Snake venom

Source: Wikipedia, the free encyclopedia.

Vipera berus
- Venom delivery apparatus

Snake venom is a highly toxic

prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.[2]

The glands that secrete zootoxins are a modification of the

vertebrates and are usually located on each side of the head, below and behind the eye, and enclosed in a muscular sheath. The venom is stored in large glands called alveoli before being conveyed by a duct to the base of channeled or tubular fangs through which it's ejected.[3][4]

Venom contains more than 20 different compounds, which are mostly proteins and

polypeptides.[3][5] The complex mixture of proteins, enzymes, and various other substances has toxic and lethal properties.[2] Venom serves to immobilize prey.[6] Enzymes in venom play an important role in the digestion of prey,[4] and various other substances are responsible for important but non-lethal biological effects.[2] Some of the proteins in snake venom have very specific effects on various biological functions, including blood coagulation, blood pressure regulation, and transmission of nerve or muscle impulses. These venoms have been studied and developed for use as pharmacological or diagnostic tools, and even drugs.[2][5]

Chemistry

red blood cells.[8] Amino acid oxidases and proteases are used for digestion. Amino acid oxidase also triggers some other enzymes and is responsible for the yellow colour of the venom of some species. Hyaluronidase increases tissue permeability to accelerate the absorption of other enzymes into tissues. Some snake venoms carry fasciculins, like the mambas (Dendroaspis), which inhibit cholinesterase to make the prey lose muscle control.[9]

Main enzymes of snake venom[2][5][10]
Type Name Origin
Oxidoreductases lactate dehydrogenase Elapidae
L-amino-acid oxidase All species
Catalase All species
Transferases
Alanine amino transferase
Hydrolases Phospholipase A2 All species
Lysophospholipase Elapidae, Viperidae
Acetylcholinesterase Elapidae
Alkaline phosphatase Bothrops atrox
Acid phosphatase
Deinagkistrodon acutus
5'-nucleotidase All species
Phosphodiesterase All species
Deoxyribonuclease All species
Ribonuclease 1 All species
Adenosine triphosphatase All species
Amylase All species
Hyaluronidase All species
NAD-Nucleotidase All species
Kininogenase Viperidae
Factor X activator Viperidae, Crotalinae
Heparinase Crotalinae
α-Fibrinogenase Viperidae, Crotalinae
β-Fibrinogenase Viperidae, Crotalinae
α-β-Fibrinogenase
Bitis gabonica
Fibrinolytic enzyme Crotalinae
Prothrombin activator Crotalinae
Collagenase Viperidae
Elastase Viperidae
Lyases Glucosaminate ammonia-lyase

Snake toxins vary greatly in their functions. The two broad classes of toxins found in snake venoms are

cytotoxins, while that of the Mojave rattlesnake
(Crotalus scutulatus), a viperid, is primarily neurotoxic. Both elapids and viperids may carry numerous other types of toxins.

α-neurotoxins
α-Bungarotoxin, α-toxin, erabutoxin, cobratoxin
β-neurotoxins (PLA2)
β-Bungarotoxin, Notexin, ammodytoxin, crotoxin, taipoxin
κ-neurotoxins
Kappa-bungarotoxin
Dendrotoxins (Kunitz)
β-Bungarotoxin
chain B
Cardiotoxins Naja nigricollis y-toxin, cardiotoxin III (aka cytotoxins)
Myotoxins Myotoxin-a, crotamine
Sarafotoxins Sarafotoxins a, b, and c
Hemorrhagins (metalloprotease) Mucrolysin, Atrolysins, Acutolysins, etc.[11]
Hemotoxins (serine protease) Venombin A

Toxins

Neurotoxins

Structure of a typical chemical synapse

The beginning of a new neural impulse goes as follows:

  1. An exchange of ions (charged atoms) across the nerve cell membrane sends a depolarizing current towards the end of the nerve cell (cell terminus).
  2. When the depolarizing current arrives at the nerve cell terminus, the neurotransmitter acetylcholine (ACh), which is held in vesicles, is released into the space between the two nerves (synapse). It moves across the synapse to the postsynaptic receptors.
  3. ACh binds to the receptors and transfers the signal to the target cell, and after a short time, it's destroyed by acetylcholinesterase.

