Neurotoxin alkaloids

Freshwater cyanobacteria blooms implicated in human and livestock intoxications have been extensively studied. And they have become a serious health problem in recent years. Blooms of marine cyanobacteria are also becoming an increasingly familiar occurrence within the tropical and subtropical regions of the world. Several systematic surveys within Europe and the USA have concluded that the two most commonly isolated groups of cyanotoxins are the alkaloids-neurotoxins and the cyclic peptide hepato-toxins, both of which are destructive to liver cells. Several genera... 

Veratridine. An alkaloid neurotoxin purified from veratrine. [McKinney et al. AB 153 33 1986]. 

Osswald, J., Rellan, S., Gago, A., Vasconcelos, V. (2007). Toxicology and detection methods of the alkaloid neurotoxin produced by cyanobacteria, anatoxin-a. Environ. Int. 33 1070-89. 

Synonyms Fhyllobates toxin Pitohui toxin Ifrita toxin poison dart frog toxin Chemical/Pharmaceutical/Other Class Steroidal alkaloid neurotoxin Chemical Formulas o Batrachotoxin C31H42N2O6 o Homobatrachotoxin C32H44N2O6 o Batrachotoxinin-A C24H35NO5... 

Veratridine (3-veratroylveracevine) [71-62-5] M 673.8, m 180 (after drying at 130°, pK 9.54 (quinolizidine N), [a] g +8.0 (c 5, EtOH). It is an alkaloid neurotoxin which prevents inactivation of Na" channels. Its solubility in EtOH is 5% and it separates as a pale yellow powder from an ethanolic solution on addition of Et20. It forms nitrate, sulfate and perchlorate salts. [McKinney et al. Anal Biochem 153 33 1986, Beilstein 21 V/13 709.]... 

A study of the interaction of selected neurotoxicants with ion channels in the synaptosomal membrane as measured by a superfusion technique is described. The alkaloid neurotoxin veratridine (10 tI) stimulated release of radiolabel from [ H]-choline loaded synaptosomes in superfusion. Hemicholinium-3 (10 tI) was inactive. Veratridine-induced release, although unaffected by picrotoxinin was strongly... 

Shichor I, Fainzilber M, Pelhate M, Malecot CO Zlotkin E, Gordon D (1996) Interactions of 5-conotoxins with alkaloid neurotoxins reveal differences between the silent and effective binding sites on voltage-sensitive sodium channels. J Neurochem 67 2451-2460... 

Rotifers are part of freshwater zooplankton. Their metabolism is unresearched. It is unknown if they produce alkaloids. However, some planktonic rotifers are known to digest toxic cyanobacterium, producing the alkaloid neurotoxin, anatoxin which inhibits their development. ... 

Cyanobacterial neurotoxins primarily target cholinergic synapses or voltagegated ion channels. For example, anatoxin-a and homoanatoxin-a are nicotinic acetylcholine receptor agonists [1-3], while anatoxin-a(s) irreversibly inhibits acetylcholinesterase activity [4, 5]. The saxitoxins, on the other hand, exert their toxicity via the inhibition of voltage-gated sodium, calcium, and potassium channels [6-8]. Despite their different modes of action, when ingested in acute doses, the alkaloid neurotoxins impart similar symptoms of paralysis and respiratory failure. 

The cyanotoxins display remarkable structural diversity, however, most can be classified as cyclic peptides, depsipeptides, lipopeptides, or alkaloids [15-17]. Among the alkaloid neurotoxins, which are the focus of this chapter, anatoxin-a and homoanatoxin-a can be described as low molecular weight secondary bicyclic... 

This chapter provides an overview of the current status of cyanobacterial alkaloid neurotoxin research, with specific focus on the chemistry, toxicology, and biosynthesis of these potent compounds. 

Strychnine is a complex lipophilic alkaloid from the plant Strychnos mx-vomica, which acts as a neurotoxin. It has been used to control vertebrate pests, including moles. The acute oral LDjq to the rat is 2 mg/kg. 

Cyanobacterial neurotoxins are small ringed alkaloids and have dramatic effects on various components of vertebrate neurons. They are all water soluble and are synthesized by several cyanobacterial genera (Table 5.1). The most commonly isolated neurotoxins are the paralytic shellfish toxins, although several other potent neurotoxic alkaloids are synthesized by freshwater cyanobacteria (Table 5.1). 

Piperidine alkaloids such as coniine and (—)-coniceine are very poisonous. They occur in hemlock (Conium maculatum L.), known as a very toxic plant. One of the characteristics of these piperidine alkaloids is smell. Moreover, they are neurotoxins which have acute effects such as chronic toxicity. 

Coniine Coniine or (5 )-2-propylpiperidine, molecular formula CgHnN, is a poisonous alkaloid found in the hemlock poison and the yellow pitcher plant (Sarracenia flava). Coniine contributes to the foul smell of hemlock. It is a neurotoxin, causes respiratory paralysis and is toxic to all classes of livestock and humans. In 399 BC, Socrates was put to death hy this poison. 

