Potent Neurotoxic Action of the Shellfish Biotoxin Yessotoxin on Cultured Cerebellar Neurons

Pérez-Gómez, Anabel; Ferrero-Gutiérrez, Amaia; Novelli, Antonello; Franco, José M.; Paz, Beatriz; Fernández-Sánchez, Maria Teresa

doi:10.1093/toxsci/kfj064

Cited by 61 publications

(38 citation statements)

References 34 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the changes in the cytoplasmic Ca 2+ concentration may induce the process of apoptosis (32,33). Previous studies indicated that YTX may induce the increase of Ca 2+ levels in several types of cells (22,23,26). Our previous studies also demonstrated that YTX may induce Ca 2+ entry in different types of human cells (21,34).…”

Section: Discussionmentioning

confidence: 82%

See 1 more Smart Citation

Effect of yessotoxin on cytosolic calcium levels in human hepatocellular carcinoma cells in vitro

et al. 2013

View full text Add to dashboard Cite

Abstract. Yessotoxin (YTX) and its analogs are a type of marine toxins found in marine environments in numerous coastal countries. These toxins tend to accumulate in filter-feeding molluscs and may threaten the shellfish industry and public health. Several previous studies indicated that YTX IntroductionYessotoxin (YTX) and its analogs are a group of lipophilic marine toxins mainly produced by the dinoflagellates Protoceratium reticulatum, Gonyaulax spinifera and Lingulodinium polyedrum. These toxins tend to accumulate in filter-feeding molluscs, have been found in numerous countries worldwide (1-6) and were first detected in shellfish samples collected from Chinese coastal areas in 2009 (7).YTX and its analogs were first isolated from Patinopecten yessoensis in Japan (8) and were long classified as one of the categories of diarrheic shellfish poisoning (DSP) toxins (9). However, as these toxins cannot induce diarrhea, nor inhibit protein phosphatase 2A, like other DSP toxins, they were classified as an independent group by the European Union Commission in 2002 (10).Apoptosis is a programmed form of cell suicide. The process of apoptosis is controlled by genes and is crucial in disease outbreaks, including cancer. Once the signaling pathway of apoptosis is activated, the process cannot be easily undergone, even by tumor cells. Thus, there is an increasing number of studies on tumor cell apoptosis, with the aim to design an effective cancer treatment (11-13). Several studies indicated that YTX may induce apoptosis in different types of cell lines (14-21). However, the exact underlying mechanisms have not been elucidated.As the chemical structure of YTX is similar to that of brevetoxins and ciguatoxins, which were shown to interfere with voltage-gated sodium channels, the effects of YTX on transmembrane ion channels were previously investigated (22,23). The present study mainly investigated the YTX-induced alterations in intracellular Ca 2+ levels in Bel7402 human hepatocellular carcinoma cells and the possible underlying mechanisms. Materials and methodsReagents. Pure YTX was purchased from the National Research Council (NRC; Ottawa, ON, Canada). Fluo-3 acetoxymethyl ester (AM) solution (5 mM) was purchased from Beyotime Institute of Biotechnology (Shanghai, China). Nifedipine was purchased from Sigma (St. Louis, MO, USA) and was dissolved in dimethyl sulfoxide (Merck KGaA, Darmstadt, Germany). All other chemicals were of analytical reagent grade or higher purity.The Hanks' balanced salt solution (HBSS) used for cell washing consisted of 137 mM NaCl, 5.6 mM KCl, 1.26 mM CaCl 2 , 0.81 mM MgSO 4 , 0.38 mM Na 2 HPO 4 , 0.44 mM KH 2 PO 4 and 4.2 mM NaHCO 3 . The pH of the HBSS was adjusted to 7.4 with 0.1 M HCl and NaOH.

show abstract

Section: Discussionmentioning

confidence: 82%

“…YTX is a low-molecular weight compound that is toxic to different mammalian and insect cell types, including cancer cells (14,15,(23)(24)(25)(26). Our previous studies demonstrated the apoptosis induced by YTX in HeLa human cervical cancer cells, Bel7402 human hepatocellular carcinoma cells and HL7702 human liver cells (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Effect of yessotoxin on cytosolic calcium levels in human hepatocellular carcinoma cells in vitro

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Perez-Gomez et al described an IC 50 of 20 nM in cerebellar granule neurons, 28 but lower doses induced also toxicity signals. We show in the present work that primary cortical neurons are more sensitive to YTX toxicity than the neurons used in the previous study, setting the IC 50 for these cells in 4.27 nM.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

Translocation of PKC by Yessotoxin in an in Vitro Model of Alzheimer’s Disease with Improvement of Tau and β-Amyloid Pathology

