Scientist Discovers Why Cobra Venom Can't Kill Other Cobras(Tha National Georgraphic News)

Zoltan Istvan
National Geographic Channel
February 20, 2004

In a cobra hunt, every move counts.

Zoltan Takacs, a herpetologist and toxinologist (natural-toxins scientist), lunges at a 5-foot long (1.5-meter) Egyptian cobra slithering away in the dry East African grassland of Tanzania.

The cobra opens its hood—kicking up dust and hissing—and strikes, narrowly missing Takacs's right hand. Takacs jumps away, gathers himself, then quickly moves in and snares the cobra's head with a wooden stick.

In his field lab the Hungarian-born Takacs, who's been fascinated by snakes since childhood, extracts tissue samples from the cobra for genetic analysis. Based at the Yale University School of Medicine in New Haven, Connecticut, Takacs has developed an international reputation for unlocking secrets of venom that promise to have significant medical potential.

But Takacs must endure tremendous risks in the field. "I have to be extremely careful in this tropical wilderness—because I'm far from any hospitals," Takacs said. "Over the years I've lost three good friends and colleagues to snakebites."

Since high school, Takacs, who holds a doctorate in molecular pharmacology from Columbia University in New York, has traveled to more than a hundred countries to collect venomous snakes.

Animal neurotoxins are nature's deadliest weapons. Nearly all creatures, except cobras, die in minutes when cobra venom enters their bloodstreams. At his Yale lab, Takacs explores why.

Cobra Venom

"Neurotoxin is the main lethal component of the cobra venom," Takacs said. "It binds to a receptor on the muscle, therefore preventing the nerve impulses to induce muscle contraction, leading to the cessation of breathing, and death."

The target of cobra neurotoxin, called the acetylcholine receptor, appears to play a role in Parkinson's disease, schizophrenia, and myasthenia gravis, which debilitates the muscles.

"Snake venoms are extraordinary biological products, with importance in many different fields," said Rick Shine, professor of evolutionary biology at the University of Sydney in New South Wales, Australia. "Understanding their mechanisms of action can help us to design better drugs—as well as to reduce the immense suffering and mortality from bites to humans."

Venomous snakes come in two main families: vipers, such as rattlesnakes, and cobras, such as kraits, mambas, and sea snakes. During the 1970s scientists discovered that vipers' bloodstreams contain molecules that neutralize the lethal components of their own venom.
Cobras deal with their venom differently from vipers, the scientists suspected. During the 1990s studies were launched to find out why.

Snake venoms are complex mixtures of peptides, enzymes, and other toxins that target the nerves, muscles, and blood circulation and coagulation. A key to the research was finding how the toxins reacted with muscle receptors.

Lock and Key

Takacs cloned a cobra's acetylcholine receptor and compared it to acetylcholine receptors from other vertebrates (animals with spinal columns). At the molecular level this cobra receptor looked the same as those in the rest of the vertebrates—except for a single different amino acid.

Takacs' experiments showed that this single difference introduces a bulky sugar molecule onto the cobra receptor. The sugar masks the so-called binding site on the receptor surface—which prevents the neurotoxin from attaching.

"If the sugar is removed, then the cobra receptor will become sensitive to its own neurotoxin, just as other animals are," Takacs explained.

To prove his theory, Takacs and his colleagues engineered a mouse muscle receptor with a sugar molecule attached—and thus created a mouse receptor that resists cobra neurotoxin.

"Like a keyhole and a key—if you change the keyhole, the key will no longer fit into it," Takacs said. That's the secret to how the cobra avoids its own venom.

"These same venom [and receptor] molecules, once purified, characterized, redesigned, and cloned, can be used in medical research as possible drugs for treating strokes, heart attacks, and metastasis as well," said John C. Perez, a professor at the Natural Toxins Research Center at Texas A&M University-Kingsville.

"These venom and receptor molecules all have important biomedical applications, making Takacs's work much more than just studying snake venom," he added.

Postsynaptic α-Neurotoxin Gene of the Spitting Cobra, Naja naja sputatrix: Structure, Organization, and Phylogenetic Analysis

Fatemeh Afifiyan, Arunmoziarasi Armugam, Chee Hong Tan, Ponnampalam Gopalakrishnakone, and Kandiah Jeyaseelan1
Department of Biochemistry, Faculty of Medicine, National University of Singapore, 119260 Singapore
1Corresponding author.
Received November 2, 1998; Accepted January 19, 1999.

