Differential Effects of Ciguatoxin
and Maitotoxin
in Primary Cultures of Cortical Neurons
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Abstract
Ciguatoxins
(CTXs) and maitotoxins (MTXs) are polyether ladder
shaped toxins derived from the dinoflagellate <i>Gambierdiscus
toxicus</i>. Despite the fact that MTXs are 3 times larger than
CTXs, part of the structure of MTXs resembles that of CTXs. To date,
the synthetic ciguatoxin, CTX 3C has been reported to activate voltage-gated
sodium channels, whereas the main effect of MTX is inducing calcium
influx into the cell leading to cell death. However, there is a lack
of information regarding the effects of these toxins in a common cellular
model. Here, in order to have an overview of the main effects of these
toxins in mice cortical neurons, we examined the effects of MTX and
the synthetic ciguatoxin CTX 3C on the main voltage dependent ion
channels in neurons, sodium, potassium, and calcium channels as well
as on membrane potential, cytosolic calcium concentration ([Ca<sup>2+</sup>]<sub>c</sub>), intracellular pH (pH<sub>i</sub>), and neuronal
viability. Regarding voltage-gated ion channels, neither CTX 3C nor
MTX affected voltage-gated calcium or potassium channels, but while
CTX 3C had a large effect on voltage-gated sodium channels (VGSC)
by shifting the activation and inactivation curves to more hyperpolarized
potentials and decreasing peak sodium channel amplitude, MTX, at 5
nM, had no effect on VGSC activation and inactivation but decreased
peak sodium current amplitude. Other major differences between both
toxins were the massive calcium influx and intracellular acidification
produced by MTX but not by CTX 3C. Indeed, the novel finding that
MTX produces acidosis supports a pathway recently described in which
MTX produces calcium influx via the sodium–hydrogen exchanger
(NHX). For the first time, we found that VGSC blockers partially blocked
the MTX-induced calcium influx, intracellular acidification, and protected
against the short-term MTX-induced cytotoxicity. The results presented
here provide the first report that shows the comparative effects of
two prototypical ciguatera toxins, CTX 3C and MTX, in a neuronal model.
We hypothesize that the analogies and differences in the bioactivity
of these two toxins, produced by the same microorganism, may be strongly
linked to their chemical structure