Journal Article

Involvement of Caspase Activation in Azaspiracid-Induced Neurotoxicity in Neocortical Neurons

Zhengyu Cao, Keith T. LePage, Michael O. Frederick, Kyriacos C. Nicolaou and Thomas F. Murray

in Toxicological Sciences

Volume 114, issue 2, pages 323-334
Published in print April 2010 | ISSN: 1096-6080
Published online January 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp312
Involvement of Caspase Activation in Azaspiracid-Induced Neurotoxicity in Neocortical Neurons

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Azaspiracids (AZAs) are a novel group of marine phycotoxins that have been associated with severe human intoxication. We found that AZA-1 exposure increased lactate dehydrogense (LDH) efflux in murine neocortical neurons. AZA-1 also produced nuclear condensation and stimulated caspase-3 activity with an half maximal effective concentration (EC50) value of 25.8nM. These data indicate that AZA-1 triggers neuronal death in neocortical neurons by both necrotic and apoptotic mechanisms. An evaluation of the structure-activity relationships of AZA analogs on LDH efflux and caspase-3 activation demonstrated that the full structure of AZAs was required to produce necrotic or apoptotic cell death. The similar potencies of AZA-1 to stimulate LDH efflux and caspase-3 activation and the parallel structure-activity relationships of azaspiracid analogs in the two assays are consistent with a common molecular target for both responses. To explore the molecular mechanism for AZA-1–induced neurotoxicity, we assessed the influence of AZA-1 on Ca2+ homeostasis. AZA-1 suppressed spontaneous Ca2+ oscillations (EC50 = 445nM) in neocortical neurons. A distinct structure-activity profile was found for inhibition of Ca2+ oscillations where both the full structure as well as analogs containing only the FGHI domain attached to a phenyl glycine methyl ester moiety were potent inhibitors. The molecular targets for inhibition of spontaneous Ca2+ oscillations and neurotoxicity may therefore differ. The caspase protease inhibitor Z-VAD-FMK produced a complete elimination of AZA-1–induced LDH efflux and nuclear condensation in neocortical neurons. Although the molecular target for AZA-induced neurotoxicity remains to be established, these results demonstrate that the observed neurotoxicity is dependent on a caspase signaling pathway.

Keywords: azaspiracid; apoptosis; caspase-3; neurotoxicity; neocortical neurons

Journal Article.  6168 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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