The venom of the spitting cobra, Naja naja sputatrix contains highly potent α-neurotoxins (NTXs) in addition to phospholipase A2 (PLA2) and cardiotoxin (CTX). In this study, we report the complete characterization of three genes that are responsible for the synthesis of three isoforms of α-NTX in the venom of a single spitting cobra. DNA amplification by long-distance polymerase chain reaction (LD-PCR) and genome walking have provided information on the gene structure including their promoter and 5′ and 3′ UTRs. Each NTX isoform is ~4 kb in size and contains three exons and two introns. The sequence homology among these isoforms was found to be 99%. Two possible transcription sites were identified by primer extension analysis and they corresponded to the adenine (A) nucleotide at positions +1 and −45. The promoter also contains two TATA boxes and a CCAAT box. Putative binding sites for transcriptional factors AP-2 and GATA are also present. The high percentage of similarity observed among the NTX gene isoforms of N. n. sputatrix as well as with the α-NTX and κ-NTX genes from other land snakes suggests that the NTX gene has probably evolved from a common ancestral gene.
[The genomic DNA sequences reported in this paper have been submitted to GenBank databases under accession nos. AF096999 toAF097001.]

Neurotoxins affecting neuroexocytosis

G Schiavo, M Matteoli, C Montecucco
Imperial Cancer Research Fund, London, United Kingdom.

Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

Pathophysiology of Snake Venom

Snake venoms are complex substances, chiefly proteins, with enzymatic activity. Although enzymes play an important role, lethal properties of venom can be due to certain smaller polypeptides. Most venom components appear to bind to multiple physiologic receptors, and attempts to classify venom as toxic to a specific system (eg, neurotoxin, hemotoxin, cardiotoxin, myotoxin) are misleading and can lead to errors in clinical judgment.

The venom of most North American pit vipers produces local effects and coagulopathy and other systemic effects. Results may include local tissue damage; vascular defects; hemolysis; a disseminated intravascular coagulation (DIC)–like (defibrination) syndrome; and pulmonary, cardiac, renal, and neurologic defects. Venom alters capillary membrane permeability, causing extravasation of electrolytes, albumin, and RBCs through vessel walls into the envenomated site. This process may occur in the lungs, myocardium, kidneys, peritoneum, and, rarely, the CNS. Initially, edema, hypoalbuminemia, and hemoconcentration occur. Later, blood and fluids pool in the microcirculation, causing hypotension, lactic acidemia, shock, and, in severe cases, multisystem organ failure. Effective circulating blood volume falls and may contribute to cardiac and renal failure. Clinically significant thrombocytopenia (platelet count < 20,000/μL) is common in severe rattlesnake bites and may occur alone or in combination with other coagulopathies. Venom-induced intravascular clotting may trigger defibrination syndrome, resulting in epistaxis, gingival bleeding, hematemesis, hematuria, internal hemorrhage, as well as spontaneous bleeding at the bite site and venipuncture sites. Renal failure may result from severe hypotension, hemolysis, rhabdomyolysis, nephrotoxic venom effects, or a DIC-like syndrome. Proteinuria, hemoglobinuria, and myoglobinuria may occur in severe rattlesnake bites. The venom of most North American pit vipers produces very minor changes in neuromuscular conduction, except for Mojave and Eastern diamondback rattlesnake venom, which may cause serious neurologic deficits.

Coral snake venom contains primarily neurotoxic components, which result in a presynaptic neuromuscular blockade, potentially causing respiratory paralysis. The lack of significant proteolytic enzyme activity accounts for the paucity of symptoms and signs at the bite site.

Epidemiology & The Risk of Snakebite

Your risk of being bitten be a snake is small, and so too is your risk of dying if bitten. Although there are an estimated 45,000 bites by all snakes in the United States each year, only about 6680 persons are treated for snake venom poisoning. However, it can be expected that at least 1000 additional bites by venomous snakes occur each year and that they are either not treated or go unreported. During the past five years, the number of deaths from snakebite in the United States has ranged between nine and 14. Most of the deaths occurred in children, in the elderly, in untreated, mistreated, or undertreated cases, in cases complicated by other serious disease states, or in members of religious sects who handle serpents as part of their worship exercises and refuse medical treatment. Almost all reported deaths have been attributed to rattlesnakes. In addition,"25 percent of all pit viper bites do not result in envenomation and another 15% are so trivial, they require only local cleansing and tetanus prophylaxis."


