Snake venom

Snake venom is a highly modified saliva that contains many different powerful toxins. There are at least 2.500 species of snakes living at the present time of which over 600 are known to produce venom. Unlike most other predators, all snakes swallow prey whole, so are especially vulnerable to injury if their prey animals are active. Most snake venoms contain specific proteins that (1) paralyze the prey so that it no longer moves (2) interfere with normal blood clotting mechanisms so that the animal goes into shock and (3) begin the process of digestion by breaking down the tissues of the prey animal. Venom also helps deter predators from harming the snake and is an important defense mechanism.

The process of introducing venom into a victim is called "envenoming". Envenoming by snakes is most often done through the wound of their bite, but some species of snake, like the 'spitting cobra', use additional methods (e.g. squirting venom onto the mucous membranes of prey animals (eyes, nose, and mouth).

Venoms differ from snake species to snake species, and appear to be specialized to dispatch the particular kinds of animals that make up that snake's preferred diet. The great majority of the many biological toxins in snake venom are proteins: generally either with enzymatic activity, the ability to block nerve or muscle cell receptors, or having activity in the protein cascades for coagulation, complement fixation or inflammation. With advances in molecular biology over the last few decades, a general schema for the expression of such proteins by genes in the specialized salivary gland cells that secrete venom is apparent. The components of the venom may even change over the course of a snake's life, in species (for example, certain rattlesnakes of the genus Crotalus) that rely on one set of prey animals as juveniles (cold-blooded lizards and other small exotherms), and a different set of prey animals as adults (warm-blooded rodents).

Toxicity: LD₅₀

Toxicity of venoms is usually expressed by the LD₅₀: the lowest dose that kills 50% of a group of experimental animals (most often rodents). That dose varies not just between the venoms tested, but also depends on which species of prey animals receive the venom. Generally, the most toxic venom is the one with the lowest LD₅₀. However, some snakes have venoms that are quite specialized for certain types of prey. Few studies have used the natural prey of a snake species, which would involve capturing a number of wild animals. Instead, most research has used inbred strains of laboratory animals. Human susceptibility to a snake venom is generally estimated from the LD₅₀ for rodents. The next factor in assessing the danger of a particular species of snake is the dose of venom that is actually introduced into the tissues with a bite. Some types of snakes have an extremely efficient mechanism of injecting venom with a single strike, others have poor success in doing so. The amount of venom produced by venomous snakes that is available for secretion with a bite also varies between kinds of snakes, and between individuals (usually by size) of any one species.

Venom characteristics and delivery of venom according to snake family

The venomous snakes are represented in only four families. These are the Atractaspididae (mole vipers, stilleto snakes) Colubridae (colubrids), Elapidae (elapids, sea-snakes) and the Viperidae (vipers, pit vipers). There are variations in the methods of envenomation according to family.

Colubridae (colubrids)

This family of snakes contains about 2/3 of all living species. These rear-fanged snakes deliver venom under low pressure as compared to the vipers (who inject venom through front fangs under higher pressure) and chemical studies of colubrid venom have been hindered by the difficulty of collecting it. As more recent collection methods have been devised that overcome some of these problems, scientists have discovered that earlier assumptions about the venom contents were sometimes mistaken. For example, Phospholipase A2 (PLA2),which had been thought to be lacking in venoms in this family has now been detected in at least two species

"Some venoms show high toxicity toward mice, and others are toxic to birds and/or frogs only. Because many colubrids feed on non-mammalian prey, lethal toxicity toward mice is likely only relevant as a measure of potential risk posed to humans. At least five species (Dispholidus typus, Thelotornis capensis, Rhabdophis tigrinus, Philodryas olfersii and Tachymenis peruviana) have caused human fatalities"

Elapidae (elapids)

"Neuromuscular paralysis usually occurs with elapid (cobra, krait, and mamba) envenomation." (reference for quote Gagandeep Singh, H.S. Pannu, P.S. Chawla, S. Malhotra: Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomationMuscle & Nerve, Volume 22, Issue 12, Date: December 1999, Pages: 1637-1643)

Effects of Venom

Shock

Hemorrhage and intravascular coagulation: disruption of the normal blood clotting pathways

Many components in snake venom act to disrupt normal blood flow and normal blood clotting (coagulation). Some common enzymes in snake venoms increase bleeding in prey animals by preventing the formation of clots, and others by breaking down established clots. Both of these types of enzymes include metalloproteases. Another group of toxins increase bleeding time by inhibiting the aggregation of platelets, the small odd-shaped blood cells that collect at the site of a tear in a blood vessel and form a plug to close it.

Profound loss of blood can cause hemorrhagic shock, and disable a prey animal.

When many tiny blood clots form in the bloodstream there is a pathological condition known as disseminated intravascular coagulation (DIC), which also causes shock. Some enzymes in snake venom set off DIC in the bloodstream of their envenomated prey by interfering with the activity of serine proteases involved in the regulation of hemostasis.

Paralysis

Some proteins secreted in snake venoms are toxins that affect nerves (neurotoxins) and the contractibilty of muscle. Most neurotoxins in snake venoms are too large to cross the blood-brain barrier, and so usually exert their effects on the peripheral nervous system rather than directly on the brain and spinal cord. Many of these neurotoxins cause paralysis by blocking the neuromuscular junction. In fact, biologists first learned some of the details of how the neuromuscular junction normally functions by using purified snake venoms in physiology experiments.

