title: Acidosis and 5-(N-ethyl-N-isopropyl)amiloride (EIPA) Attenuate Zinc/Kainate Toxicity in Cultured Cerebellar Granule Neurons.
abstract: Cultured cerebellar granule neurons (CGNs) are resistant to the toxic effect of ZnCl2 (0.005 mM, 3 h) and slightly sensitive to the effect of kainate (0.1 mM, 3 h). Simultaneous treatment of CGNs with kainate and ZnCl2 caused intensive neuronal death, which was attenuated by external acidosis (pH 6.5) or 5-(N-ethyl-N-isopropyl)amiloride (EIPA, Na+/H+ exchange blocker, 0.03 mM). Intracellular zinc and calcium ion concentrations ([Zn2+]i and [Ca2+]i) were increased under the toxic action of kainate + ZnCl2, this effect being significantly decreased on external acidosis and increased in case of EIPA addition. Neuronal Zn2+ imaging demonstrated that EIPA increases the cytosolic concentration of free Zn2+ on incubation in Zn2+-containing solution. These data imply that acidosis reduces ZnCl2/kainate toxic effects by decreasing Zn2+ entry into neurons, and EIPA prevents zinc stores from being overloaded with zinc.
authors.affiliation: Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, 125367, Russia. estelmash@mail.ru.
authors.forename: E V
authors.initials: EV
authors.lastname: Stelmashook
authors.forename: S V
authors.initials: SV
authors.lastname: Novikova
authors.forename: G A
authors.initials: GA
authors.lastname: Amelkina
authors.forename: E G
authors.initials: EG
authors.lastname: Ivashkin
authors.forename: E E
authors.initials: EE
authors.lastname: Genrikhs
authors.forename: L G
authors.initials: LG
authors.lastname: Khaspekov
authors.forename: N K
authors.initials: NK
authors.lastname: Isaev
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002413:Cations, Divalent; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000473:pathology; D004347:Drug Interactions; D007608:Kainic Acid / Q000378:metabolism / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000633:toxicity
chemical_list: D000584:Amiloride; D002118:Calcium; D002413:Cations, Divalent; D007608:Kainic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D017923:Sodium-Hydrogen Exchangers; D015032:Zinc; C039614:ethylisopropylamiloride