Approximately 75 percent of all snakebites occur in people aged between 19 and 30 years, 1 percent to 2 percent occur in women, and less than 1 percent occur in blacks. Approximately 40 percent of all snakebites occur in people who are handling or playing with snakes, and 40 percent of all people bitten had a blood alcohol level of greater than 0.1 percent. Sixty-five percent of snakebites occur on the hand or fingers, 24 percent on the foot or ankle, and 11 percent elsewhere. One case was reported of a snakebite on the glans penis.

So it seems that getting drunk and messing about snakes is a big cause of getting bitten. It also seems that male yahooism is a precursor to snake toxin poisoning. Women are unlikely to get themselves bitten, and if they do get bitten, it is unlikely that they got that way by doing something stupid. Here is some more interesting data on that point from Curry et al. in Annals of Emergency Medicine 1989 18(6):658-63:

A recent study reviewed medical records of 85 consecutive snakebite victims cared for at a single medical center to determine legitimacy of snakebites. A bite was considered illegitimate if, before being bitten, the victim recognized an encounter with a snake but did not attempt to move away from the snake. A legitimate bite was said to have occurred if a person was bitten before an encounter with a snake was recognized or was bitten while attempting to move away from a snake. The study group was made up of 75 male (87.2 percent) and 11 female (12.8 percent) victims. Seventy-four percent were 18 to 50 years old, and 15 percent had been bitten previously. Only 43.4 percent of all bites were considered legitimate, and pet (captive) snakes accounted for almost one third of all illegitimate bites. The ingestion of alcoholic beverages was associated with 56.5 percent of illegitimate bites versus 16.7 percent of legitimate bites. While 74.4 percent of bites were to upper extremities, only 27 percent of upper extremity bites were legitimate. All bites to the lower extremities were legitimate. Of 14 individuals bitten by pet snakes, all were men and 64.3 percent were under the influence of alcohol at the time of the bite. In our patient population, the data suggest that a 16 percent reduction in rattlesnake bites would result if rattlesnakes were not kept as pets, and more than one half of all rattlesnake bites would be eliminated if persons simply would attempt to move away from a rattlesnake after an encounter is recognized.

It is worth noting that only one woman in Curry et al.'s study group received an illegitimate bite.

What are the symptoms of poisonous bites?

If you get bit, DON'T PANIC. Many people who "died from a snakebite" actually died from something reckless they did while in a panicked state after being bit.While each individual may experience symptoms differently, the following are the most common symptoms of poisonous snake bites:

1.bloody wound discharge
2.fang marks in the skin and swelling at the site of the bite
3.severe localized pain
4.diarrhea
5.burning
6.convulsions
7.fainting
8.dizziness
9.weakness
10.blurred vision
11.excessive sweating
12.fever
13.increased thirst
14.loss of muscle coordination
15.nausea and vomiting
16.numbness and tingling
17.rapid pulse

How are snake bites treated?
Call for emergency assistance immediately if someone has been bitten by a snake. Responding quickly in this type of emergency is crucial. While waiting for emergency assistance:

Wash the bite with soap and water.
Immobilize the bitten area and keep it lower than the heart.
Cover the area with a clean, cool compress or a moist dressing to minimize swelling and discomfort.
Monitor vital signs.
If a victim is unable to reach medical care within 30 minutes, the American Red Cross recommends:

Apply a bandage, wrapped two to four inches above the bite, to help slow the venom. This should not cut off the flow of blood from a vein or artery - the band should be loose enough to slip a finger under it.
A suction device can be placed over the bite to help draw venom out of the wound without making cuts. These devices are often included in commercial snake bite kits.
Most often, physicians use antivenin -- an antidote to snake venom -- to treat serious snake bites. Antivenin is derived from antibodies created in a horse's blood serum when the animal is injected with snake venom. Because antivenin is obtained from horses, snake bite victims sensitive to horse products must be carefully managed.

