Neosaxitoxin

Last updated
Neosaxitoxin
Neosaxitoxin.svg
NSTX-3D-balls-by-AHRLS-2012.png
Names
IUPAC name
[(3aS,4R,10aS)-5,10,10-Trihydroxy-2,6-diiminooctahydro-1H,8H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate [1] [2]
Other names
1H,10H-Pyrrolo(1,2-c)purine-10,10-diol, 2-amino-4-(((aminocarbonyl)oxy)methyl)-3a,4,5,6,8,9-hexahydro-5-hydroxy-6-imino-, (3aS,4R,10aS)-; 1H,10H-Pyrrolo(1,2-c)purine-10,10-diol, 2-amino-4-((aminocarbonyl)oxy)methyl-3a,4,5,6,8,9-hexahydro-5-hydroxy-6-imino-,(3aS,4R,10aS)-; 1H,10H-Pyrrolo(1,2-c)purine-10,10-diol, 2-amino-4-((aminocarbonyl)oxy)methyl-3a,4,5,6,8,9-hexahydro-5-hydroxy-6-imino-,(3aS-(3aalpha,4alpha,10aR*))-
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.237.662 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C10H17N7O5/c11-6-14-5-4(3-22-8(13)18)17(21)7(12)16-2-1-9(19,20)10(5,16)15-6/h4-5,12,19-21H,1-3H2,(H2,13,18)(H3,11,14,15)/t4-,5-,10-/m0/s1
    Key: PPEKGEBBBBNZKS-HGRQIUPRSA-N
  • InChI=1/C10H17N7O5/c11-6-14-5-4(3-22-8(13)18)17(21)7(12)16-2-1-9(19,20)10(5,16)15-6/h4-5,12,19-21H,1-3H2,(H2,13,18)(H3,11,14,15)/t4-,5-,10-/m0/s1
    Key: PPEKGEBBBBNZKS-HGRQIUPRBS
  • C1CN2C(=N)N([C@H]([C@H]3[C@]2(C1(O)O)NC(=N)N3)COC(=O)N)O
Properties
C10H17N7O5
Molar mass 315.286
Hazards
GHS labelling:
GHS-pictogram-skull.svg
Danger
H300
P264, P270, P301+P310, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives. [3]

Contents

Sources

NSTX, and other PSTs, are produced by several species of marine dinoflagellates (eukaryotes) and freshwater cyanobacteria, blue-green algae (prokaryotes), which can form extensive blooms around the world. [4] Under special conditions, during harmful algal blooms (HAB) or red tide, all these toxins may build up in filter-feeding shellfish, such as mussels, clams and oysters, and can produce an outbreak of Paralytic Shellfish Poisoning (PSP). [5]

Saxitoxin analogues associated to PSP can be divided into three categories: [6]

Structure and properties

NSTX is quite similar to saxitoxin, like all the neurotoxins associated to PSP, the only difference is that NSTX shows one hydroxyl group bonded to nitrogen "1", where saxitoxyn contains one hydrogen. [7]

This purine is highly hydrophilic [8] and thermostable, it is not destroyed by cooking. [9] Moreover, is very stable in usual storage, specially in acidic condition. [10]

Mechanism of action

NSTX blocks the extracellular portion, [11] the outer vestibule, [12] of some voltage gated sodium channels in a very powerful and reversible manner, without affection of other ion channels.

