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PubMed1997

Neuronal nitric oxide synthase and calmodulin-dependent protein kinase IIalpha undergo neurotoxin-induced proteolysis.

Calpain (calcium-activated neutral protease) has been implicated as playing a role of neuronal injury in cerebral ischemia and excitotoxicity. Here we report that, in addition to extreme excitotoxic conditions [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate challenges], other neurotoxins such as maitotoxin, A23187, and okadaic acid also induce calpain activation, as detected by m-calpain autolytic fragmentation and nonerythroid alpha-spectrin breakdown. Under the same conditions, calmodulin-dependent protein kinase II-alpha (CaMPK-IIalpha) and neuronal nitric oxide synthase (nNOS) are both proteolytically cleaved by calpain. Such fragmentation can be reduced by calpain inhibitors (acetyl-Leu-Leu-Nle-CHO and PD151746). In vitro digestion of protein extract from cortical cultures with purified mu- and m-calpain produced fragmentation patterns for CaMPK-IIalpha and nNOS similar to those produced in situ. Also, several other calpain-sensitive calmodulin-binding proteins (plasma membrane calcium pump, microtubule-associated protein 2, and calcineurin A) and protein kinase C-alpha are also degraded in neurotoxin-treated cultures. Lastly, in a rat pup model of acute excitotoxicity, intrastriatal injection of NMDA resulted in breakdown of CaMPK-IIalpha and nNOS. The degradation of CaMPK-IIalpha, nNOS, and other endogenous calpain substrates may contribute to the neuronal injury associated with various neurotoxins.

Animals↗
PubMed1990

Characterization of palytoxin-induced channels in mouse neuroblastoma cells.

Palytoxin-induced whole-cell and single channel currents were recorded in mouse neuroblastoma cells. Palytoxin-induced single channel currents had a slope conductance of 26 pS (20-22 degrees C). Palytoxin-induced channels were permeable to sodium and potassium and slightly permeable to calcium, choline and tetramethylammonium. They did not seem to be significantly permeable to chloride or protons. Both the steady-state and the rate of the dose-dependent effects of palytoxin could be accounted for if one assumed that a palytoxin-induced channel resulted from the binding of two palytoxin molecules to a membrane receptor with respective dissociation constants of 5 nM and 10 pM. In the continued presence of low palytoxin concentrations (less than 1 nM) the effect was maintained. Higher palytoxin concentrations induced a transient and irreproducible effect. The effect of palytoxin was decreased when either external sodium was replaced by potassium or in the absence of calcium in external and/or internal media. The results suggest that ionic currents result from the binding of palytoxin molecules to a membrane receptor and that receptor-toxin complexes can be internalized.

Acrylamides↗
PubMed2000

Binding properties of (3)H-PbTx-3 and (3)H-saxitoxin to brain membranes and to skeletal muscle membranes of puffer fish Fugu pardalis and the primary structure of a voltage-gated Na(+) channel alpha-subunit (fMNa1) from skeletal muscle of F. pardalis.

The dissociation constants for (3)H-saxitoxin to brain membranes and to skeletal muscle membranes of puffer fish Fugu pardalis have been estimated to be 190- and 460-fold, respectively, larger than those to corresponding membranes of rat, by a rapid filtration assay, while these values for (3)H-PbTx-3 have been estimated to be one-third and one-half of those to rat, respectively. We have obtained a cDNA, encoding an entire voltage-gated Na(+) channel alpha-subunit (fMNa1, 1880 residues) from skeletal muscle of F. pardalis by composition of the fragments obtained from cDNA library and RT-PCR products. In fMNa1 protein, the residues for ion-selective filter and voltage sensor and the charged residues in SS2 regions of domains I-IV were conserved, but the aromatic amino acid (Phe/Tyr), commonly located in the SS2 region of domain I of tetrodotoxin-sensitive Na(+) channels, was replaced by Asn. With this particular criterion, we propose that the fMNa1 protein is a tetrodotoxin-resistant Na(+) channel.

Amino Acid Sequence↗
PubMed1992

Monoclonal antibody-based enzyme-linked immunoassays for the measurement of palytoxin in biological samples.