Preventing snake bites:
Some bites, such as those inflicted when you accidentally step on a snake in the woods, are nearly impossible to prevent. However, there are precautions that can reduce your chances of being bitten by a snake. These include:

Leave snakes alone. Many people are bitten because they try to kill a snake or get too close to it.
Stay out of tall grass unless you wear thick leather boots and remain on hiking paths as much as possible.
Keep hands and feet out of areas you cannot see. Do not pick up rocks or firewood unless you are out of a snake's striking distance.
Be cautious and alert when climbing rocks.

Snake Venom May Slow Cancer Growth, Studies Hint

Jennifer Hile
National Geographic Channel,June 1, 2004

Preliminary research shows a natural compound in some snake venoms may prevent the growth of cancerous tumors, potentially transforming one of nature's deadliest toxins into a curative agent.

"Snakes use venom to alter biological functions, and that's what medicine does too," explained John Perez, director of the Natural Toxins Research Center at Texas A&M University-Kingsville. "This is why venoms have always been of interest to medical researchers."

Today roughly a dozen diagnostic tests and drugs are derived from snake venom, according to Zoltan Takacs, a toxinologist (natural-toxins scientist) and herpetologist based at the Yale University School of Medicine in New Haven, Connecticut.

ACE inhibitors, a class of drugs used to treat high blood pressure and other cardiovascular disorders, were developed from the venom of a Brazilian snake. Scientists anticipate that this is just the beginning.

Of the nearly 3,000 species of snakes in the world, about 650 are venomous. Ten of the most deadly live in Australia, making it a logical base for new experiments.

"We knew Australia could be a rich source of drugs because there are so many venomous creatures here," said Tony Woods, a biologist at the University of South Australia in Adelaide. Woods is co-leader of a project to investigate whether the toxins in venom can be used to destroy blood vessels that feed cancerous tumors.

The Power of Nature's Toxins

Venoms are exquisitely complex, composed of as many as a hundred different peptides, enzymes, and toxins. Not only are the venoms of every snake species different, there are also subtle variations within each species.

"There are differences between [venoms of] juveniles and adults, and even among different geographic regions," Takacs said. "These differences may be due to different evolutionary pressures, like different ancestry, prey, and environments."

The variations between venom types and the number of venomous snakes worldwide create a rich molecular hunting ground for researchers, like Woods, seeking to design new drugs.

"A tumor is made of tissue," Woods said. "Like tissue in any part of the body, if you can prevent it from developing a blood supply, or interfere with that supply, then you will have an effect on the growth of that tissue."
Woods is working with Michael Venning, a pharmacologist at the University of South Australia, and graduate student Emma Bateman. Peter Mirtschin, a toxinologist at Venom Supplies in Tanunda, South Australia, is providing the venom directly from the snakes.

Woods's group has found a compound in snake venom that disrupts endothelial cells, which line the inner surface of blood vessels. "It causes the cells to separate from one another, which kills them," Woods said. "When that happens, the function of the blood vessel is inhibited, preventing or at least interfering with blood flow to the tumor [effectively starving it of nutrients]."

Woods will not specify which snake venoms his team is studying, because the compounds have not yet been patented.

The Cure That Doesn't Kill

The advantage of these venom-derived toxins is that they seem to act only on certain types of cells.

Chemotherapy and many other drug treatments do not distinguish between tumor cells and other healthy cells, causing debilitating side effects. But natural toxins have evolved to impact very specific targets.

"We believe the cells that line blood vessels in tumors are different in subtle ways from similar cells elsewhere in the body, because they are exposed to different stimulation and chemicals," Woods said. That means toxins inhibiting tumor blood vessels may not effect surrounding healthy cells, which would theoretically leave patients using these toxins feeling better than those who go through chemotherapy.

Woods anticipates that he will begin testing the venom-derived toxin in animals within the year. Those results will reveal whether the drug is suitable for human clinical trials.

"I don't actually like snakes, they scare me to death, but I'm fascinated by their venom," Woods said. "So long as it's provided to me in nice plastic tubes, I'm very comfortable with handling it."