Fasciculins

These toxins attack
mice, they cause severe, generalized and long-lasting (5-7 h) fasciculations
(rapid muscle contractions).
Snake example: found mostly in the venom of mambas (Dendroaspis spp.) and some rattlesnakes (Crotalus spp.)

Dendrotoxins

Dendrotoxins inhibit neurotransmissions by blocking the exchange of positive and negative ions across the neuronal membrane lead to no nerve impulse, thereby paralyzing the nerves.
Snake example: mambas

α-neurotoxins

Alpha-neurotoxins are a large group; over 100 postsynaptic neurotoxins having been identified and sequenced.[12] α-neurotoxins attack the Nicotinic acetylcholine receptors
of cholinergic neurons. They mimic the shape of the acetylcholine molecule, and so fit into the receptors, where they block the ACh flow, leading to a feeling of numbness and paralysis.
Snake examples:
cobras (Naja spp.) (known as cobratoxin
)

Cytotoxins

Fully functional membrane
Destroyed membrane

Phospholipases

Phospholipase is an enzyme that transforms the phospholipid molecule into a lysophospholipid (soap) → the new molecule attracts and binds fat and ruptures cell membranes. Phospholipase A2 is one specific type of phospholipases found in snake venom.
Snake example:
Okinawan habu
(Trimeresurus flavoviridis)

Cardiotoxins / Cytotoxins

Cardiotoxins are components that are specifically toxic to the heart. They bind to particular sites on the surface of muscle cells and cause depolarisation → the toxin prevents muscle contraction. These toxins may cause the heart to beat irregularly or stop beating, causing death. An example is the three-fingered cardiotoxin III from Chinese cobra, an example of the short three-fingered family (InterPro: IPR003572
).
Snake example: mambas, and some Naja species

Hemotoxins

Hemotoxins cause hemolysis, the destruction of red blood cells (erythrocytes), or induce blood coagulation (clotting, e.g. mucrocetin). A common family of hemotoxins includes snake venom metalloproteinases such as mucrolysin.[11][14]
Snake examples: most vipers and many cobra species: The tropical rattlesnake Crotalus durissus produces convulxin, a coagulant.[15]

Myotoxins

tertiary structure of crotamine (PDB: 1H5O
​)

diaphragmatic
paralysis.

The first myotoxin to be identified and isolated was

molecular structure and gene
responsible for its synthesis were all elucidated in the last two decades.

Determining venom toxicity (LD50)

Snake venom toxicity is assessed by a toxicological test called the

ecological variables, genetic variation (either adaptive or incidental), and other molecular and ecological evolutionary factors.[citation needed
] This is true even for members of one species. Such variation is smaller in captive populations in laboratory settings, though it cannot be eliminated. However, studies to determine snake venom potency must be designed to minimize variability.

Several techniques have been designed to this end. One approach is to use 0.1% bovine serum albumin (also known as "fraction V" in

disulfide bonds; it's unique in that it has the highest solubility and lowest isoelectric point of major plasma proteins. This makes it the final fraction to be precipitated from its solution. Bovine serum albumin is located in fraction V. The precipitation of albumin is done by reducing the pH to 4.8, near the pH of the proteins, and maintaining the ethanol concentration at 40%, with a protein concentration of 1%. Thus, only 1% of the original plasma remains in the fifth fraction.[20]

When the ultimate goal of plasma processing is a purified plasma component for

ion exchange chromatography steps. After ion exchange, generally purification steps and buffer exchange occur.[21]