The Neuromuscular Junction

The neuromuscular junction is the microscopic connection between a motor nerve fiber and a muscle fiber, and is a type of synapse. Muscle contractions are normally regulated by the electrical activity of large nerve cells in the spinal cord and brainstem, called motor neurons or motoneurons. These neurons have long axons ('nerve fibres') that end in contact usually with just a single muscle fibre. The axon endings make a specialized contact with the muscle fiber, that is very like the synapses 'synaptic contacts' between nerve cells in the brain. This contact zone is called the neuromuscular junction, and on both the muscle side and the nerve side of this junction there are specialized structures and specific proteins for regulating the passage of information from neuron to muscle fiber. The nerve ending is filled with small synaptic vesicles that contain neurotransmitters - chemical messengers. When the brain gives the command to move a muscle, electrical signals (action potentials) are propagated down the motoneuron axons to the endings. The endings are depolarized by these signals and as a result voltage-dependent calcium channels open in the nerve ending. This calcium entry causes some of the synaptic vesicles to fuse with the nerve cell membrane, causing them to release their chemical contents into the narrow cleft between nerve ending and muscle fiber. The most important of these messengers at the neuromuscular junction is acetylcholine. Across this tiny space between the nerve ending and the muscle cell membrane, the acetylcholine molecules bind to other molecules - the acetylcholine receptor molecules, and this now causes the muscle fiber to become depolarized and allow calcium to enter. The entry of calcium causes the muscle fiber to contract.

The effect of acetylcholine is normally very short lived, as it is very quickly destroyed by acetylcholinesterase, an enzyme produced both by the muscle fibres and by the motoneurons that specifically and very efficiently breaks down the acetylcholine molecule. Without acetylcholinesterase, enough aceytlcholine would remain in the cleft between nerve fiber and muscle cell to keep reactivating the muscle contraction mechanism for a long time, producing a form of tetany.

Acethylcholine receptor blocked by cobra venom

Neurotoxins in snake venom can block transmission of acetylcholine from nerve to muscle at the side of the nerve ending (pre-synaptic literally, before the synapse) or affect the activity of the muscle fiber past the synapse (post-synaptic literally after the synapse). Most commonly, the postsynaptic method of producing paralysis is an anti-cholinesterase toxin in venom that prevents acetylcholinesterase from degradingthe acetylcholine. Most snake venoms contain toxins that cause paralysis by both methods: pre and postsynaptic interference. . Presynaptic neurotoxins are commonly called [beta]-neurotoxins and have been isolated from venoms of snakes of families Elapidae and Viperidae. [beta]-Bungarotoxin was the first presynaptically active toxin to be isolated from Bungarus multicinctus (banded krait), which is an elapid.

Role of snake venom in medical and biological research

Outline for authors: 1. Discuss how neuromuscular junction physiology largely elucidated by use of snake venoms. 2.Discuss medicinal uses snake venoms Fibrinolytic enzymes isolated from venom can directly break down a fibrin clot. Current medical research seeks to find such an enzyme to remove clots causing heart attacks and strokes.

Natural protection from venom: genes and antibodies

Among other animals

There are particular kinds of animals that have been noted to have some resistance to the effects of venom. Just as there seems to be a correlation between the toxic mix in snake venom and a prey animal, such that a given snake's venom is particularly toxic to that species preferred prey, some of the animals noted to have resistance to snake venom themselves prey on venomous snakes.

Mongoose

The mongoose is a mammal native to who eats snakes, including venemous snakes such as the cobra. This animal has been observed to survive envenomation by ,and was often thought to be somehow "immune" to the snake's venom. Although the animal has no special immune powers against venom, there are some genetic traits that are protective.

Research has shown the acetylcholine receptor of the mongoose has been altered by genes so that it has a slightly different protein sequence than that of animals who are easily paralyzed by (alpha)-bungarotoxin. In laboratory experiments, the reconstituted mongoose AChR alpha-subunit of the acetylcholine receptor did not bind (alpha)-bungarotoxin (Asher O. Lupu-Meiri M. Jensen BS. Paperna T. Oron Y. Fuchs S. How does the mongoose cope with alpha-bungarotoxin? Analysis of the mongoose muscle AChR alpha-subunit. [Journal Article] Annals of the New York Academy of Sciences. 841:97-100, 1998 May 13. UI: 9668225). This is a specific example of natural resistance of the mongoose to a component of cobra venom, but does not imply "immunity" in the sense of some protection afforded the mongoose by its immune system.

Antivenin

Antivenin is blood serum made by injecting partially denatured proteins from snake venom into large host animals, such as horses or sheep, in low enough doses so that the animal is not harmed, but antibodies are produced to counteract the active components of the venom. Early antivenins were problematic, because whole horse serum was used and many people suffered reactions to the plasma. As refinements have been made in the purification of the antibody fractions of the serum, allergic and other reactions have been reduced.

Since antivenins are specific antidotes that neutralize the particular active toxins of venoms, the type of antivenom must be properly matched to the snake responsible for the bite. Antivenins have revolutionized the treatment for the more deadly snake envenomations. For example, a recent report of the first manufacture of a horse antivenin against against bites from Bungarus candidus in Vietnam changed the course of a group of patients from an 80% mortality to 100% recovery.

Regional considerations

Even in those areas where laws against the keeping venomous snakes in captivity exist, enforcement is not strict enough to prevent this practice entirely. Additionally, although rare in occurrence, snakes can be introduced into distant locations through importation of goods. Therefore, snake bite by a a venomous snake that is not native to a particular geographic region is possible. However, statistically, the number and type of snake bites in the general population occurs in geographic distribution that reflects the native habitat of these snakes, and, sometimes, occupations and recreational practices by residents and travellers that are higher risk for snake bite. Most envenomations from snakes occur in tropical countries.