CNS and anticonvulsant activity of a non-protein toxin (KC-MMTx) isolated from King Cobra (Ophiophagus hannah) venom

A Saha , A Gomes , A K Chakravarty , A K Biswas , B Giri , S C Dasgupta

In the present study, King Cobra (Ophiophagus hannah) venom was subjected to TLC followed by column chromatography/HPLC to isolate and purify a non-protein toxin designated as KC-MMTx. (1)H NMR, IR and EIMS studies showed KC-MMTx likely to be a 282 D unsaturated aliphatic acid having molecular formula C(18)H(34)O(2). The minimum lethal dose of KC-MMTx was 200mug/kg (i.v.) and 350mug/kg (i.p.) in Swiss albino male mice. It significantly increased pentobarbitone induced sleeping time and significantly decreased the body temperature of male albino mice. It provided protection against amphetamine aggregate toxicity in mice but failed to protect amphetamine stereotypy in male albino rats. KC-MMTx provided significant protection against drug (strychnine, pentylenetetrazole, yohimbine) induced convulsions in male albino mice. It increased serum Na(+) and decreased serum Ca(2+) significantly in male mice. MAO activity and brain neurotransmitter levels in male mice were altered significantly. Further detailed study is warranted on the CNS, anticonvulsant potential of KC-MMTx, which may lead to the development of newer therapeutic tools in the near future.

Role of snake venom in medical and biological research

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, and is an important defense mechanism for the snake.
Introduction
The process of introducing venom into a victim is called "envenoming". Envenoming by snakes is most often through their bite, but some species, like the 'spitting cobra', use additional methods such as squirting venom onto the mucous membranes of prey animals (eyes, nose, and mouth). Venoms differ from snake species to snake species, and seem 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: some haveenzymatic activity, some can block nerve or muscle cell receptors, and some have activity in the protein cascades for coagulation, complement fixation or inflammation. Effects of snake venom in the tissues envenomated by the bite are called local effects. Other actions arise from toxins transported through the blood vessels or through lymph vessels, and are called systemic effects.

With advances in molecular biology, a general schema for the expression of such proteins by genes in the specialized salivary gland cells that secrete venom has become 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).[1]
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. 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 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.

[edit]Venom characteristics and delivery of venom according to snake family
The venomous snakes are represented in only four families. There are variations in the methods of envenomation according to family.

[edit]Atractaspididae (atractaspidids)
(common names of well-known members: burrowing asps, mole vipers, 'stilleto snakes')

[edit]Colubridae (colubrids)
(common names of well-known members: boomslang)

This family of snakes contains about 2/3 of all living species. A minority have somewhat enlarged grooved teeth at the back of the upper jaw for delivering venom under low pressure. This unsophisticated system for venom delivery makes it more difficult for scientists to collect colubrid venom for chemical studies than the venom from vipers and most elapids, which inject venom through front fangs under higher pressure. Often, couloubrid venoms were collected only in relatively small quanitites and with impurites from other mouth contents from the snake. As more recent collection methods have been devised that overcome some of these problems, researchers 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 probably only relevant as a measure of risk posed to humans. At least five species (Dispholidus typus, Thelotornis capensis, Rhabdophis tigrinus, Philodryas olfersii and Tachymenis peruviana) have caused human fatalities."[2]

[edit]Elapidae (elapids)
(common names of well-known members: cobras , kraits, coral snakes, mambas, sea snakes, sea kraits, Australian elapids)

The venom of elapid snakes is notorious for the potency of its neurotoxins. These snakes have similarities in their XXXXX. Venemous elapid snakes greatly range in size, aggressiveness, and in habitat. "The king cobra (Ophiophagus hannah) is the world’s longest venomous snake, growing up to 5.5 m (18.5 ft). The main constituent of king cobra venom is a postsynaptic neurotoxin, and a single bite can deliver up to 400–500 mg of venom, ...about fifteen thousand times the LD50 dose for mice. The world’s most venomous snake is the Australian elapid small-scaled snake (Oxyuranus microlepidotus), can deliver up to 100 mg of venom with an LD50 for mice of 0.01 mg.kg)1, giving up to 500 000 LD50 mice doses. [3].

Although sea snakes have some of the world's most potent venom, the numbers of human fatalities from snake bites is apparently limited by their marine environment and behavior (more coming with references).

For prey animals, and in cases of defensive behavior towards humans, "neuromuscular paralysis usually occurs with elapid (cobra, krait, and mamba) envenomation." [4], however, many elapid snakes have venoms that also include toxins that cause bleeding. For example, the venom of , all contain metalloproteinases that interfere with platelet aggregation.

