Na plus /K plus -ATPase inhibitor palytoxin enhances vulnerability of cultured cerebellar neurons to domoic acid via sodium-dependent mechanisms

作者：Perez Gomez Anabel; Novelli Antonello; Teresa Fernandez Sanchez M

来源：Journal of Neurochemistry, 2010, 114(1): 28-38.

DOI：10.1111/j.1471-4159.2010.06602.x

• cerebellar granule neurons
• DIDS
• excitotoxicity
• Na
• K plus -ATPase
• non-NMDA receptors
• synergism

P>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.

• 出版日期2010-7