Involvement of caspase activation in azaspiracid-induced neurotoxicity in neocortical neurons

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

Research output: Contribution to journalArticle

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Abstract

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 structureactivity 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.

Original languageEnglish
Pages (from-to)323-334
Number of pages12
JournalToxicological Sciences
Volume114
Issue number2
DOIs
StatePublished - Jan 4 2010

Fingerprint

Caspases
Neurons
Chemical activation
Lactic Acid
Caspase 3
azaspiracid
Condensation
Caspase Inhibitors
Cell death
Structure-Activity Relationship
Protease Inhibitors
Assays
Homeostasis
Cell Death

All Science Journal Classification (ASJC) codes

  • Toxicology

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Involvement of caspase activation in azaspiracid-induced neurotoxicity in neocortical neurons. / Cao, Zhengyu; LePage, Keith T.; Frederick, Michael O.; Nicolaou, Kyriacos C.; Murray, Thomas F.

In: Toxicological Sciences, Vol. 114, No. 2, 04.01.2010, p. 323-334.

Research output: Contribution to journalArticle

Cao, Zhengyu ; LePage, Keith T. ; Frederick, Michael O. ; Nicolaou, Kyriacos C. ; Murray, Thomas F. / Involvement of caspase activation in azaspiracid-induced neurotoxicity in neocortical neurons. In: Toxicological Sciences. 2010 ; Vol. 114, No. 2. pp. 323-334.
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