However, chromatographic methods began to be adopted in the 1980s.[

anion exchange chromatography
, cation exchange chromatography, and gel filtration chromatography. The recovered purified material is formulated with combinations of sodium octanoate and sodium N-acetyl tryptophanate and then subjected to viral inactivation procedures, including pasteurization at 60 °C. This is a more efficient alternative than the Cohn process because:

Compared with the Cohn process, albumin purity increased from about 95% to 98% using chromatography, and the yield increased from about 65% to 85%. Small percentage increases make a difference in regard to sensitive measurements such as purity. The big drawback has to do with the economics. Although the method offered efficient, acquiring the necessary equipment was difficult. Large machinery is necessary, and for a long time, the lack of equipment availability limited its widespread use.[citation needed]

Evolution

Main article: Evolution of snake venom

Venom evolved just once among all

Iguania.[24] Several snake lineages have since lost the ability to produce venom, often due to a change in diet or a change in predatory tactics.[23] In addition to this, venom strength and composition has changed due to changes in the prey of certain snake species. For example, the venom of the marbled sea snake (Aipysurus eydouxii) became significantly less toxic after the diet of this species changed from fish to strictly fish eggs.[23] The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.[23][25]

The mechanism of evolution in most cases has been gene duplication in tissues unrelated to the venom.[24] Pre-existing salivary proteins are the likely ancestors of most venom toxin genes.[26] Expression of the new protein in the venom gland followed duplication.[24] Then proceeded natural selection for adaptive traits following the birth-and-death model, where duplication is followed by functional diversification, resulting in the creation of structurally related proteins that have slightly different functions.[23][24][27] The study of venom evolution has been a high priority for scientists in terms of scientific research, due to the medical relevance of snake venom, in terms of making antivenom and cancer research. Knowing more about the composition of venom and the ways it can potentially evolve is very beneficial. Three main factors that affect venom evolution have been closely studied: predators of the snake that are resistant to snake venom, prey that are in an evolutionary arms race with snakes, and the specific diets that affect the intraspecific evolution of venom.[23][28] Venoms continue to evolve as specific toxins and are modified to target a specific prey, and toxins are found to vary according to diet in some species.[29][30]

Rapid venom evolution can also be explained by the arms race between venom-targeted molecules in resistant predators, such as the opossum, and the snake venom that targets the molecules. Scientists performed experiments on the opossums and found that multiple trials showed replacement to silent substitutions in the von Willebrand factor (vWf) gene that encodes for a venom-targeted hemostatic blood protein. These substitutions are thought to weaken the connection between vWf and a toxic snake venom ligand (botrocetin), which changes the net charge and hydrophobicity. These results are significant to the venom evolution because it's the first citation of rapid evolution in a venom-targeted molecule. This shows that an evolutionary arms race may be occurring in terms of defensive purposes. Alternative hypotheses suggest that venom evolution is due to trophic adaption, whereas these scientists believe, in this case, that selection would occur on traits that help with prey survival in terms of venom evolution instead of predation success. Several other predators of the pit viper (mongooses and hedgehogs) show the same type of relationship between snakes, which helps to support the hypothesis that venom has a very strong defensive role along with a trophic role. Which in turn supports the idea that predation on the snakes can be the arms race that produces snake venom evolution.[31]

Some of the various adaptations produced by this process include venom more toxic to specific prey in several lineages,

gut.[38] These various adaptations of venom have also led to considerable debate about the definition of venom and venomous snakes.[23]

Injection

Vipers

In

maxillary bone, to the basal orifice of the venom fang, which is ensheathed in a thick fold of mucous membrane
. By means of the movable maxillary bone hinged to the prefrontal bone and connected with the transverse bone, which is pushed forward by muscles set in action by the opening of the mouth, the fang is erected and the venom discharged through the distal orifice. When the snake bites, the jaws close and the muscles surrounding the gland contract, causing venom to be ejected via the fangs.

Elapids

In the

elapids
, the fangs are tubular, but are short and do not possess the mobility seen in vipers.

