Stimulation of kainate toxicity by zinc in cultured cerebellar granule neurons and the role of mitochondria in this process.
Zinc chloride (0.01 mM kept for 3h) is not toxic to cultured cerebellar granule neurons (CGNs) while kainate (0.1mM kept for 3h) demonstrates some but very low toxicity towards these cells. Measurements of the relative intraneuronal zinc ion concentration showed that increase in [Zn(2+)](i) under the simultaneous action of ZnCl(2) and kainate was significantly stronger compared to their separate action. Simultaneous treatment of CGNs with kainate and zinc chloride caused the swelling of neuronal mitochondria and consequent intensive neuronal death, which was totally prevented by NBQX (an AMPA/kainate-receptors blocker) or ruthenium red (a mitochondrial Ca(2+) uniporter blocker). These data imply that Zn(2+) synergistically to kainate increase their separate toxic effects on mitochondria leading to rapid neuronal death.
A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia.
Ekaterina R
ER
Lozier
Elena V
EV
Stelmashook
Rustem E
RE
Uzbekov
Svetlana V
SV
Novikova
Savva D
SD
Zorov
Irina B
IB
Alieva
Brigitte
B
Arbeille
Dmitry B
DB
Zorov
Nickolay K
NK
Isaev
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D002712:Chlorides / Q000633:toxicity*; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*; D017967:Zinc Compounds / Q000633:toxicity*
D002712:Chlorides; D018690:Excitatory Amino Acid Agonists; D017967:Zinc Compounds; C016837:zinc chloride; D015032:Zinc; D007608:Kainic Acid; D002118:Calcium