Besides neurotoxins and metalloproteinases, there are additional types of bioactive proteins and polypeptides that are common in elapid venom. "A second group of toxins are cell membrane poisons that act in a general fashion, but their chief effect is on the heart, producing arrhythmias and impaired contractility. The third group of toxins contains enzymes that break down protein and connective tissue. These necrosis-producing toxins are typical of the venom from the spitting cobras (Naja spp.) of Africa, China, and Sumatra." [5]

[edit]Viperidae (viperids)
(common names of well-known members: pitless vipers, pit vipers)

Bites by snakes of the family Viperidae often induce local breakdown of muscle and tissues which may result in permanent deformity in the region of the bite (Myotoxic phospholipases).[6] Some types of vipers inject venom that travels though the bloodstream and breaks down muscle cells systemically, with relatively little reaction at the site of the bite, but enough muscle cells throughout the body release their contents into the victim's bloodstream to cause a condition known as rhabdomyolysis. In rhabdomyolysis (literally rhabdo=rod , myo=muscle cell, lysis= breaks apart) the large iron-containing protein myoglobin is released into the circulation (myoglobulinemia). When myoglobin reaches the kidney, the renal system attempts to filter it out of the blood. If the amount of myoglobin is very large, acute renal failure results, and the blood is no longer properly filtered of even normal body wastes by the kidneys.

The common names of vipers frequently fail to identify an actual species. For example, the name, Rock viper refers to two entirely different kinds of snakes.

[edit]Crotalinae (crotalines)
(common names of well-known members: pit vipers, including lanceheads, moccasins, rattlesnakes)

Pit viper venom characteristically contains a potent mix of enzymes that produce an emphatic degree of tissue destruction at the site of the bite. As with most venoms, there can be both local and systemic effects. However, unless a bite by a pit viper is "dry" (meaning no venom injected), there will ordinarily be marked inflammation at the site of the bite and possibly systemic effects.

Rattlesnakes range in size from small (pigmy rattlesnakes, Sistrurus) to large (many species of Crotalus, such as the Eastern diamondback, Crotalus adamanteus). Most pit vipers are potentially very active and aggressive snakes. The strike can be lightning quick, measured in one study as under 50ms [7].

[edit]Effects of Venom
Snake venoms contain molecules that are biologically active. The poison gland of snakes adds these molecules to saliva, which is the digestive juice produced by the mouth of most all land vertebrates. In nonvenemous snakes, and in other creatures, such as we humans, saliva moistens the food and initiates digestion with enzymes. In venemous snakes, the toxic molecules added to their specialized venom include some of the most powerful substances known in their effects on biological systems.

Some toxins take effect at the site of the bite, others are only active in certain tissues and cause their harmful effects once they reach these tissues through the blood stream. The effects of the snake venom on that victim are not always direct, sometimes the toxic substances trigger cascades of reactions, that, like a toppling row of dominoes, lead to many cumulative disruptions.

[edit]Shock
Hemorrhage and intravascular coagulation: disruption of the normal blood clotting pathways
Many components in snake venom disrupt normal blood flow and normal blood clotting (coagulation). Some common enzymes in snake venoms increase bleeding by preventing the formation of clots, and others by breaking down established clots. Both of these types of enzymes include metalloproteases. Other 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.

Infarction: Stroke and Heart Attack
Toxins that set off clotting within the blood vessels of envenomated animals can cause both stroke and heart attacks. Infarction is a medical term that means death to tissues because of a block in their blood supply, and clots within the arteries of the neck and brain, as well as the coronary arteries can deprive the blood supply enough to cause infarctions in these organs.

[edit]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 they 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.

[edit]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-sensitive 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, the acetylcholine molecules bind to other molecules - the acetylcholine receptor molecules (specifically, muscle-type nicotinic acetylcholine receptors). This receptor is a ligand-gated ion channel; when acetylcholine binds to it, the channel opens, allowing sodium to enter the muscle cell. The inflow of sodium ions causes the muscle fiber to become depolarized and as a result, voltage-sensitive calcium channels open, allowing calcium to enter. As calcium enters, it triggers further calcium release from stores inside the cell (in the sarcoplasmic reticulum), resulting in a 'wave' of calcium that spreads throughout the muscle fiber. The calcium interacts with filaments inside the muscle cell called myofibrils, causing them, and as a result the whole muscle fiber, to contract.