"Voltage-gated", also called "voltage-sensitive" and "voltage-dependent" sodium channel also known as "VGSCs" or "Nav channel" are crucial elements of normal physiology in a variety of animals, including flies, leeches, squid and jellyfish, as well as mammalian and non-mammalian vertebrates. This large integral membrane protein plays an essential role in the initiation and propagation of action potentials in neurons, myocytes and other excitable cells. [13]

Nav channels form the basis for electrical excitability in animals. Nav channels evolved from Ca2+ channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na+ and Ca2+. Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. [14]

Sodium-channel proteins in the mammalian brain are composed of an association that include one alpha subunit and one or more auxiliary beta subunits. Nine types of alpha subunits have been described (Nav1.1 to Nav1.9), and a tenth related isoform (Nax) may also play some role as a Nav channel. Based in this information, ten Nav classes can be described: Nav1.1 to Nav1.9, and Nax. [15]

Former five, [16] but more recently, six [17] neurotoxin receptor sites have been recognized between the seven receptor site [18] located in the vertebrate sodium channel receptor alpha subunit:

NSTX and other site 1 blockers have high affinity (very low dissociation constant) and high specificity for Nav channels. The action of NSTX produces minimal effect on cardiac Nav, where it exhibits about 20–60 fold lesser affinity than in Nav channels from rat skeletal muscle and rat brain. [19] Most data emphasize the role of "STX resistant" Nav channel 1.5 in human heart. [20] [21]

Toxins such as neosaxitoxin and tetrodotoxin have less affinity for most cardiac Nav channels than for most Nav channels in nerve tissue. Moreover, NSTX is so active on nerve Nav channel than is roughly a million-fold more potent than lidocaine. [22]

Effects on humans

This mechanism of action can produce two well known kinds of effects in humans:

Toxic effect, associated to plasmatic levels of NSTX

It can be approximately described using one of the classical model of neurotoxic disease, known from ancient times as red tide, the most harmful algal bloom (HAB). This well known clinical model is the "paralytic shellfish poisoning". [23]

Of course, there are great differences between different algal blooms, [24] [25] [26] [27] because of the mix of species included in each HAB, usually related to environmental conditions; [28] because of the levels and quality of PSTs produced in each HAB, that may be modulated by concurrent microorganism; [29] [30] [31] [32] and, last but not least, because of the specific properties of each kind of PST, for example:

In spite of its heterogeneous and poorly understood epidemiology, the clinical picture of PSP could be useful to anticipate clinical effects of systemic NSTX.

Usually, the victims of mild and severe acute intoxications eliminate the toxin in urine during the first 24 hours after ingestion, and improve to full recovery in the first day of intrahospital care (when vital support is provided in a timely manner). [40]

When outbreaks of PSP occur in remote locations, where medical assistance is limited, reported lethality is under 10% in adults, but can reach 50% in children younger than six years old. This difference could be secondary to dissimilar doses and composition of involved mixes of PSTs; delay in medical support; or some kind of susceptibility of children. [41] More recent information suggest that lethality could be around 1% of symptomatic patients, [42] including cases where air transportation was required from remote locations of Alaska. [43]

Electrophysiologic observations demonstrated sub clinical abnormalities lasting for some days [44] or weeks [45] after clinical recovery .

Some evidence suggest the presence of metabolic pathways for the sequential oxidation and glucuronidation of PST in vitro, both being the initial detoxication reactions for the excretion of these toxins in humans. [46]

Forensic analysis of fatalities after severe cases, conclude that PSP toxins are metabolically transformed by humans and that they are removed from the body by excretion in the urine and feces like any other xenobiotic compound. [47]

Considering the heterogeneous nature of toxins mixes contained in contaminated bivalve molluscs, the safe limit of toxin content in shellfish adequate for human ingestion is expressed in "saxitoxin equivalents". According to the Food and Agriculture Organization of the United Nations (FAO) and European Parliament, this limit is 80 microgram of saxitoxin equivalent per 100 gram of mussel meat (each mussel weights around 23 g). [48] [49] The U.S. Food and Drug Administration extends the same definition to "fish" quality, but the term "fish" refers to fresh or saltwater fin fish, crustaceans, other forms of aquatic animal life other than birds or mammals, and all mollusks; and incorporate the use of "ppm" as another measure for saxitoxin equivalent concentration in mentioned foods. [50]

