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TOXICOLOGY

Gambierol Acts as a Functional Antagonist of Neurotoxin Site 5 on Voltage-Gated Sodium Channels in Cerebellar Granule Neurons

Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana (K.T.L.); Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R., H.W.B.J.); Center for Marine Science, University of North Carolina at Wilmington, Wilmington, North Carolina (D.G.B.); and Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (T.F.M.)

The marine toxin gambierol, a polyether ladder toxin derived from the marine dinoflagellate Gambierdiscus toxicus, was evaluated for interaction with voltage-gated sodium channels (VGSCs) in cerebellar granule neuron (CGN) cultures. At concentrations ranging from 10 nM to 10 µM, gambierol alone had no effect on the intracellular Ca²⁺ concentration [Ca²⁺]_i of exposed CGN cultures. Furthermore, there was no evidence of neurotoxicity in CGN cultures exposed for 2 h to gambierol (1 nM–10 µM). However, gambierol was a potent inhibitor (IC₅₀ = 189 nM) of the elevation of [Ca²⁺]_i that accompanies exposure of CGN cultures to the VGSC activator brevetoxin-2 (PbTx-2). To further explore the potential interaction of gambierol with VGSCs, the influence of gambierol on PbTx-2-induced neurotoxicity was assessed. Gambierol reduced the PbTx-2-induced efflux of lactate dehydrogenase in exposed CGN cultures in a concentration-dependent manner (IC₅₀ = 471 nM). It is noteworthy that the potencies of gambierol as an inhibitor of both PbTx-2-induced Ca²⁺ influx and cytotoxicity were coincident. Finally, the inhibitory effects of gambierol on PbTx-2-induced elevation of [Ca²⁺]_i were compared with those of brevenal, a natural inhibitor of the toxic effects of brevetoxin isolated from cultures of Karina brevis. Like gambierol, brevenal inhibited PbTx-2-induced elevation of [Ca²⁺]_i in a concentration-dependent manner (IC₅₀ = 108.6 nM). These results provide evidence for gambierol acting as a functional antagonist of neurotoxin site 5 on neuronal VGSCs.

Address correspondence to: Dr. Thomas F. Murray, Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178. E-mail: tfmurray{at}creighton.edu

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