The effect of acetylcholine is normally very short lived, as it is rapidly destroyed by acetylcholinesterase, an enzyme produced both by the muscle fibres and by the motoneurons that very efficiently breaks down the acetylcholine. 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 venomNeurotoxins 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 degrading the acetylcholine. Most snake venoms contain toxins that cause paralysis by both methods: pre and postsynaptic interference. [8]. Presynaptic neurotoxins are commonly called ß-neurotoxins and have been isolated from venoms of snakes of families Elapidae and Viperidae. ß-Bungarotoxin was the first presynaptically active toxin to be isolated from Bungarus multicinctus (banded krait), which is an elapid. ß-bungarotoxin has a phospholipase subunit and a K+ channel binding subunit, and their combined effects are to destroy sensory and motor neurons [9] The banded krait venom also contains alpha-bungarotoxin, which binds to nicotinic acetylcholine receptors, thus preventing acetylcholine from doing so (i.e. it is a receptor antagonist), and kappa bungarotoxin, which is an antagonist of neuronal acetylcholine receptors.[10]

[edit]Pain
[edit]Relief of pain (analgesia) and feeling of well-being (euphoria)
One of the toxins of Crotalus durissus has been shown to act as a pain reliever in mice, apparently by a novel mechanism.

In a case report of a human bite by a king cobra, Ophiophagus hannah, in New York City, a 30 year old reptile importer was struck by a captive in the baggage department of Kennedy Airport. "The patient instantly felt a generalized "warm rush" soon followed by euphoria, "brightly colored visual hallucinations", a distorted perception of the passage of time and "razor-like pain" throughout the right arm." (reference for quote:Warren W. Wetzel and Nicholas P. Christy: A king cobra bite in New York City • SHORT COMMUNICATION, Toxicon, Volume 27, Issue 3, (1989) Pages 393-395)

[edit]Role of snake venom in medical and biological research
[edit]Basic research in physiology
[edit]Laboratory tests in medicine
Phospholipase A2 (which sets off the coagualtion of clotting factors in blood) makes up the majority of protein toxins in the venom of Russell's viper (Daboia russelii sp..). Dilute venom is sold commercially to medical laboratories. Russell's Viper Venom Clotting Time tests are routinely used to help diagnose certain kinds of abnormal antibodies. anticoagulants) in the serum of patients with the autoimmune disease, Lupus.

[edit]Therapeutic removal of thrombus
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.

[edit]Disintegrins
[edit]Natural protection from venom: genes and antibodies
[edit]Among snakes
[edit]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 that have resistance to snake venom themselves prey on venomous snakes.

[edit]Mongoose
There are more than 30 species of mongoose, these small mammalian carnivores are found in Asia, Africa, the Caribbean, and southern Europe. Some species, particularly H. edwardsii, the Indian mongoose, eat snakes, including venemous snakes such as the cobra: Rudyard Kipling's story Rikki-Tikki-Tavi from The Jungle Book is about a young mongoose's fight with two cobras. The mongoose has been observed to survive envenomation by snakes, and was often thought to be somehow "immune" to the venom. Although the mongoose has no special immune powers against venom, there are some genetic traits that are protective.

In particular, the acetylcholine receptor in the mongoose 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 [11]. This is an example of natural resistance of the mongoose to a component of cobra venom, but it does not imply "immunity" in the sense of protection afforded the mongoose by its immune system.

[edit]Antivenin
Venom is milked from rear-fanged snake in Thailand.Antivenin is blood serum that is made by injecting partially denatured proteins from snake venom into large host animals, such as horses or sheep. These are given in low enough doses so that the animal is not harmed, but antibodies are produced to counter-act the active components of the venom. Early antivenins were problematic, because whole horse serum was used and many people suffered adverse 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.

As 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, the first 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.[12]

[edit]Venomous snake bite
Not every snakebite involves venom. Not only are dry bites common among venomous snakes, but bites by nonvenomous snakes are commonly feared to have been inflicted by "the poisonous kind". Adding to the difficulty of accurately identifying a fleeing snake in the wild, is the fact that some snakes of both venomous and nonvenomous kinds are called by the exact same common name. For example, the name Puff adder is applied to entirely different kinds of snakes.

