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Comparative Toxicological Study of the Novel Protein Phosphatase Inhibitor 19-Epi-Okadaic Acid in Primary Cultures of Rat Cerebellar Cells

AuthorsFernández-Sánchez, María-Teresa; Cabrera-García, David; Ferrero-Gutiérrez, Amaia; Pérez-Gómez, Anabel; Cruz, Patricia G.; Hernández Daranas, Antonio ; Fernández, José J.; Norte, Manuel; Novelli, Antonello
KeywordsOkadaic acid
Diarrheic shellfish poisoning
Issue Date18-Apr-2013
PublisherOxford University Press
CitationToxicological Sciences 132(2): 409–418 (2013)
AbstractOkadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structure analysis of the isolated OKA analogue 19-epi-OKA showed important conformation differences expected to result in lower protein phosphatase (PP) inhibitory potencies than OKA. However, 19-epi-OKA and OKA inhibitory activities versus PP2A were unexpectedly found to be virtually equipotent. To investigate the toxicological relevance of these findings, we tested the effects of 19-epi-OKA on cultured cerebellar cells and compared them with those of OKA and its isomer dinophysistoxin-2. 19-epi-OKA caused degeneration of neurites and neuronal death with much lower potency than its congeners. The concentration of 19-epi-OKA that reduced after 24h the maximum neuronal survival (EC5024) by 50% was ~300nM compared with ~2nM and ~8nM for OKA and dinophysistoxin-2, respectively. Exposure to 19-epi-OKA resulted also in less toxicity for cultured glial cells (EC5024,19-epi-OKA ~ 600nM; EC5024,OKA ~ 20nM). 19-epi-OKA induced apoptotic condensation and fragmentation of chromatin, activation of caspases, and activation of ERK1/2 MAP kinases, features previously reported for OKA and dinophysistoxin-2. Also, differential sensitivity to 19-epi-OKA was observed between neuronal and glial cells, a specific characteristic shared by OKA and dinophysistoxin-2 but not by other toxins. Our results are consistent with 19-epi-OKA being included among the group of toxins of OKA and derivatives and support the suitability of cellular bioassays for the detection of these compounds.
Publisher version (URL)https://doi.org/10.1093/toxsci/kft006
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