Aconite alkaloids Aconitine, molecular formula C34H47NO11, is an example of an aconite alkaloid. It is soluble in organic solvents, e.g. CHCI3 and CeHg, and sfightly soluble in alcohol or ether, but insoluble in water. Aconitine is an extremely toxic substance obtained from the plants of the genus Aconitum (family Ranunculaceae), commonly known as aconite or monkshood . It is a neurotoxin, and used for creating models of cardiac arrhythmia. 

Bacteria, protozoa, and venomous animals synthesize numerous toxins that are used to kill their prey or to defend themselves. Sea anemones, jellyfish, cone snails, insects, spiders, scorpions, and snakes all make potent and highly specific neurotoxins. Plants form a host of alkaloids and other specialized products, some of which are specifically neurotoxic and able to deter predators. More than 500 species of marine cone snails of the genus Conus synthesize a vast array of polypeptide toxins (conotoxins), 487-489 some with unusual posttranslational modifications.490 491 The slow-moving snails are voracious predators that use their toxins, which they inject with a disposible harpoonlike tooth,492 to paralyze fish, molluscs, or worms.493... 

Aconites, commonly called wolfsbane or monkshood, are species of Aconitum (Ranunculaceae), valued ornamental herbaceous plants, grown for their showy blue or purple flowers, which are shaped like a monk s cowl. Their alkaloid content, mainly in the roots, makes them some of the most toxic plants commonly encountered. The dried roots of Aconitum napellus were once used, mainly externally for relief of pain, e.g. in rheumatism. The toxic alkaloids (0.3-1.5%) are complex diterpene-derived esters. Aconitine (Figure 6.124) is the principal component (about 30%) and is a diester of aconine with acetic and benzoic acids. Hydrolysis products benzoylaconine and aconine are also present in dried plant material. These alkaloids appear to behave as neurotoxins by acting on sodium channels. All species of Aconitum and Delphinium are potentially toxic to man and animals and must be treated with caution. 

Psilocybin can be isolated and crystallized or synthesized to nearly 100% purity. Research indicates that Psilocybe mushrooms produce a bitter alkaloid as an insecticide to protect itself from predators. In humans, psilocybin is a neurotoxin that can cause hallucinations. 

Psilocybin powder is the most potent form of this hallucinogenic alkaloid. It was isolated in 1958 and can be synthesized to nearly 100% purity. The human body is very sensitive to this neurotoxin and just 0.01 g of psilocybin powder contains the equivalent psilocybin found in 30 fresh Psilocybe mushrooms. 

A plant neurotoxin that is receiving much current publicity because of its effectiveness in the chemotherapeutic treatment of at least one form of cancer is taxol, a complex molecule that belongs to the class of taxine alkaloids. Taxol occurs in most tissues of Taxus breviofolia, the western yew tree, and is isolated from the bark of that tree (once considered a nuisance tree in forestry, but in short supply following discovery of the therapeutic value of taxol until alternate sources were developed). Ingestion of taxol causes a number of neurotoxic effects, including sensory neuropathy, nausea and gastrointestinal disturbances, and impaired respiration and cardiac function. It also causes blood disorders (leukopenia and thrombocytopenia). The mechanism of taxol neurotoxicity involves binding to tubulin, a protein involved in the assembly of microtubules, which assemble... 

In 1976 Scott et al. (186) isolated the neurotoxin roquefortine (144) from the fungus Penicillium roqueforti. Structure 144 was deduced on the basis of spectroscopic data and degradative products. The alkaloid appeared to be the same as roquefortine C, isolated by Ohmomo et al. in 1975 (187). The latter authors confirmed the structure by spectroscopic evidence (188) they also isolated roquefortine D. Reduction of roquefortine D with zinc in acetic acid yielded two dihydro derivatives. The properties of roquefortine C and of one of the isomers correlated very well. Thus, roquefortine D is dihydro-roquefortine C (189). The stereochemistry still remains to be solved. 

Many alkaloids fall into the class of spedflc modulators and have been modified during evolution in such a way that they mimic endogenous ligands, hormones, or substrates [1,3,18,19]. We have termed this selection process evolutionary molecular modeling [12,13,19,23]. Many alkaloids are strong neurotoxins that were selected for defense against animals [2,3,19]. Table 1.1 summarizes the potential neuronal targets that can be affected by alkaloids. Extensive reviews on this topic have been published [2,3,19]. 

Many alkaloids are infamous for their strong toxicity towards animals and humans. Most of the deadly alkaloids fall into the class of neurotoxins (see above). The others have cytotoxic properties (Table 1.2). A cytotoxic effect can be generated when cell membranes are made leaky (as by saponins or steroidal alkaloids), or when elements of the cytoskeleton are inhibited. The spindle poisons vinblastine, vincristine, colchicine, and taxol are particularly famous. Actin filament formation is blocked by fungal poisons such as phalloidin from Amanita phalloides. 

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