Effects of Azaspiracid-1, A Potent Cytotoxic Agent, on Primary Neuronal Cultures. A Structure−Activity Relationship Study

Vale, Carmen; Nicolaou, K. C.; Frederick, Michael O.; Gómez-Limia, Belén; Alfonso, Amparo; Vieytes, Mercedes R.; Botana, Luís M.

doi:10.1021/jm061063g

Cited by 57 publications

(82 citation statements)

References 31 publications

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“…We have recently shown that AZA-1 is a potent neurotoxic agent in primary neuronal cultures showing an effect several orders of magnitude higher than the cytotoxic effects previously described in different cell lines [14,15]. The cytotoxic action of AZA-1 in neurons was independent of an alteration on the cytosolic calcium concentration or on F-actin cytoskeleton disruption and it needed the whole molecular structure of the toxin [15]. In view of the high cytotoxic effect of AZA-1 in neuronal cultures we conducted a pharmacological and molecular approach to explore several potential pharmacological targets of azaspiracids in nervous tissue.…”

Section: Introductionmentioning

confidence: 78%

“…So far, there is no information about the mechanism of action of the AZAs or of their specific cellular targets. We have recently shown that AZA-1 is a potent neurotoxic agent in primary neuronal cultures showing an effect several orders of magnitude higher than the cytotoxic effects previously described in different cell lines [14,15]. The cytotoxic action of AZA-1 in neurons was independent of an alteration on the cytosolic calcium concentration or on F-actin cytoskeleton disruption and it needed the whole molecular structure of the toxin [15].…”

Section: Introductionmentioning

confidence: 84%

“…Primary cultures of cerebellar granule cell were obtained from cerebella of 7-day-old mice as previously described [15,[18][19][20]. In brief, cells were dissociated by mild trypsinization at 37°C, followed by trituration in a DNAse solution (0.004% w/v) containing a soybean trypsin inhibitor (0.05% w/v).…”

Section: Cell Culturesmentioning

confidence: 99%

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The c-Jun-N-Terminal Kinase is Involved in the Neurotoxic Effect of Azaspiracid-1

Vale¹,

Gómez-Limia²,

Nicolaou

et al. 2007

Cell Physiol Biochem

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Aims: Azaspiracids (AZAs) are marine phycotoxins with an unknown mechanism of action, recently implicated in human intoxications. The predominant analog in nature, AZA-1 targets several organs in vivo, including the central nervous system and exhibits high neurotoxicity in vitro. Methods: We used pharmacological tools to inhibit the cytotoxic effect of the toxin in primary cultured neurons. Immunocytochemical techniques in combination with confocal microscopy were employed to examine the cellular mechanisms involved in the neurotoxic effect of AZA-1. Results: Several targets for azaspiracid-induced neurotoxicity, specifically the cAMP pathway, or protein kinase C and phosphatidylinositol 3-kinase activation were excluded. Interestingly, the specific c-Jun-N-terminal protein kinase (JNK) inhibitor SP 600125 protected cultured neurons against AZA-induced cytotoxicity. Immunocytochemistry experiments showed that AZA-1 increased the amount of phosphorylated JNK and caused nuclear translocation of the active protein that was prevented by SP 600125. Conclusion: Our data constitute the relationship between azaspiracid-induced cytotoxicity and specific modifications in cellular transduction signals, specifically we found that JNK activation is associated with the cytotoxic effect of the toxin. These results should provide the basis to identify the mechanism of action of this group of toxins.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 84%

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The c-Jun-N-Terminal Kinase is Involved in the Neurotoxic Effect of Azaspiracid-1

Vale¹,

Gómez-Limia²,

Nicolaou

et al. 2007

Cell Physiol Biochem

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“…A. obesum and A. caudatum are the only members of the genus Azadinium established in culture for which no AZA has been detected. While the AZAs produced by A. spinosum have been shown empirically to be toxic (Ito et al 2002, Román et al 2002, Colman et al 2005, Alfonso et al 2006, Kulagina et al 2006, Vale et al 2007, research is pending for the new AZAs.…”

Section: Introductionmentioning

confidence: 99%

Feeding by heterotrophic protists and copepods on the photosynthetic dinoflagellate Azadinium cf. poporum from western Korean waters

Potvin¹,

Hwang²,

Yoo³

et al. 2013

Aquat. Microb. Ecol.

