Inhibition of Na+/Ca2+ exchange enhances delayed neuronal death elicited by glutamate in cerebellar granule cell cultures.
Experiments have been carried out on the primary cerebellar granule cell cultures from 7- to 8-day-old Wistar rats. To study a possible contribution of Na+/Ca2+ exchange to the toxic effect of glutamate, two amiloride derivatives, 3',4'-dichlorobenzamil (DCB) and 5-(N-4-chlorobenzyl)-2',4'-dimethylbenzamil (CBDMB), known to be the potent inhibitors of this exchange system, were used. Addition of DCB or CBDMB (at 30 and 10 microM, respectively) to a 25 microM glutamate solution dramatically enhanced the delayed neuronal death observed during the 4 h after termination of glutamate treatment. Similar but insignificantly smaller effects were obtained when these agents were added to the cultures in the post-glutamate period. Removal of Na+ (by substituting for choline chloride) from the external Mg2+-free solution in the post-glutamate period also enhanced a delayed neuronal damage. The data obtained suggest that Na+/Ca2+ exchanger does not constitute the route for Ca2+ entry during the post-glutamate period but, on the contrary, attenuates glutamate neurotoxicity providing Ca2+ extrusion from the cells under the conditions of a sustained Ca2+ influx.
Brain Research Institute, Academy of Medical Sciences, Moscow, U.S.S.R.
N
N
Andreeva
B
B
Khodorov
E
E
Stelmashook
E
E
Cragoe
I
I
Victorov
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000648:ultrastructure; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D005971:Glutamates; D019831:Sodium-Calcium Exchanger; C041470:3',4'-dichlorobenzamil; C054391:5-(N-4-chlorobenzyl)-N-(2',4'-dimethyl)benzamil; D018698:Glutamic Acid; D000584:Amiloride; D002118:Calcium