A Comparative Study of the Effect of Ciguatoxins on Voltage-Dependent Na<sup>+</sup> and K<sup>+</sup> Channels in Cerebellar Neurons

Pérez, Sheila; Vale, Carmen; Albrecht, Eva; Alfonso, Carmen; Rodrí­guez, Pilar Rodriguez; Otero, Paz; Alfonso, Amparo; Vale, Paulo; Hirama, Masahiro; Vieytes, Mercedes R.; Botana, Luís M.

doi:10.1021/tx200043j

Cited by 31 publications

(28 citation statements)

References 36 publications

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“…First, the effect of a 24 h exposure of cortical neurons to CTX 3C was evaluated in Na V and K V channels since the primary target of CTXs are Na V channels, although CTXs can also act on K V channels in some neuronal preparations. 39 However, the effect of a chronic exposure of cortical neurons to CTXs on these channels has not been previously evaluated. In all experiments, neurons were treated with the synthetic ciguatoxin CTX 3C at 5 nM, a concentration that causes a rapid activation of Na V channels after a 5 min exposure of cortical neurons and produces a rapid membrane depolarization (companion article, DOI: 10.1021/tx500503d) but is not neurotoxic for cortical neurons at 24 h. 16 To measure voltage gated K + currents (I K ), neurons were voltage clamped at a membrane holding potential of −60 mV, and total I K was evoked by 200 ms depolarizing pulses from V m to +75 mV in 15 mV steps (Figure 2, inset).…”

Section: Ctx 3c Enhances the Expression Of Arc And Egr1mentioning

confidence: 99%

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Martı́n

Vale

Rubiolo

et al. 2015

Chem. Res. Toxicol.

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Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.

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Section: Ctx 3c Enhances the Expression Of Arc And Egr1mentioning

confidence: 99%

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Martı́n

Vale

Rubiolo

et al. 2015

Chem. Res. Toxicol.

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“…Similarly, P-CTX-4B inhibited potassium channels in frog myelinated axons with an IC 50 of approximately 12 nM, but was less potent than P-CTX-1B at inhibiting Na v channels (Schlumberger et al 2010). A direct comparison of the effects of several ciguatoxins in cerebellar ganglion neurons showed that all ciguatoxin inhibited potassium currents, with P-CTX-1B being approximately equipotent at inhibiting I K and I A , while CTX-3C was particularly potent at inhibiting I K but had little effect on I A (Perez et al 2011). In mouse taste cells, CTX-3C had no significant effect on potassium channels, while gambierol, a related polyether presently only identified in Gambierdiscus cultures, potently blocked potassium currents (Ghiaroni et al 2006).…”

Section: Ciguatoxin Mode Of Actionmentioning

confidence: 96%

“…In addition to profound effects on Na + conductance, ciguatoxins also inhibit neuronal potassium channels (Hidalgo et al 2002;Birinyi-Strachan et al 2005b;Schlumberger et al 2010;Perez et al 2011Perez et al , 2012. In dorsal root ganglion neurons, inhibition of the I K(DR) and the I KA currents in particular leads to prolonged action potential and afterhyperpolarization (AHP) duration and contributes to the increased neuronal excitability, altered membrane potential, and spontaneous action potential firing induced by P-CTX-1 (Birinyi- Strachan et al 2005b).…”

Section: Ciguatoxin Mode Of Actionmentioning

confidence: 99%

Ciguatoxin and Ciguatera

Lewis

Vetter

2016

Marine and Freshwater Toxins

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“…As a functional assay for detection and quantification of CFP toxins, a competitive receptor binding assay was developed and evaluated legrand and lotte, 1994;lombet et al, 1987;Perez et al, 2011). this assay is based on the competitive binding of radio-labeled [ 3 H]-brevetoxin-3 to sodium-channels in rat brain synaptosomes in the presence of CTX-group toxins.…”

Section: Functional Biochemical and Biomolecular Assaysmentioning

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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A Comparative Study of the Effect of Ciguatoxins on Voltage-Dependent Na⁺ and K⁺ Channels in Cerebellar Neurons

Cited by 31 publications

References 36 publications

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Ciguatoxin and Ciguatera

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

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A Comparative Study of the Effect of Ciguatoxins on Voltage-Dependent Na+ and K+ Channels in Cerebellar Neurons

Cited by 31 publications

References 36 publications

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Ciguatoxin and Ciguatera

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

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A Comparative Study of the Effect of Ciguatoxins on Voltage-Dependent Na⁺ and K⁺ Channels in Cerebellar Neurons