Colubrids

colubrids have enlarged, grooved teeth situated at the posterior extremity of the maxilla
, where a small posterior portion of the upper labial or salivary gland produces venom.

Mechanics of biting

European adder
(Vipera berus), one fang with a small venom stain in glove, the other still in place

Several genera, including Asian coral snakes (Calliophis), burrowing asps (Atractaspis), and night adders (Causus), are remarkable for having exceptionally long venom glands, extending along each side of the body, in some cases extending posterially as far as the heart. Instead of the muscles of the temporal region serving to press out the venom into the duct, this action is performed by those of the side of the body.

Considerable variability in biting behavior is seen among snakes. When biting, viperid snakes often strike quickly, discharging venom as the fangs penetrate the skin, and then immediately release. Alternatively, as in the case of a feeding response, some viperids (e.g. Lachesis) bite and hold. A

opisthoglyph
may close its jaws and bite or chew firmly for a considerable time.

Differences in fang length between the various venomous snakes are likely due to the evolution of different striking strategies.[39] Additionally, it has been shown that the fangs of different species of venomous snakes have different sizes and shapes depending on the biomechanical properties of the snake's prey.[40]

Mechanics of spitting

Hemachatus
, when irritated or threatened, may eject streams or a spray of venom a distance of 1.2 metres (4 ft) to 2.4 metres (8 ft). These snakes' fangs have been modified for the purposes of spitting; inside the fangs, the channel makes a 90° bend to the lower front of the fang. Spitters may spit repeatedly and still be able to deliver a fatal bite.

Spitting is a defensive reaction only. The snakes tend to aim for the eyes of a perceived threat. A direct hit can cause temporary shock and blindness through severe inflammation of the cornea and conjunctiva. Although usually no serious symptoms result if the venom is washed away immediately with plenty of water, blindness can become permanent if left untreated. Brief contact with the skin is not immediately dangerous, but open wounds may be vectors for envenomation.

Physiological effects

The four distinct types of venom act on the body differently:

  • Proteolytic
    venom dismantles the molecular surroundings, including at the site of the bite.
  • Hemotoxic
    venom acts on the cardiovascular system, including the heart and blood.
  • Neurotoxic
    venom acts on the nervous system, including the brain.
  • Cytotoxic
    venom has a localized action at the site of the bite.

Proteroglyphous snakes

The effect of the venom of

Parasuta), bandy-bandies (Vermicella
), etc.

Vipers

Viper venom (

nerve-cells appears to be picked out, and the effect upon respiration is not so direct; the influence upon the circulation explains the great depression, which is a symptom of viperine envenomation. The pain of the wound is severe and is rapidly followed by swelling and discoloration. The symptoms produced by the bite of the European vipers are thus described by Martin and Lamb:[41]

The bite is immediately followed by the local pain of a burning character; the limb soon swells and becomes discolored, and within one to three hours great prostration, accompanied by

suppuration
. That cases of death, in adults as well as in children, are not infrequent in some parts of the Continent is mentioned in the last chapter of this Introduction.

The Viperidae differ much among themselves in the toxicity of their venoms. Some, such as the Indian Russell's viper (Daboia russelli) and saw-scaled viper (E. carinatus); the American rattlesnakes (Crotalus spp.), bushmasters (Lachesis spp.), and lanceheads (Bothrops spp.); and the African adders (Bitis spp.), night adders (Causus spp.), and horned vipers (Cerastes spp.), cause fatal results unless a remedy is speedily applied. The bite of the larger European vipers may be very dangerous, and followed by fatal results, especially in children, at least in the hotter parts of the Continent; whilst the small meadow viper (Vipera ursinii), which hardly ever bites unless roughly handled, does not seem to be possessed of a very virulent venom, and although very common in some parts of Austria and Hungary, is not known to have ever caused a serious accident.

