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

Abstract

By mediating the Ca(2+) influx, Ca(2+) channels play a central role in neurotransmission. Chemical agents that potentially interfere with Ca(2+) homeostasis are potential toxic agents. In the present investigation, changes in Ca(2+) 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 micro M) increased Ca(2+) influx; diphenyl ditelluride (40-400 micro M) decreased Ca(2+) in all concentrations tested; and diphenyl diselenide decreased Ca(2+) influx at 40 and 100 micro M, but had no effect at 400 micro M. In the presence of KCl as depolarizing agent, ebselen and diphenyl ditelluride decreased Ca(2+) influx in a linear fashion. In contrast, diphenyl diselenide did not modify Ca(2+) influx into isolated nerve terminals. In the presence of 4-AP (3 mM) as depolarizing agent, ebselen (400 micro M) caused a significant increase, whereas diphenyl diselenide and diphenyl ditelluride inhibited Ca(2+) 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 Ca(2+) is not exactly coincident. The mechanism by which diphenyl ditelluride and ebselen interact with Ca(2+) 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.

Pharmacology and toxicology of diphenyl diselenide in several biological models

“…DPDS reduced 45 Ca influx into isolated nerve endings of rat synaptosomes when a non-depolarizing condition was used or when 4-aminopyridine was used as a depolarizing agent (35). However, the same effects were not observed on excitotoxicity induced by glutamate in an isolated chick retina model (36).…”

Evaluation of antioxidant activity and potential toxicity of 1-buthyltelurenyl-2-methylthioheptene

“…Accordingly, thiol-containing enzymes, such as δ-aminolevulinate dehydratase (δ-ALA-D) (Barbosa et al, 1998;Maciel et al, 2000;Meotti et al, 2003;Nogueira et al, 2003), Na + , K + ATPase (Borges et al, 2005) and squalene monooxygenase (Laden and Porter, 2001) are inhibited by organotellurium compounds. In addition, our research group has obtained persuasive evidences indicating that diphenyl ditelluride is a neurotoxic compound in mice (Nogueira et al, 2001(Nogueira et al, , 2002Moretto et al, 2003) and teratogenic in rat fetuses (Stangherlin et al, 2005).…”

Pro-oxidant action of diphenyl diselenide in the yeast Saccharomyces cerevisiae exposed to ROS-generating conditions

“…Our results clearly show that DPDS acts as a pro-oxidant in this yeast. Consequently, we examined the mechanism of this pro-oxidant property that could be the reason for the observed toxicity for DPDS (Maciel et al, 2000;Moretto et al, 2003).…”