Paradoxically, the chronic and/or repeated exposure to marine seafood toxins, which is a much more realistic phenomenon, has not been fully examined. [51] [52] One study in rats exposed to chronic (12 weeks) NSTX administration demonstrated some reduction in water and food intake, and a mild degree of transient cholestasis, probably associated to fasting, without other abnormalities. [53]

Anesthetic effect, produced by local infiltration of NSTX

This action has been demonstrated in animals [54] and humans. [55] [56] [57] [58] [59]

The medical use of the NSTX anesthetic effect is supported by three reasons:

  1. NSTX anesthetic duration:
    • Any current available local anesthetic hardly produces clinical effects 12 hours after a single injection. [60] Then, in cases of severe or prolonged pain, some patients need repeated injections, catheters, pumps and opioids [61] [62] to feel comfortable, with different kinds of side effects, costs and risks. [63]
    • On the other hand, NSTX local infiltration produces long lasting anesthesia, well over all the current available local anesthetics. Some investigations demonstrated anesthetic effect lasting over one week after single injection in rodents, using extended release formulation, without histologic or functional sequelae. [64]
    • Additionally, two human reports demonstrated strong potentiation between NSTX anesthetic effect, bupivacaine and epinephrine. [65] [66]
  2. NSTX local safety:
    • All available local anesthetic are associated with local damage in different models. [67] [68] [69] [70] [71] This undesired effect could be enhanced by sustained release formulations. [72]
    • On the contrary, several investigations show local safety of saxitoxin-related neurotoxins, including very sensitive models, and there is no reason to presume otherwise for NSTX. [73] [74] [75] [76]
  3. NSTX systemic safety:
    • In spite of advances of ultrasound guided injections, acute systemic local anesthetic toxicity is still an unsolved clinical problem, and can produce devastating consequences, related to the neurologic and cardiovascular effects of all available local anesthetics. [77] [78]
    • Otherwise, clinical experience and animal models shows the relative safety of accidental and experimental NSTX intoxication (when appropriate support therapy is provided in a timely manner). [79]
    • Recent investigation in sheep shows a safe limit, due to motor block, over 1 μg/kg for intravenous injection of NSTX, with full recovery after a brief course of mechanical ventilation. [80]
    • Regarding systemic safety, saxitoxins diffuse through the blood–brain barrier, [81] but, because of Nav channel specificity, acute toxicity is associated to a very low risk of seizures. This establishes an important difference with current local anesthetic toxicity. [82]
    • As could be predicted from its ion channel selectivity, [83] NSTX intoxication clinical picture is almost devoid of arrhythmias, establishing another difference with available local anesthetic's numerous cardiac effects. [84]
    • And last but not least, some degree of improving in therapeutic index of NSTX can be observed when is mixed with bupivacaine and/or epinephrine. [85]

In conclusion, NSTX is a well defined molecule with a long-lasting and sometimes dangerous relationship with human subjects. Recent investigations suggest a clinical application as a new local anesthetic that sounds "too good to be true", but more investigation is required. [86]

See also

Related Research Articles

<span class="mw-page-title-main">Local anesthetic</span> Medications to reversibly block pain

A local anesthetic (LA) is a medication that causes absence of all sensation in a specific body part without loss of consciousness, providing local anesthesia, as opposed to a general anesthetic, which eliminates all sensation in the entire body and causes unconsciousness. Local anesthetics are most commonly used to eliminate pain during or after surgery. When it is used on specific nerve pathways, paralysis also can be induced.

<span class="mw-page-title-main">Tetrodotoxin</span> Neurotoxin

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals. It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in symbiotic relationships with animals and plants.

<span class="mw-page-title-main">Batrachotoxin</span> Chemical compound

Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. In certain frogs, this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.

<span class="mw-page-title-main">Saxitoxin</span> Paralytic shellfish toxin

Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin. Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP).

