title: Na+/K+-ATPase inhibitor palytoxin enhances vulnerability of cultured cerebellar neurons to domoic acid via sodium-dependent mechanisms.
abstract: Dysfunction or deficiency of the Na(+)/K(+)-ATPase appears to be a common event in a variety of pathological conditions in the central nervous system. Studies on neurotoxicity associated to impaired Na(+)/K(+)-ATPase activity have focused on NMDA receptors, while the involvement of non-NMDA receptors has been much less explored. We show that mild, non-toxic, exposures to the Na(+)/K(+)-ATPase inhibitor palytoxin (PTX) synergistically sensitized the vulnerability of neurons to normally non-toxic concentrations of domoic acid, leaving NMDA receptor-mediated excitotoxic response unaltered. Enhancement of excitotoxicity required at least 1 h pre-exposure to PTX, was not observed after longer exposures to PTX, and did not require RNA synthesis. PTX caused a voltage-sensitive Na(+) channel-independent increase in intracellular Na(+). Both intracellular Na(+) increase and potentiation of excitotoxicity depended upon the external concentrations of Na(+) and Cl(-), and were suppressed by the anion exchanger blocker 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid in a dose-dependent manner. Other stilbene derivatives, chloride channel antagonists or Na(+) cotransporter inhibitors proved ineffective. Our results demonstrate a crucial role for Na(+)/K(+)-ATPase activity in determining neuronal vulnerability to domoic acid-mediated excitotoxicity. They also raise reasonable concern about possible risks for human health associated to the ingestion of low amounts of phycotoxins PTX and domoic acid in food.
authors.affiliation: Departament of Biochemistry and Molecular Biology, Institute of Biotechnlogy of Asturias, University of Oviedo, 33006 Oviedo, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: Pérez-Gómez
authors.forename: Antonello
authors.initials: A
authors.lastname: Novelli
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Fernández-Sánchez
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003064:Cnidarian Venoms; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D012964:Sodium / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000502:physiology; D013997:Time Factors; D000095702:Polyether Toxins
chemical_list: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D000178:Acrylamides; D002118:Calcium; D002121:Calcium Channel Blockers; D003064:Cnidarian Venoms; D007608:Kainic Acid; D009498:Neurotoxins; D012313:RNA; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; C012301:domoic acid; C010272:palytoxin; D000095702:Polyether Toxins