Reduced mitochondrial manganese-superoxide dismutase activity exacerbates glutamate toxicity in cultured mouse cortical neurons.
Studies of neuronal injury and death after cerebral ischemia and various neurodegenerative diseases have increasingly focused on the interactions between mitochondrial function, reactive oxygen species (ROS) production and glutamate neurotoxicity. Recent findings suggest that increased mitochondrial ROS production precedes neuronal death after glutamate treatment. It is hypothesized that under pathological conditions when mitochondrial function is compromised, extracellular glutamate may exacerbate neuronal injury. In the present study, we focus on the relationship between mitochondrial superoxide production and glutamate neurotoxicity in cultured cortical neurons with normal or reduced levels of manganese-superoxide dismutase (MnSOD) activity. Our results demonstrate that neurons with reduced MnSOD activity are significantly more sensitive to transient exposure to extracellular glutamate. The increased sensitivity of cultured cortical neurons with reduced MnSOD activity is characteristically subject only to treatment by glutamate but not to other glutamate receptor agonists, such as N-methyl-d-aspartate, kainate and quisqualate. We suggest that the reduced MnSOD activity in neurons may exacerbate glutamate neurotoxicity via a mechanism independent of receptor activation.
Li
Y
Y
Department of Neurological Surgery, University of California, School of Medicine, San Francisco, CA 94143-0651, USA.
Copin
J C
JC
Reola
L F
LF
Calagui
B
B
Gobbel
G T
GT
Chen
S F
SF
Sato
S
S
Epstein
C J
CJ
Chan
P H
PH
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity*; D006720:Homozygote; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D010084:Oxidation-Reduction; D016318:Quisqualic Acid / Q000633:toxicity; D013482:Superoxide Dismutase / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D013482:Superoxide Dismutase; D007608:Kainic Acid