Opisthoglyphous colubrids

Biologists had long known that some snakes had rear fangs, 'inferior' venom injection mechanisms that might immobilize prey; although a few fatalities were on record, until 1957, the possibility that such snakes were deadly to humans seemed at most remote. The deaths of two prominent herpetologists, Robert Mertens and Karl Schmidt, from African colubrid bites, changed that assessment, and recent events reveal that several other species of rear-fanged snakes have venoms that are potentially lethal to large vertebrates.

Boomslang (Dispholidus typus) and twig snake (Thelotornis spp.) venoms are toxic to blood cells and thin the blood (hemotoxic, hemorrhagic). Early symptoms include headaches, nausea, diarrhea, lethargy, mental disorientation, bruising, and bleeding at the site and all body openings. Exsanguination is the main cause of death from such a bite.

The boomslang's venom is the most potent of all rear-fanged snakes in the world based on LD50. Although its venom may be more potent than some vipers and elapids, it causes fewer fatalities owing to various factors (for example, the fangs' effectiveness is not high compared with many other snakes, the venom dose delivered is low, and boomslangs are generally less aggressive in comparison to other venomous snakes such as cobras and mambas). Symptoms of a bite from these snakes include nausea and internal bleeding, and one could die from a

brain hemorrhage and respiratory collapse
.

Aglyphous snakes

Experiments made with the secretion of the

aglyphous
snakes are not entirely devoid of venom, and point to the conclusion that the physiological difference between so-called harmless and venomous snakes is only one of degree, just as various steps exist in the transformation of an ordinary parotid gland into a venom gland or of a solid tooth into a tubular or grooved fang.

Use of snake venoms to treat disease

Given that snake venom contains many biologically active ingredients, some may be useful to treat disease.[42]

For instance,

Macrovipera lebetina have been found to have antitumor activity.[43] Anticancer activity has been also reported for other compounds in snake venom.[44][45] PLA2s hydrolyze phospholipids, thus could act on bacterial cell surfaces, providing novel antimicrobial (antibiotic) activities.[46]

The analgesic (pain-killing) activity of many snake venom proteins has been long known.[47][48] The main challenge, however, is how to deliver protein to the nerve cells: proteins usually are not applicable as pills.

Immunity

Among snakes

The question whether individual snakes are immune to their own venom has not yet been definitively settled, though an example is known of a cobra that self-envenomated, resulting in a large

European adder (Vipera berus) and the European asp
(Vipera aspis), this being due to the presence, in the blood of the harmless snake, of toxic principles secreted by the parotid and labial glands, and analogous to those of the venom of these vipers. Several North American species of rat snakes, as well as king snakes, have proven to be immune or highly resistant to the venom of rattlesnake species. The king cobra, which does prey on cobras, is said to be immune to their venom.

Among other animals

The hedgehog (Erinaceidae), the mongoose (Herpestidae), the honey badger (Mellivora capensis) and the opossum are known to be immune to a dose of snake venom.[citation needed] Recently, the honey badger and domestic pig were found to have convergently evolved amino-acid replacements in their nicotinic acetylcholine receptor, which are known to confer resistance to alpha-neurotoxins in hedgehogs.[50] Whether the pig may be considered immune is still uncertain, though early studies show endogenous resistance in pigs tested against neurotoxins.[51] Though the pig's subcutaneous layer of fat may protect it against snake venom, most venoms pass easily through vascular fat layers, making this unlikely to contribute to its ability to resist venoms. The garden dormouse (Eliomys quercinus) has recently been added to the list of animals refractory to viper venom. Some populations of California ground squirrel (Otospermophilus beecheyi) are at least partially immune to rattlesnake venom as adults.