Mouse monoclonal and rabbit polyclonal antibodies were produced against conjugates of keyhole limpet hemocyanin and chemically defined palytoxin haptens. Palytoxin haptens were produced by derivatization of the primary amino group with sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate or succinimidyl 3-(2-pyridyldithio)propionate. Selected antibodies were used to develop five palytoxin-specific enzyme-linked immunoassay formats for the quantitation of palytoxin in biological matrices, including crude extracts of Palythoa tuberculosa. The formats developed include an indirect competitive inhibition enzyme-linked immunoassay, two types of direct competitive inhibition enzyme-linked immunoassays, and both indirect and direct sandwich enzyme-linked immunosorbent assays. The sandwich enzyme-linked immunosorbent assays are capable of detecting as little as 10 pg palytoxin per test, but may be subject to matrix interference. The direct competitive inhibition enzyme-linked immunoassays detect as little as 30 pg palytoxin per test with a total assay time of only 4 hr. The enzyme-linked immunoassays do not cross-react with the other marine toxins tested, but do cross-react with certain non-toxic, treated preparations of palytoxin. The enzyme-linked immunoassays were used to quantitate palytoxin in P. tuberculosa extracts and to monitor toxin isolation. These enzyme-linked immunoassay systems can substitute for the mouse bioassay of palytoxin, providing a rapid, sensitive, and accurate means of toxin detection.

Acrylamides↗
PubMed1999

Distribution and sequestration of palytoxin in coral reef animals.

In the reefs off the Colombian coast (Caribbean Sea) and around Lizard Island, Australia (Pacific), palytoxin (PTX), which has been detected in zoanthid species of the genus Palythoa, also occurred in various other marine organisms living in close association with zoanthid colonies, e.g. sponges (Porifera), soft corals (Alcyonaria), gorgonians (Gorgonaria), mussels, and crustaceans. Predators, e.g. polychaete worms (Hermodice carunculata), a starfish (Acanthaster planci) and fish (Chaetodon species) feeding on Palythoa colonies, accumulate high toxin concentrations in their organs, where PTX is stored in its active form. The high level of toxin tolerance observed in marine animals may enable the wide distribution of PTX in marine biota and its transport and sequestration in food chains.

Acrylamides↗
PubMed2003

Relaxation of rabbit corpus cavernosum by selective activators of voltage-gated sodium channels: role of nitric oxide-cyclic guanosine monophosphate pathway.

OBJECTIVES: To investigate the capacity of voltage-gated Na(+) channel activators such as batrachotoxin, aconitine, veratridine, Ts1 (formerly Tityus gamma-toxin), and brevetoxin-3 to induce relaxation of rabbit isolated corpus cavernosum (RbCC) and the pharmacologic mechanisms underlying this phenomenon. The voltage-gated Na(+) channels of the corpus cavernosum are essential for erectile function. A number of biologic toxins exert their effects by modifying the properties of these channels. METHODS: Male New Zealand white rabbits were anesthetized with pentobarbital sodium. Strips of RbCC were transferred to 10-mL organ baths containing oxygenated and warmed Krebs solution. The RbCC strips were connected to force-displacement transducers, and changes in isometric force were recorded using a PowerLab 400 data acquisition system. Corporeal smooth muscle was precontracted submaximally with phenylephrine (10 micromol/L). RESULTS: The binding site-2 (batrachotoxin, aconitine, and veratridine) and binding site-5 (brevetoxin-3) voltage-gated Na(+) channel activators caused slow-onset RbCC relaxations, and the binding site-4 activator Ts1 produced transitory relaxations followed by a return to baseline. The Na(+)channel blockers tetrodotoxin and saxitoxin (0.1 micromol/L each) abolished the relaxations induced by these agonists. Similarly, the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (100 micromol/L) markedly reduced the relaxations and l-arginine (1 mmol/L) restored the relaxations. The soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (10 micromol/L) reduced the relaxations, and the phosphodiesterase type 5 inhibitor sildenafil (100 nmol/L) significantly potentiated the relaxations by all activators. CONCLUSIONS: Our results indicate that the relaxations evoked by selective activators of voltage-gated Na(+) channels are mediated by the release of nitric oxide from nitrergic nerves and the activation of the nitric oxide-cyclic guanosine monophosphate pathway in the smooth muscle cells of erectile tissue.

Aconitine↗
PubMed2006

The Genoa 2005 outbreak. Determination of putative palytoxin in Mediterranean Ostreopsis ovata by a new liquid chromatography tandem mass spectrometry method.

