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J Neurosci Res. 2001;63(5):377-87.
Urushitani, M., Nakamizo, T., Inoue, R., Sawada, H., Kihara, T., Honda, K., Akaike, A., & Shimohama, S. (2001). N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. Journal of Neuroscience Research, 63(5), 377-87.
Urushitani M, et al. N-methyl-D-aspartate Receptor-mediated Mitochondrial Ca(2+) Overload in Acute Excitotoxic Motor Neuron Death: a Mechanism Distinct From Chronic Neurotoxicity After Ca(2+) Influx. J Neurosci Res. 2001 Mar 1;63(5):377-87. PubMed PMID: 11223912.
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TY - JOUR T1 - N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. AU - Urushitani,M, AU - Nakamizo,T, AU - Inoue,R, AU - Sawada,H, AU - Kihara,T, AU - Honda,K, AU - Akaike,A, AU - Shimohama,S, PY - 2001/2/27/pubmed PY - 2001/5/22/medline PY - 2001/2/27/entrez SP - 377 EP - 87 JF - Journal of neuroscience research JO - J Neurosci Res VL - 63 IS - 5 N2 - Mitochondrial uptake of Ca(2+) has recently been found to play an important role in glutamate-induced neurotoxicity (GNT) as well as in the activation of Ca(2+)-dependent molecules, such as calmodulin and neuronal nitric oxide synthase (nNOS), in the cytoplasm. Prolonged exposure to glutamate injures motor neurons predominantly through the activation of Ca(2+)/calmodulin-nNOS, as previously reported, and is, in part, associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated how mitochondrial uptake of Ca(2+) is involved in GNT in spinal motor neurons. Acute excitotoxicity induced by exposure to 0.5 mM glutamate for 5 min was found in both motor and nonmotor neurons in cultured spinal cords from rat embryos and was dependent on extracellular Ca(2+) and on N-methyl-D-aspartate (NMDA) receptor activation. Mitochondrial uncouplers markedly blocked acute excitotoxicity, and membrane-permeable superoxide dismutase mimics attenuated acute excitotoxicity induced by glutamate and NMDA but not by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate. Fluorimetric analysis showed that mitochondrial Ca(2+) was elevated promptly with subsequent accumulation of reactive oxygen species (ROS) in the mitochondria. An NMDA receptor antagonist and a mitochondrial uncoupler eliminated the increase in fluorescence of mitochondrial Ca(2+) and ROS indicators. These data indicate that acute excitotoxicity in spinal neurons is mediated by mitochondrial Ca(2+) overload and ROS generation through the activation of NMDA receptors. This mechanism is different from that of chronic GNT. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/11223912/N_methyl_D_aspartate_receptor_mediated_mitochondrial_Ca_2+__overload_in_acute_excitotoxic_motor_neuron_death:_a_mechanism_distinct_from_chronic_neurotoxicity_after_Ca_2+__influx_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0360-4012&date=2001&volume=63&issue=5&spage=377 DB - PRIME DP - Unbound Medicine ER -