Short-term block of Na+/K+-ATPase in neuro-glial cell cultures of cerebellum induces glutamate dependent damage of granule cells.
Granule cells in a dissociated neuro-glial cell culture of cerebellum when exposed to ouabain (10(-3) M) for 25 min apparently swell, increase their [Ca2+]i with obvious depolarization of the mitochondrial membrane. In 3 h after ouabain was omitted from the solution, 62 +/- 3% of granule cells had pycnotic nuclei. The supplement of a solution with competitive specific antagonist of NMDA receptors, L-2-amino-7-phosphonoheptanoate (10(-4) M, APH) together with ouabain prevented cells from swelling, mitochondrial deenergization, neuronal death and increase of [Ca2+]i. These data suggest that cellular Na+/K+-ATPase inactivation in neuro-glial cell cultures of cerebellum leads to glutamate (Glu) accumulation, hyperstimulation of glutamate receptors, higher Ca2+ and Na+ influxes into the cells through the channels activated by Glu. This process leads to cell swelling, mitochondrial deenergization and death of granule cells. Possibly, the decrease of Na+/K+-ATPase activity in brain cells can lead to the onset of at least some chronic neurological disorders.
Stelmashook
E V
EV
Brain Research Institute, Russian Academy of Medical Sciences, Moscow.
Weih
M
M
Zorov
D
D
Victorov
I
I
Dirnagl
U
U
Isaev
N
N
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008094:Lithium / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D014966:Xanthenes / Q000378:metabolism
D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D014966:Xanthenes; D020112:Rhodamine 123; C059715:Fluo-3; D018698:Glutamic Acid; D010042:Ouabain; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D008094:Lithium; D000254:Sodium-Potassium-Exchanging ATPase; C031231:2-amino-7-phosphonoheptanoic acid; D002118:Calcium