Voltage-dependent ebselen and diorganochalcogenides inhibition of 45Ca2+ influx into brain synaptosomes

By mediating the Ca2+ influx, Ca2+ channels play a central role in neurotransmission. Chemical agents that potentially interfere with Ca2+ homeostasis are potential toxic agents. In the present investigation, changes in Ca2+ influx into synaptosomes by organic forms of selenium and tellurium were examined under nondepolarizing and depolarizing conditions induced by high KCl concentration (135 mM) or by 4-aminopyridine (4-AP). Under nondepolarizing conditions, ebselen (400 muM) increased Ca2+ influx; diphenyl ditelluride (40-400 M) decreased Ca2+ in all concentrations tested; and diphenyl diselenide decreased Ca2+ influx at 40 and 100 muM, but had no effect at 400 muM. In the presence of KCl as depolarizing agent, ebselen and diphenyl ditelluride decreased Ca2+ influx in a linear fashion. In contrast, diphenyl diselenide did not modify Ca2+ influx into isolated nerve terminals. In the presence of 4-AP (3 mM) as depolarizing agent, ebselen (400 muM) caused a significant increase, whereas diphenyl diselenide and diphenyl ditelluride inhibited Ca2+ influx into synaptosomes. The results can be explained by the fact that the mechanism through which 4-AP and high K+ induced elevation of intracellular Ca2+ is not exactly coincident. The mechanism by which diphenyl ditelluride and ebselen interact with Ca2+ channel is unknown, but may be related to reactivity with critical sulfhydryl groups in the protein complex. The results of the present study indicate that the effects of organochalcogenides were rather complex depending on the condition and the depolarizing agent used. (C) 2003 Wiley Periodicals, Inc.