A new method for sensitive, specific, and direct determination of palytoxin is proposed herein. It is based on combination of reversed-phase liquid chromatography with mass spectrometry (LC-MS). The new method was set up on a turbo ion spray-triple quadrupole MS instrument operating in selected ion monitoring (SIM) and multiple reaction monitoring (MRM) acquisition modes (positive ions). The minimum detection levels for matrix-free toxin on column were thus estimated from the data to be 200 and 125 pg in SIM and MRM modes, respectively. Spiking experiments before and after extraction allowed us to assess limits of detection and quantitation for palytoxin in matrix, accuracy, and intraday and interday reproducibility of the method. The developed method was decisive for the analysis of a plankton sample collected along Genoa coasts in July 2005 when respiratory illness in people exposed to marine aerosols occurred. It is suggested that putative palytoxin was the causative agent responsible for patients' symptoms and demonstrated for the first time the presence of such a toxin in Italian waters.

Acrylamides↗
PubMed2005

Distribution of brevetoxin (PbTx-3) in mouse plasma: association with high-density lipoproteins.

We investigated the brevetoxin congener PbTx-3 to determine its distribution among carrier proteins, including albumin and blood lipoproteins. Using a radiolabeled brevetoxin tracer (PbTx-3), we found that 39% of the radiolabel remained associated with components in mouse plasma after > 15 kDa cutoff dialysis. Of this portion, only 6.8% was bound to serum albumin. We also examined the binding of brevetoxin to various lipoprotein fractions. Plasma, either spiked with PbTx-3 or from mice treated for 30 min with PbTx-3, was fractionated into different-sized lipoproteins by iodixanol gradient ultracentrifugation. Each fraction was then characterized and quantified by agarose gel electrophoresis and brevetoxin radioimmunoassay, respectively. In both the in vitro and in vivo experiments, the majority of brevetoxin immunoreactivity was restricted to only those gradient fractions that contained high-density lipoproteins (HDLs). Independent confirmation of brevetoxin binding to HDLs was provided by high molecular weight (100 kDa cutoff) dialysis of [3H]PbTx-3 from lipoprotein fractions as well as a scintillation proximity assay using [3H]PbTx-3 and purified human HDLs. This information on the association of brevetoxins with HDLs provides a new foundation for understanding the process by which the toxin is delivered to and removed from tissues and may permit more effective therapeutic measures to treat intoxication from brevetoxins and the related ciguatoxins.

Albumins↗
PubMed2005

Brevetoxin augments NMDA receptor signaling in murine neocortical neurons.

Brevetoxins (PbTx) are potent allosteric enhancers of voltage-gated sodium channel (VGSC) function and are associated with periodic "red tide" blooms. These neurotoxins produce neuronal injury and death in cerebellar granule cells (CGC) following acute exposure. In murine neocortical neurons, brevetoxin induces Ca(2+) influx that is mediated through both glutamatergic and non-glutamatergic pathways. Inasmuch as Src kinase is capable of upregulating the NMDA subtype of glutamate receptors, we determined whether Src kinase participated in PbTx-2-induced Ca(2+) influx. Inhibition of Src kinase blocked PbTx-2-induced Ca(2+) influx. PbTx-2 treatment moreover increased tyrosine phosphorylation of the NR2B subunit. A rise in intracellular [Na(+)] and phosphorylation of NMDA receptors by Src kinase is known to increase NMDA receptor activity. We therefore explored the influence of brevetoxin on NMDA receptor function. We found that PbTx-2 augments NMDA receptor-mediated Ca(2+) influx in both spontaneously oscillating mature neurons and in non-oscillatory immature neurons. PbTx-2 also enhanced the effect of bath-applied NMDA on extracellular signal-regulated kinase 2 (ERK2) activation. These results suggest that brevetoxin augments NMDA receptor signaling in neocortical neurons, and this upregulation may be mediated by coincidence of an elevation in intracellular [Na(+)] and Src kinase activation.

Animals↗
PubMed1987

Occurrence of palytoxin in the trigger fish Melichtys vidua.

The trigger fish Melichtys vidua, collected at Pingelap Atoll in Ponape in The Federated States of Micronesia, contained a potent toxin in the viscera, flesh, and digestive tracts with contents. The toxic principle appeared identical to palytoxin on the basis of toxicity and chromatographic properties.

Acrylamides↗
PubMed1991

Properties of palytoxin-induced whole cell current in single rat ventricular myocytes.

