Role of the sodium hydrogen exchanger in maitotoxin-induced cell death in cultured rat cortical neurons

Wang, Yushan; Weiss, M.; Yin, Junfei; Frew, Robert; Tenn, Catherine; Nelson, Peggy; Vair, Cory; Sawyer, Thomas W.

doi:10.1016/j.toxicon.2009.03.018

Cited by 13 publications

(24 citation statements)

References 40 publications

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“…CTXs are selective activators of voltage-dependent Na + channels in cells [24][25][26][27] whereas MTXs are water-soluble and alter the ion transport systems, causing an increase in free intracellular Ca 2+ [28][29][30][31][32]. Although highly toxic [33], MTXs do not induce CFP, because of their low oral potency and inability to accumulate in the muscle tissue of fish [7].…”

Section: Introductionmentioning

confidence: 99%

Toxicity Characterisation of Gambierdiscus Species from the Canary Islands

Rossignoli

Tudó

Bravo

et al. 2020

Toxins

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In the last decade, several outbreaks of ciguatera fish poisoning (CFP) have been reported in the Canary Islands (central northeast Atlantic Ocean), confirming ciguatera as an emerging alimentary risk in this region. Five Gambierdiscus species, G. australes, G. excentricus, G. silvae, G. carolinianus and G. caribaeus, have been detected in macrophytes from this area and are known to produce the ciguatoxins (CTXs) that cause CFP. A characterization of the toxicity of these species is the first step in identifying locations in the Canary Islands at risk of CFP. Therefore, in this study the toxicity of 63 strains of these five Gambierdiscus species were analysed using the erythrocyte lysis assay to evaluate their maitotoxin (MTX) content. In addition, 20 of the strains were also analysed in a neuroblastoma Neuro-2a (N2a) cytotoxicity assay to determine their CTX-like toxicity. The results allowed the different species to be grouped according to their ratios of CTX-like and MTX-like toxicity. MTX-like toxicity was especially high in G. excentricus and G. australes but much lower in the other species and lowest in G. silvae. CTX-like toxicity was highest in G. excentricus, which produced the toxin in amounts ranging between 128.2 ± 25.68 and 510.6 ± 134.2 fg CTX1B equivalents (eq) cell−1 (mean ± SD). In the other species, CTX concentrations were as follows: G. carolinianus (100.84 ± 18.05 fg CTX1B eq cell−1), G. australes (31.1 ± 0.56 to 107.16 ± 21.88 fg CTX1B eq cell−1), G. silvae (12.19 ± 0.62 to 76.79 ± 4.97 fg CTX1B eq cell−1) and G. caribaeus (<LOD to 90.37 ± 15.89 fg CTX1B eq cell−1). Unlike the similar CTX-like toxicity of G. australes and G. silvae strains from different locations, G. excentricus and G. caribaeus differed considerably according to the origin of the strain. These differences emphasise the importance of species identification to assess the regional risk of CFP.

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Section: Introductionmentioning

confidence: 99%

Toxicity Characterisation of Gambierdiscus Species from the Canary Islands

Rossignoli

Tudó

Bravo

et al. 2020

Toxins

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“…The activation of the sodium-calcium exchanger in reverse mode has also been observed in rat aortic smooth muscle cells [ 45 ]. The activation of the sodium-hydrogen exchanger equally appears to play a role in MTX cytotoxic activity in cortical neurons [ 46 ] and it may be a consequence of MTX-induced intracellular acidification, probably involving voltage-gated sodium channels [ 47 ]. Maitotoxin is also likely to convert the Ca 2+ -ATPase (PCMA) pump into a Ca 2+ -permeable non-selective ion channel, as demonstrated in PCMA-overexpressed Spodoptera frugiperda (Sf9) insect cells and human embryonic kidneys (HEK-293 cells) [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Maitotoxin-4, a Novel MTX Analog Produced by Gambierdiscus excentricus