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We explored the interactions between the photosynthetic dinoflagellate Azadinium cf. poporum isolated from Korean waters and potential predators, including engulfment feeders, a pallium feeder, peduncle feeders, and filter feeders. We measured the growth and/or ingestion rates of Oxyrrhis marina, Strobilidium sp., and Acartia spp. on A. cf. poporum as a function of prey concentrations. We also calculated grazing coefficients by using field data on abundance of Strobilidium sp.-sized naked ciliates co-occurring with A. cf. poporum and laboratory data on ingestion rates obtained in this study. Most of the tested organisms were able to feed on A. cf. poporum, but only O. marina, Strobilidium sp., and Acartia spp. showed sustained growth and/or ingestion on A. cf. poporum. Thus, some heterotrophic dinoflagellates using engulfment and filter feeders, such as ciliates and copepods, are likely to be optimal predators, while peduncle-feeding heterotrophic dinoflagellates are unlikely to efficiently feed due to the handling of the theca. The predators had low ratios of maximum growth rate to maximum ingestion rate on A. cf. poporum, as well as low gross growth efficiencies. Therefore, A. cf. poporum appears to be a low-quality prey for the predators tested. Grazing coefficients ranged between 0.052 and 0.446 d −1 , suggesting that Strobilidium sp.-sized naked ciliates may sometimes have a high impact on A. cf. poporum populations, leading to the removal of up to 36% of the population in 1 d. However, the low quality of the prey and predator selectivity in a more complex microbial community may reduce this impact.

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“…In vitro experiments with mammalian cell lines showed alterations in the cytoskeletal structure (Roman et al, 2002;twiner et al, 2005;Ronzitti et al, 2007;Vilarino et al, 2006;Paredes et al, 2011). AZP toxins increase intracellular Ca 2+ concentrations and cAMP levels in human lymphocytes and primary cultures of cerebellar granule cells (Roman et al, 2002;Vale et al, 2007b). In addition these toxins induce increased phosphorylated Junkinases in primary cultured neurons (Vale et al, 2007a).…”

Section: Mode Of Actionmentioning

confidence: 99%

A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems

Daneshian

2013

ALTEX

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Summary Aquatic food accounts for over 40% of global animal food products, and the potential contamination with toxins of algal origin -marine biotoxins -poses a health threat for consumers. The gold standards to assess toxins in aquatic food have traditionally been in vivo methodssingle marine biotoxins or combinations of marine biotoxins and intoxication symptomatology as well as monitoring the "success" of controls implemented during fishery and aquaculture production, processing, and retailing. For this reason, a workshop was organized in ermatingen, Switzerland by the Center for Alternatives to Animal testing -europe (CAAteurope) within the framework of the transatlantic think tank for toxicology (t 4 ).In contrast to other food products where hygiene and potential contamination with microbes or mold toxins is the prime issue, the emphasis in aquatic products (shellfish and finfish) is, beyond viral and bacterial contaminations, primarily placed on potential contamination with marine biotoxins owing to the numerous and recurring human intoxications.The gold standards to assess toxins in aquatic food have traditionally been in vivo methods, i.e., the mouse and the rat bioassays. Besides the ethical issues of in vivo bioassays there are specific difficulties, e.g., different exposure route (i.p. versus oral), low inter-species comparability, high intra-species variability, and questionable extrapolation of quantitative risk to humans, thus highlighting the need for the development of more reliable detection and quantification methods. Based on this reasoning, the european Food Safety Authority (eFSA) advocates the use of an analytical method, i.e., LC-MS (Liquid Chromatography coupled Mass Spectrometry), as a substitute for in vivo bioassays for almost all classes of marine toxins. However, although lC-MS is a very sensitive method that has the advantages of being able to detect multiple toxins in a single analysis and being good for confirming the identity of toxins, the quality of quantitative analysis is dependent on the availability of calibration standards. While many new toxin structural analogues have been detected and identified using LC-MS, this technique -as with most other methods -is not good at detecting new toxin types. When new toxin analogues are detected but accurate standards are not yet available, only an approximate quantitation is possible using estimated response factors.For the purpose of risk assessment of food, however, it is imperative to focus on the possible adverse effects, independent of whether they stem from one toxin or a combination of toxins. As toxicity is defined by functional and structural changes of biological systems, the development of a human-relevant in vitro system for appropriate risk assessment of marine biotoxins in seafood stands to reason. Moreover, poor correlation of human intoxications, of acute symptomatology and long-term adverse effects, and of predictive in vitro, in vivo, and analytical detection methodologies of marine biotoxins stems not least from a...

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Effects of Azaspiracid-1, A Potent Cytotoxic Agent, on Primary Neuronal Cultures. A Structure−Activity Relationship Study

Cited by 57 publications

References 31 publications

The c-Jun-N-Terminal Kinase is Involved in the Neurotoxic Effect of Azaspiracid-1

The c-Jun-N-Terminal Kinase is Involved in the Neurotoxic Effect of Azaspiracid-1

Feeding by heterotrophic protists and copepods on the photosynthetic dinoflagellate Azadinium cf. poporum from western Korean waters

A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems

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