Among humans

The acquisition of human immunity against snake venom is ancient (from around 60 CE, Psylli tribe). Research into development of vaccines that will lead to immunity is ongoing. Bill Haast, owner and director of the Miami Serpentarium, injected himself with snake venom during most of his adult life, in an effort to build up an immunity to a broad array of venomous snakes, in a practice known as mithridatism. Haast lived to age 100, and survived a reported 172 snake bites. He donated his blood to be used in treating snake-bite patients when a suitable antivenom was not available. More than 20 so-treated individuals recovered.[52][53][54] Amateur researcher Tim Friede also lets venomous snakes bite him in the hopes of a vaccine against snake venom being developed, and has survived over 160 bites from different species as of January 2016.[55]

Traditional treatments

For approaches proven effective by modern medicine, see Snakebite § Treatment.

The World Health Organization estimates that 80% of the world's population depends on traditional medicine for their primary health-care needs.[56] Methods of traditional treatments of snakebites, although of questionable efficacy and perhaps even harmful, are nonetheless relevant.

Plants used to treat snakebites in Trinidad and Tobago are made into tinctures with alcohol or olive oil and kept in rum flasks called snake bottles, which contain several different plants and/or insects. The plants used include the vine called monkey ladder (

Bauhinia cumanensis or Bauhinia excisa, Fabaceae), which is pounded and put on the bite. Alternatively, a tincture is made with a piece of the vine and kept in a snake bottle. Other plants used include mat root (Aristolochia rugosa), cat's claw (Pithecellobim unguis-cati), tobacco (Nicotiana tabacum), snake bush (Barleria lupulina), obie seed (Cola nitida), and wild gri gri root (Acrocomia aculeata). Some snake bottles also contain the caterpillars (Battus polydamas, Papilionidae) that eat tree leaves (Aristolochia trilobata). Emergency snake medicines are obtained by chewing a three-inch piece of the root of bois canôt (Cecropia peltata) and administering this chewed-root solution to the bitten subject (usually a hunting dog). This is a common native plant of Latin America and the Caribbean, which makes it appropriate as an emergency remedy. Another native plant used is mardi gras (Renealmia alpinia) (berries), which are crushed together with the juice of wild cane (Costus scaber) and given to the bitten. Quick fixes have included applying chewed tobacco from cigarettes, cigars, or pipes.[57] Making cuts around the puncture or sucking out the venom had been thought helpful in the past, but this course of treatment is now strongly discouraged, due to the risk of self-envenomation through knife cuts or cuts in the mouth (suction cups from snake bite kits can be used, but suctioning seldom provides any measurable benefit).[58][59]

Serotherapy

Serotherapy using antivenom is a common current treatment and has been described back in 1913.[note 1] Both adaptive immunity and serotherapy are specific to the type of snake; venom with identical physiological action do not cross-neutralize. Boulenger 1913 describes the following cases:

A European in Australia who had become immune to the venom of the deadly Australian tiger snake (Notechis scutatus), manipulating these snakes with impunity, and was under the impression that his immunity extended also to other species, when bitten by a lowland copperhead (Austrelaps superbus), an allied elapine, died the following day.

In

kraits (Bungarus), Russell's viper (Daboia russelli), saw-scaled viper (Echis carinatus), and Pope's pit viper (Trimeresurus popeiorum). Russell's viper serum is without effect on colubrine venoms, or those of Echis and Trimeresurus
.

In Brazil, serum prepared with the venom of lanceheads (Bothrops spp.) is without action on rattlesnake (Crotalus spp.) venom.

Antivenom snakebite treatment must be matched as the type of envenomation that has occurred. In the Americas, polyvalent antivenoms are available that are effective against the bites of most pit vipers.

Crofab is the antivenom developed to treat the bite of North American pit vipers.[60] These are not effective against coral snake
envenomation, which requires a specific antivenom to their neurotoxic venom. The situation is even more complex in countries such as India, with its rich mix of vipers (Viperidae) and highly neurotoxic cobras and kraits of the Elapidae.

Notes

  1. ^ This section is based on the 1913 book The Snakes of Europe, by G. A. Boulenger, which is now in the public domain in the United States (and possibly elsewhere) Because of its age, the text in this article should not necessarily be viewed as reflecting the current knowledge of snake venom

See also

References

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Further reading

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