et al. 2017

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Maitotoxins (MTXs) are among the most potent toxins known. These toxins are produced by epi-benthic dinoflagellates of the genera Gambierdiscus and Fukuyoa and may play a role in causing the symptoms associated with Ciguatera Fish Poisoning. A recent survey revealed that, of the species tested, the newly described species from the Canary Islands, G. excentricus, is one of the most maitotoxic. The goal of the present study was to characterize MTX-related compounds produced by this species. Initially, lysates of cells from two Canary Island G. excentricus strains VGO791 and VGO792 were partially purified by (i) liquid-liquid partitioning between dichloromethane and aqueous methanol followed by (ii) size-exclusion chromatography. Fractions from chromatographic separation were screened for MTX toxicity using both the neuroblastoma neuro-2a (N2a) cytotoxicity and Ca2+ flux functional assays. Fractions containing MTX activity were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to pinpoint potential MTX analogs. Subsequent non-targeted HRMS analysis permitted the identification of a novel MTX analog, maitotoxin-4 (MTX4, accurate mono-isotopic mass of 3292.4860 Da, as free acid form) in the most toxic fractions. HRMS/MS spectra of MTX4 as well as of MTX are presented. In addition, crude methanolic extracts of five other strains of G. excentricus and 37 other strains representing one Fukuyoa species and ten species, one ribotype and one undetermined strain/species of Gambierdiscus were screened for the presence of MTXs using low resolution tandem mass spectrometry (LRMS/MS). This targeted analysis indicated the original maitotoxin (MTX) was only present in one strain (G. australes S080911_1). Putative maitotoxin-2 (p-MTX2) and maitotoxin-3 (p-MTX3) were identified in several other species, but confirmation was not possible because of the lack of reference material. Maitotoxin-4 was detected in all seven strains of G. excentricus examined, independently of their origin (Brazil, Canary Islands and Caribbean), and not detected in any other species. MTX4 may therefore serve as a biomarker for the highly toxic G. excentricus in the Atlantic area.

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“…A second part of this work involved supplemental studies to verify that MTX produced by Gambierdiscus was the compound likely responsible for causing hemolytic activity (Yasumoto et al, 1979b; Nakajima et al, 1981; Takahashi et al, 1982,1983; Murata et al, 1992; Yasumoto, 2000). MTX alters ion transport systems causing an increase in free intracellular Ca 2+ (Ohizumi and Yasumoto, 1983; Murata et al, 1994; Lundy et al, 2004; Frew et al, 2008; Wang et al, 2009). The increase in intracellular Ca 2+ alters nerve transmission and triggers muscle contraction, breakdown of phosphoinositides, activation of calcium-dependent, non-lysosomal cysteine proteases (calpains), and release of arachidonic acid and neurotransmitters (Frew et al, 2008; Wang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Differences in the toxicity of six Gambierdiscus (Dinophyceae) species measured using an in vitro human erythrocyte lysis assay

Holland

Litaker

Tomas

et al. 2013

Toxicon

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This study examined the toxicity of six Gambierdiscus species (Gambierdiscus belizeanus, Gambierdiscus caribaeus, Gambierdiscus carolinianus, Gambierdiscus carpenteri, Gambierdiscus ribotype 2 and Gambierdiscus ruetzleri) using a human erythrocyte lysis assay. In all, 56 isolates were tested. The results showed certain species were significantly more toxic than others. Depending on the species, hemolytic activity consistently increased by ∼7-40% from log phase growth to late log - early stationary growth phase and then declined in mid-stationary growth phase. Increasing growth temperatures from 20 to 31 °C for clones of G. caribaeus showed only a slight increase in hemolytic activity between 20 and 27 °C. Hemolytic activity in the G. carolinianus isolates from different regions grown over the same 20-31 °C range remained constant. These data suggest that growth temperature is not a significant factor in modulating the inter-isolate and interspecific differences in hemolytic activity. The hemolytic activity of various isolates measured repeatedly over a 2 year period remained constant, consistent with the hemolytic compounds being constitutively produced and under strong genetic control. Depending on species, greater than 60-90% of the total hemolytic activity was initially associated with the cell membranes but diffused into solution over a 24 h assay incubation period at 4 °C. These findings suggest that hemolytic compounds produced by Gambierdiscus isolates were held in membrane bound vesicles as reported for brevetoxins produced by Karenia brevis. Gambierdiscus isolates obtained from other parts of the world exhibited hemolytic activities comparable to those found in the Caribbean and Gulf of Mexico confirming the range of toxicities is similar among Gambierdiscus species worldwide. Experiments using specific inhibitors of the MTX pathway and purified MTX, Gambierdiscus whole cell extracts, and hydrophilic cell extracts containing MTX, were consistent with MTX as the primary hemolytic compound produced by Gambierdiscus species. While the results from inhibition studies require validation by LC-MS analysis, the available data strongly suggest differences in hemolytic activity observed in this study reflect maitotoxicity.

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Role of the sodium hydrogen exchanger in maitotoxin-induced cell death in cultured rat cortical neurons

Cited by 13 publications

References 40 publications

Toxicity Characterisation of Gambierdiscus Species from the Canary Islands

Toxicity Characterisation of Gambierdiscus Species from the Canary Islands

Maitotoxin-4, a Novel MTX Analog Produced by Gambierdiscus excentricus

Differences in the toxicity of six Gambierdiscus (Dinophyceae) species measured using an in vitro human erythrocyte lysis assay

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