Even where there are laws against the keeping venomous snakes in captivity, enforcement is not strict enough to prevent this entirely. Additionally, though rarely, snakes can be introduced into distant locations through importation of goods. Therefore, a bite by 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 a geographic distribution that reflects the native habitat of these snakes, and, sometimes, occupations and recreational practices by residents and travellers that are at higher risk for snake bite.

Most envenomations from snakes occur in tropical countries. In areas where antivenom is available, along with technologically sophisticated medical care, mortality from venomous snake bite is very low. The World Health Organization has indicated that treatment for venomous snake bite is a health issue for the developing world.

Most snakebites in North America that require medical intervention are from pit vipers. "Eastern and western diamondback rattlesnakes (Crotalus adamanteus and C. atrox, respectively) are responsible for most snakebite deaths in the United States. However,the mortality rate is <1% for victims receiving antivenom". [13] Elapid envenomations do occur in the USA and Mexico from coral snakes. North American coral snakes include the eastern coral snake (Micrurus fulvius), the Texas coral snake (M. tener), and the Arizona (Sonoran) coral snake (Micruroides euryxanthus).
Central America
South America
Despite the paucity of native venomous snakes in Europe, there are reports of venomous snakebite. In 1970–77, 17 people in the UK were victims of 32 bites by foreign venomous snakes.
In North Africa and the Middle East, the desert horned vipers (genus Cerastes) is a distinctive snake of the desert sands, implicated in cases of snake bite reported in Dharan, Saudi Arabia. This snake is not uncommonly kept as a pet, and some cases reported by physicians have been due to the snake biting its captor during handling and occurred in places like Switzerland. [14]
Asia
Pit vipers exclusive to China include the large and spectacular Mt. Mang Viper (Trimeresurus mangshanensis) of the Hunan province. Many of the widespread elapid snakes, such as the King Cobra (Ophiophagus hannah), in southern China , are also native to Southeast Asia, including India and the Phillipines.
In Southern Asia, cobras are large snakes with potent venom that adapt to living in areas of human habitation. Although it is estimated that up to 45% of their bites are dry, in Burma and India, an annual mortality incidence of between 3 and 10 per 100,000 has been reported (but as most snake bites occur in areas without consistent medical reporting, estimates are very imprecise).
Every species of snake native to Australia is venomous. These include tiger snakes (Notechis), brown snakes (Pseudonaja).

Snake Venom-Medicinal value

Snake Venom is a complicated substance. It was once believed that snakes have venom that is either hemotoxic or neurotoxic. It is now known that venom is not this simple. Most snake venom is composed of many types of compounds, primarily proteins and enzymes that effect the body in different ways. Thus, even a snake typically known as having only hemotoxic venom, most likely has some neurotoxic compounds as well.


Some common compounds found in snake venom include the list below:
1) Hyaluronidases-Catalyze reactions that break mucopolysaccharide links in connective tissues, thereby enhancing diffusion of venom-Several genera
2) Proteolytic enzymes-Catalyze the breakdown of structural components of tissues-All venomous species.
3) Phospholipases-Catalyze reactions that harm musculature and nerves-Almost all venomous species.
4) Proteases-Catalyze reactions that disrupt protein peptide bonds in tissues, causing blood vessel wall damage and hemorrhaging and muscle-fiber deterioration-Vipers and Pitvipers.
5) Thrombinlike enzymes-Inhibit blood clotting-Vipers, pitvipers, and a few rare elapids.
6) Peptide bradykinin potentiators-Enhancement of one of the body's natural responses to injury by dilating and increasing permeability of blood vessels, stimulates pain receptors and contracts some smooth muscles. This allows the venom to diffuse quickly into the bloodstream, increases bleeding and inhibits the ability to flee-Bothrops and Crotalus genera.
7) Polypeptide toxins-Disrupts nerve-impulse transmission, causing heart or respiratory failure-Mambas, Vipera, Crotalus, Bungarus, Naja, Laticaua, Hydrophis all with different types of toxin.
8) Nerve growth factor-Stimulates the growth of nerve cells-Agkistrodon, Crotalus.