<span class="mw-page-title-main">Bupivacaine</span> Local anaesthetic drug

Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease sensation in a specific small area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space. It is available mixed with a small amount of epinephrine to increase the duration of its action. It typically begins working within 15 minutes and lasts for 2 to 8 hours.

<span class="mw-page-title-main">Paralytic shellfish poisoning</span> Syndrome of shellfish poisoning

Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks. These shellfish are filter feeders and accumulate neurotoxins, chiefly saxitoxin, produced by microscopic algae, such as dinoflagellates, diatoms, and cyanobacteria. Dinoflagellates of the genus Alexandrium are the most numerous and widespread saxitoxin producers and are responsible for PSP blooms in subarctic, temperate, and tropical locations. The majority of toxic blooms have been caused by the morphospecies Alexandrium catenella, Alexandrium tamarense, Gonyaulax catenella and Alexandrium fundyense, which together comprise the A. tamarense species complex. In Asia, PSP is mostly associated with the occurrence of the species Pyrodinium bahamense.

<span class="mw-page-title-main">Sodium voltage-gated channel alpha subunit 9</span> Protein-coding gene in the species Homo sapiens

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<i>Anabaena circinalis</i> Species of bacterium

Anabaena circinalis is a species of Gram-negative, photosynthetic cyanobacteria common to freshwater environments throughout the world. Much of the scientific interest in A. circinalis owes to its production of several potentially harmful cyanotoxins, ranging in potency from irritating to lethal. Under favorable conditions for growth, A. circinalis forms large algae-like blooms, potentially harming the flora and fauna of an area.

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

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CgNa is a peptide toxin isolated from the sea anemone Condylactis gigantea. It causes an increased action potential duration by slowing down the inactivation of tetrodotoxin-sensitive sodium channels.

<span class="mw-page-title-main">Cll1</span> Scorpion protein

Toxin Cll1 is a toxin from the venom of the Mexican scorpion Centruroides limpidus limpidus, which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability.

<span class="mw-page-title-main">Antillatoxin</span> Chemical compound

Antillatoxin (ATX) is a potent lipopeptide neurotoxin produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channels, which can cause cell depolarisation, NMDA-receptor overactivity, excess calcium influx and neuronal necrosis.

<span class="mw-page-title-main">Gonyautoxin</span> Chemical compound

Gonyautoxins (GTX) are a few similar toxic molecules that are naturally produced by algae. They are part of the group of saxitoxins, a large group of neurotoxins along with a molecule that is also referred to as saxitoxin (STX), neosaxitoxin (NSTX) and decarbamoylsaxitoxin (dcSTX). Currently eight molecules are assigned to the group of gonyautoxins, known as gonyautoxin 1 (GTX-1) to gonyautoxin 8 (GTX-8). Ingestion of gonyautoxins through consumption of mollusks contaminated by toxic algae can cause a human illness called paralytic shellfish poisoning (PSP).

LmαTX3 is an α-scorpion toxin from Lychas mucronatus. that inhibits fast inactivation of voltage gated sodium-channels (VGSCs).

<span class="mw-page-title-main">Decarbamoylsaxitoxin</span> Chemical compound

Decarbamoylsaxitoxin, abbreviated as dcSTX, is a neurotoxin which is naturally produced in dinoflagellate. DcSTX is one of the many analogues of saxitoxin (STX).

Beta-toxin Cll2, shortened to Cll2, is a toxin in the venom of the Mexican Scorpion species Centruroides limpidus limpidus. The toxin belongs to the β-class family of sodium channel-inhibiting scorpion toxins. It affects voltage-dependent activation, conductance and resurgent currents of voltage gated sodium channels by binding to site 4.

<span class="mw-page-title-main">GiTx1</span>

GiTx1 (β/κ-theraphotoxin-Gi1a) is a peptide toxin present in the venom of Grammostola iheringi. It reduces both inward and outward currents by blocking voltage-gated sodium and potassium channels, respectively.

References

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