Oral administration of sodium pyrithione (NaP) causes hindlimb weakness in rodents, but not in primates. Previous work using Aplysia neurons has demonstrated that NaP produces a persistent influx of Ca2+ ions across the plasma membrane. To determine whether this also occurs in mammalian neurons and whether this could underlie the inter-species difference between rodents and primates, we have tested the effects of NaP on intracellular Ca2+ levels ([Ca2+](i)) in rat and monkey motor neurons in vitro. Motor neurons present in spinal cord slices from rhesus monkey embryos (E37 and 56) and from rat E 16 were dissected and cultured on glass coverslips. Following 2 weeks (rhesus) or 2-3 days (rat) in culture, neurons were loaded with fura-PE3/AM, and examined for [Ca2+](i) changes in response to NaP. Rhesus motor neurons were identified by immunostaining for Islet-1 (MN specific antigen) and neuron specific enolase (NSE). Motor neurons from both species exhibited dose-dependent NaP-evoked increases in [Ca2+](i) However, the dose-response curve for the Rhesus motor neurons was significantly shifted to the right of the rat dose-response curve, whereas the overall amplitude of the Ca2+ rise was similar in both species. As shown previously for the Aplysia neurons, the action of NaP is attenuated by SKF 96365, an inhibitor of store-operated calcium entry. In contrast the action of NaP is unaffected by nifedipine and tetrodotoxin, blockers of voltage-dependent Ca2+ and Na+ channels, respectively, or by ouabain, an inhibitor of the plasma membrane Na+/K+ ATPase. Our results indicate that the NaP-induced increase in [Ca2+], is conserved across species and suggest that the toxicological sensitivity of rodent over primate to pyrithione could be due to the enhanced sensitivity of rodent motor neurons to NaP-evoked intracellular Ca2+ elevation. (C) 2007 Elsevier Inc. All rights reserved.