title: Li+ protects nerve cells against destabilization of Ca2+ homeostasis and delayed death caused by removal of external Na+.
abstract: In experiments with fura-2 loaded cultured rat cerebellar granule cells we have compared the changes in [Ca2+]i homeostasis produced by replacement of external Na+ with the organic cation N-methyl-D-glucamine (NMDG) or Li+. The Na+/NMDG replacement caused an increase in baseline [Ca2+]i and a considerable delay in [Ca2+]i recovery following a glutamate (Glu) pulse in almost all the cells. In contrast Na+/Li+ replacement usually did not change baseline [Ca2+]i and produced only a small (if any) delay in the post-glutamate [Ca2+]i recovery. Previously [Storozhevykh et al. (1998) FEBS Lett. 431, 215-218] we revealed that perturbation of [Ca2+]i homeostasis caused by Na+/NMDG replacement cannot be explained by a reversal of the Na+/Ca2+ exchange but is mainly due to Ca2+ influx through NMDA channels activated by Na+ dependent release of endogenous excitatory amino acids ('reversed Glu uptake'). In the present work we confirmed this conclusion and obtained evidence suggesting that in contrast to NMDG Li+ interferes with the 'reversed Glu uptake' triggered by removal of external Na+. Thus it has been shown that the addition of Li+ (20 mM) to a Na+-free NMDG-containing solution suppressed both the perturbation of [Ca2+]i homeostasis and delayed neuronal death caused by Na+/NMDG replacement. Li+ is also able to abolish the [Ca2+]i response induced by PDC which at high concentrations (> 200 microM) is shown to stimulate the release of endogenous Glu. In contrast to Na+/Li+, Na+/NMDG replacement greatly enhances [Ca2+]i increase caused by PDC. Control experiments showed that Na+/Li+ replacement does not decrease the [Ca2+]i response to the Glu pulse. Therefore we concluded that a considerable quantitative difference between the effects of Na+/NMDG and Na+/Li+ replacements on both [Ca2+]i homeostasis and cell viability resulted mainly from the ability of Li+ to attenuate the release of endogenous Glu in response to the removal of external Na+.
authors.affiliation: Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow. rans@rans.msk.ru
authors.forename: B
authors.initials: B
authors.lastname: Khodorov
authors.forename: V
authors.initials: V
authors.lastname: Pinelis
authors.forename: N
authors.initials: N
authors.lastname: Vinskaya
authors.forename: E
authors.initials: E
authors.lastname: Sorokina
authors.forename: N
authors.initials: N
authors.lastname: Grigortsevich
authors.forename: T
authors.initials: T
authors.lastname: Storozhevykh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D006706:Homeostasis; D008094:Lithium / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*
chemical_list: D016202:N-Methylaspartate; D008094:Lithium; D012964:Sodium; D002118:Calcium