We examined the properties of the current induced by palytoxin in single ventricular cells of rats. The current was measured by a whole cell voltage clamp method. When the cell was held at -75 mV, palytoxin induced a sustained inward current in a concentration-dependent manner (2-100 pmol/l). The time-course of the inward current paralleled that of the depolarization. At a holding potential of +50 mV, it caused an outward current. Palytoxin-induced current reversed at 0 mV and its current-voltage relation was almost linear at either negative or positive voltage. Substitution of external NaCl with choline-Cl suppressed the palytoxin-induced inward current but not the outward current, by shifting the reversal potential to levels more negative than -50 mV. A cardiac glycoside, cymarin (10 and 100 mumol/l) partially inhibited the palytoxin-induced current without changing the reversal potential, only when applied before palytoxin. Palytoxin decreased the nicardipine-sensitive Ca2+ current. These data suggest that palytoxin-induced inward current is carried by extracellular Na+ and the outward current is carried mainly by intracellular K+, and that the inward current is responsible for the toxin's depolarizing action. The antagonism by cysmarin indicates that the site of action of palytoxin is in the vicinity of the binding site of cardiac glycosides.

Acrylamides↗
PubMed1994

Palytoxin-induced transmitter release in the autonomic nervous system of the rat.

A combination of pharmacological, histochemical, immunocytochemical, neurochemical and microscopic techniques has been used to test the hypothesis that smooth muscle contractions caused by palytoxin are primarily a response to toxin-induced release of transmitter from motor nerve terminals. In the anococcygeus, palytoxin caused a dose-dependent contraction; the dose-response curve was particularly steep in the dose range 0.3-100 nM. This part of the response was abolished by phentolamine and absent in the muscles of reserpinized animals. A single, large dose of palytoxin (100 nM) caused a biphasic contraction. Phentolamine blocked the first phase by 50% and the second by > 80%. Transmitter overflow studies showed that the toxin enhanced the release of 3H after loading with 3H-NA, and immunofluorescence showed the loss of adrenergic transmitters from the innervation. In the vas deferens, palytoxin caused a biphasic contraction of the muscle. Phentolamine blocked first phase by > 80% and the second by 47%. Immunofluorescence studies showed that stores of adrenergic transmitter were depleted but stores of NPY were not greatly affected. Indirect evidence suggested that palytoxin did not cause the release of purinergic transmitters. A direct component to the contraction was apparently present in most preparations, but though variable in extent it was usually slight. It is concluded that the contractions of smooth muscle caused by palytoxin are primarily the result of toxin-induced transmitter release.

Acrylamides↗
PubMed1995

Interaction of palytoxin with red cells: structure-function studies.

Palytoxin (PTX), a potent toxin isolated from the marine soft coral Palythoa tuberculosa increases the cationic permeability of red cell membranes and inhibits the (Na+,K+)-activated ATPase, effects that are completely reversed by ouabain. It has also been shown to compete with ouabain for a binding site and it has been suggested that it binds to the Na+,K(+)-pump molecule in cells. In a search for analogues of PTX that would bind covalently and could thus be used to identify and characterize the binding site, we have used compounds which differed from PTX at one end or at both ends simultaneously. In order to determine whether these derivatives could be used to replace palytoxin, we tested their potency to induce an increased cation flux, complete with ouabain for its binding site, and inhibit the isolated, purified (Na+,K(+)-ATPase). The results obtained indicate that departures from the PTX structure at one end or at both ends simultaneously substantially decrease the ability of the compounds to increase the cationic permeability of red blood cells and to inhibit the (Na+,K(+)-ATPase). These actions were found to be completely reversed by ouabain, but the analogues are two to three orders of magnitude less potent than PTX in competing with ouabain for its binding site. These results suggest that both ends of the palytoxin molecule participate in the interactions of the toxin with its receptor and that modifications in these regions of the molecule produce significant alterations in its binding and subsequent action on red cell membranes.

Acrylamides↗
PubMed2006

Comparative analysis of purified Pacific and Caribbean ciguatoxin congeners and related marine toxins using a modified ELISA technique.

