Journal Article

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

Maria-Teresa Fernández-Sánchez, David Cabrera-García, Amaia Ferrero-Gutierrez, Anabel Pérez-Gómez, Patricia G. Cruz, Antonio H. Daranas, José J. Fernández, Manuel Norte and Antonello Novelli

in Toxicological Sciences

Volume 132, issue 2, pages 409-418
Published in print April 2013 | ISSN: 1096-6080
Published online January 2013 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kft006
Comparative Toxicological Study of the Novel Protein Phosphatase Inhibitor 19-Epi-Okadaic Acid in Primary Cultures of Rat Cerebellar Cells

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Okadaic 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.

Keywords: okadaic acid; diarrheic shellfish poisoning; neurotoxicity.

Journal Article.  7360 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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