Albrecht

Vale

Vieytes

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Yessotoxin is a marine phycotoxin that induces motor alterations in mice after intraperitoneal injection. In primary cortical neurons, yessotoxin treatment induced a caspase-independent cell death with an IC 50 of 4.27 nM. This neurotoxicity was enhanced by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid and partially blocked by amiloride. Unlike previous studies, yessotoxin did not increase cyclic adenosine monophosphate levels or produce any change in phosphodiesterase 4 steady state expression in triple transgenic neurons. Since phosphodiesterases (PDEs) are engaged in learning and memory, we studied the in vitro effect of the toxin against Alzheimer's disease hallmarks and observed that pretreatment of cortical 3xTg-AD neurons with a low nanomolar concentration of yessotoxin showed a decrease expression of hyperphosphorylated tau isoforms and intracellular accumulation of amyloid-beta. These effects were accompanied with an increase in the level of the inactive isoform of the glycogen synthase kinase 3 and also by a translocation of protein kinase C from cytosol to membrane, pointing to its activation. In fact, inhibition of protein kinase C with GF109203X blocked the effect of yessotoxin over tau protein. The data presented here shows that 1 nM yessotoxin activates protein kinase C with beneficial effects over the main Alzheimer's disease hallmarks, tau and Aβ, in a cellular model obtained from 3xTg-AD fetuses. KEYWORDS: Marine toxin, yessotoxin, Alzheimer's disease, protein kinase C Y essotoxin (YTX) is a marine phycotoxin with more than 40 analogues isolated for the first time in Japanese waters. It is produced by different dinoflagellates, among them, Protoceratium reticulatum and Lingulodinium polyedrum. 1−3Originally, the toxin was included with the okadaic acid (OA) in the group of diarrheic shellfish poisoning (DSP) toxins, because they used to appear together during toxic episodes. Later, it was separated in its own group, due to different biological origin and different in vivo effects. 4 One of the main differences with OA is that YTX shows no inhibition of protein phosphatase 2A (PP2A). 5 Recently, it has been observed that, in fact, YTX and OA show an immunoregulatory effect over lymphocytes, although through protein kinase C (PKC) mediated mechanisms in the case of YTX and through PP2A mechanisms in the case of OA. 6PKC is widely expressed in neurons, and it is implicated in neuroprotection, synaptic function, and plasticity. This turns it into an important molecule in learning and memory, and its signaling disruption causes impairment in these processes. 7−9Moreover, reduced PKC levels were found in samples from patients with Alzheimer's disease (AD).10 Several pieces of evidence indicate that amyloid beta (Aβ) peptide can reduce PKC levels and also block the activation and normal function of the enzyme.11 All these findings indicate that PKC activators may constitute an interesting target for AD related pathology, as PKC isoforms are involved in memory processing and the enzyme c...

show abstract

“…The chemical structure of YTX is similar to that of the neurotoxic brevetoxins, and interactions between YTX and transmembrane ion channels have been studied (20,21). Furthermore, YTX has been identified as an inducer of apoptosis in the BE (2)-M17 neuroblastoma cell line (22), in primary neuronal cultures (21), in myoblast cell lines from rat and mouse (23,24) and in the HeLa human cervical cancer cell line (25). However, the exact molecular mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Yessotoxin induces apoptosis in HL7702 human liver cells

et al. 2011

View full text Add to dashboard Cite

Abstract. The marine toxin yessotoxin (YTX) is found in numerous aquatic environments and poses a potential threat to the shellfish industry and to public health. We analyzed the toxicity of YTX on HL7702 human liver cells using optical microscopy, Hoechst 33342 chromatin staining, DNA gel electrophoresis, rhodamine 123 staining and calcium-sensitive laser scanning confocal microscopy. The results demonstrated that YTX induced the usual hallmarks of apoptosis, including chromatin condensation, DNA laddering, activity of caspase-3 deregulation and loss of mitochondrial membrane potential. Furthermore, YTX caused cytosolic calcium levels to increase in HL7702 cells. YTX may cause liver damage through hepatocyte apoptosis.

show abstract

Potent Neurotoxic Action of the Shellfish Biotoxin Yessotoxin on Cultured Cerebellar Neurons

Cited by 61 publications

References 34 publications

Effect of yessotoxin on cytosolic calcium levels in human hepatocellular carcinoma cells in vitro

Effect of yessotoxin on cytosolic calcium levels in human hepatocellular carcinoma cells in vitro

Translocation of PKC by Yessotoxin in an in Vitro Model of Alzheimer’s Disease with Improvement of Tau and β-Amyloid Pathology

Yessotoxin induces apoptosis in HL7702 human liver cells

Contact Info

Product

Resources

About