The monoclonal antibody to ciguatoxin (CTX) produced from a hybridoma cell line was assayed for the detection of four congeners of CTX: Pacific ciguatoxin-1 (P-CTX-1), Pacific ciguatoxin-2 (P-CTX-2), Pacific ciguatoxin-3 (P-CTX-3), and Caribbean ciguatoxin-1 (C-CTX-1) and related marine toxins, including domoic acid, palytoxin, and okadaic acid, using a modified enzyme-linked immunosorbent assay (ELISA). Lower detection limits were assessed and linearity was statistically established (P<0.05) for P-CTX-1, P-CTX-2, and P-CTX-3 and C-CTX-1 at concentrations ranging from 0 to 5.00 ng, while the other marine toxins showed statistically insignificant cross-reactivities at similar concentrations. Thus, the monoclonal antibody to CTX is able to specifically detect various CTX congeners at levels comparable to those naturally occurring in ciguatoxic fish.

Acrylamides↗
PubMed1983

A method for the isolation of the caribbean palytoxin (C-PTX) from the coelenterate (zooanthid) Palythoa caribaeorum.

Chromatographically pure toxin was isolated from the zooanthid Palythoa caribaeorum. Toxin isolation was achieved by extraction with 50% ethanol from the homogenized specimens, gel filtration on Sephadex G-50 and ion exchange chromatography on QAE- and SP-Sephadex. Final purification was obtained by gel filtration on Biogel P-6. The LD50 tested on the shore crab Carcinus maenas was 62.5 ng/kg.

Acrylamides↗
PubMed1999

Identification of putative palytoxin as the cause of clupeotoxism.

In 1994 in Madagascar a woman died after eating a sardine, Herklotsichthys quadrimaculatus. Two heads removed, respectively, from a toxic and a nontoxic fish before cooking were retrieved, kept frozen, and used for toxin analysis. The causative toxin was identified as palytoxin or its analogs based on its cytotoxicity, delayed hemolysis, neutralization with an anti-palytoxin antibody, chromatographic properties on different columns, and MS data. The gill and esophagus of the fish contained large amount of bottom sediments indicating that the fish had fed on the bottom and thus probably obtained the toxin from a benthic organism. The benthic dinoflagellate Ostreopsis siamensis that produces palytoxin and its analogs was inferred as the probable toxin source. This is the first study to shed light on clupeotoxism, a highly fatal form of human intoxication due to ingestion of clupeoid fish.

Acrylamides↗
PubMed1996

Inhibition of sodium-dependent uptake processes in purified rat brain synaptosomes by Lophozozymus pictor toxin and palytoxin.

To get an insight into the mechanism of neurotoxicity exhibited by Lophozozymus pictor toxin (LPTX) and the toxin isolated from P.caribaeorum (C-PTX) studies were carried out on the effect of these toxins on the uptake of selected substrates (neurotransmitters, amino acids and glucose) in isolated nerve endings. The toxins were found to inhibit the uptake of gamma-aminobutyric acid (GABA), noradrenaline, choline, L-leucine and 2-deoxy-D-glucose in rat brain synaptosomes. LPTX- or C-PTX-induced inhibition of synaptosomal uptake was reduced in the absence of Na+ in the assay medium. Synaptosomes exposed to LPTX and C-PTX release K+ in a dose-dependent manner. Ouabain, a selective inhibitor of the plasma membrane Na+, K(+)-ATPase could inhibit LPTX- and C-PTX-induced K+ efflux from synaptosomes and alleviate the toxin-induced inhibition of synaptosomal GABA uptake. It appears that the induction of ionic flux is the primary cause of toxicity by these toxins leading to the inhibition of Na(+)-dependent uptake processes in synaptosomes. The antagonistic action of ouabain suggests the involvement of the membrane sodium pump in the development of cytotoxicity.

Acrylamides↗
PubMed1992

Sea anemone Radianthus macrodactylus--a new source of palytoxin.

A very potent non-protein toxin was isolated from the sea anemone Radianthus macrodactylus with the use of chromatography on polytetrafluoroethylene, CM-Sephadex C-25 and by cation and anion exchange HPLC. The toxin was identified as palytoxin by u.v.-, i.r.- and 500 MHz 1H NMR spectroscopy. Its LD50 was 0.74 +/- 0.29 micrograms/kg by i.v. injection into mice. So far, palytoxin has been associated with zoanthids only. The toxin caused the loss of haemoglobin from erythrocytes but only in about 2 hr after the beginning of incubation, which is characteristic for palytoxin from zoanthids. Sea anemone palytoxin was divided into major and minor components by HPLC. The latter proved to be a product of degradation of palytoxin.

Acrylamides↗