Analgesic Properties of …. Snail Venom?

I know what you’re probably thinking; snails have venom? This was exactly what I had thought when I came across a post on the popular social media website, Reddit. I was intrigued because I didn’t even know that snails have venoms and that they could even be used as painkillers. Turns out, the post wasn’t referring to the typical snails you find in a garden, but instead, the cone snails that are typically found in warm and tropical seas and oceans. Interested by the topic, I decided to investigate more on how exactly the snail venom can act as an analgesic, and its possible significance in the medical field.
Analgesics are commonly known as painkillers, and are divided into two types, mild and strong. Mild analgesics, such as aspirin and paracetamol, are used to treat the typical headaches, toothaches, or sore throats by, “preventing the stimulation of nerve endings at the site of pain and by inhibiting the release of prostaglandins, the chemical responsible for the widening of blood vessels near the site of the injury, from the site of injury to provide relief to inflammation, fever and pain” (Brown, Ford, 2008). For more severe pains, strong analgesics bind to opioid receptors in the brain to alter the perception of pain by blocking the transmission of pain signals between brain cells (Brown, Ford, 2008). Today, many cancer patients, diabetic patients, and other victims of chronic pain are treated with strong analgesics like morphine and heroine. The problem is that these opioids are highly addictive and repeated usage can lead to tolerance, which a reduced response to the drug. Scientists have discovered that the venom found in cone snails have analgesic properties that are 10000 times more powerful than morphine, and the best part about the venom is that it is not addictive. (National Geographic, n.d.) Since cone snail venom is clearly a better analgesic than opioids, I questioned why isn’t it replacing morphine and heroine as the common analgesics to treat victims with chronic pain?
deadly cone

Figure 1: Image of a Marble Cone Snail (National Geographic, (n.d.))

Although they are only about four to six inches long, these carnivorous mollusks they have venoms poisonous enough to kill 15 adult human beings (Compassionate Healthcare Network, 2004). To do this, the cone snails have teeth that are similar to hypodermic needles that inject venom into their preys. The venom instantly paralyzes the victims by interfering with the communications of the nervous systems. In a typical nervous system, the neurons transmit chemical signals to another neuron through ion channels. The chemical signals are repeatedly transmitted from neuron to neuron until it reaches a muscle cell and tells it to contract. The venom of cone snails contain hundreds of thousands of short polypeptide proteins that blocks specific ion channels to prevent neurons from transmitting chemical signals, inhibiting muscle movement, leading to paralysis (Chadwick, 2013)(Discovery News, 2013).
So how can something so deadly be beneficial to humans? For many years, scientists have studied several hundreds of the short polypeptide proteins, called conotoxins, before the isolating analgesic conotoxin agent and creating the synthetic version named Ziconotide, or often known by the name Prialt. Unlike other analgesics, Ziconotide inhibits pain in a different way. People feel pain because electrical signals are carried across a synapse from the pain fibers to the nerve cells in the spinal cord that signals the brain. In order for the electrical signals to cross the synapses, electrical signals has to be converted into a chemical signal with the help of calcium. Ziconotide blocks the calcium gateways in the nerve fibers so that the chemical signals cannot cross the synapse to reach the nerve cells in the spinal cord. As a result, the brain does not receive the signal and therefore, one does not perceive pain (Compassionate Healthcare Network, 2004).
Although Ziconotide is 10000 times more powerful than morphine and is non-addictive, it is not commonly use to treat patients with chronic pain. This is because like any other drug, Ziconotide comes with many side effects such as abnormal vision, amnesia, vertigo, anxiety and possibly more undiscovered side effects. Furthermore, ziconotide cannot be administered orally because the body will break down the swallowed ziconotide before it can reach the receptors they need to reach. Therefore, zinconotide is currently administered with a direct injection into the spinal cord, a costly and invasive method of drug delivery.
107452-89-1

Figure 2: Structure of Ziconotide (ChemBlink, (n.d.))

The discovery of Ziconotide has many implications in the medical field. Firstly, future research can be synthesized or modified Ziconotide to withstand the digestive processes of the body so that zinconotide can be taken more conveniently and without economic strain. In fact, scientists have already engineered a circular shaped synthetic Ziconotide conotoxin that is more stable to be administered orally (Discovery News, 2013). Ziconotide that can be administered orally will be more accessible to patients with chronic pain that have developed tolerance to morphine and heroine and need stronger analgesics to suppress the pain. Secondly, the discovery of Ziconotide suggest a bigger picture that many medical issues that people face today could possibly be cured by something in nature. There are so many microorganisms, animals and plants on Earth that have not yet been discovered. Perhaps, the secret to the cures of cancer and other illnesses lie in the Amazon jungle or at the bottom of the Mirana Trench.

References:
Brown, C., Ford, M. (2008). Higher Level Chemistry Developed Specifically for
the IB Diploma. England: Pearson Education Limited.

Chadwick, A. (2013). Venom. The Cone Snail. Retrieved September 5, 2013, from
http://www.theconesnail.com/explore-cone-snails/venom

Compassionate Healthcare Network. (2004). Cone Snail Venom Attacking Pain.
Compassionate Healthcare Network. Retrieved September 5, 2013 from http://www.chninternational.com/cone_snail_venom_attacking_pain.htm

Discovery News. (2013, February 11). Snail Venom Inspires Powerful Pain
Reliever. Discovery News. Retrieved September 5, 2013, from http://news.discovery.com/human/snail-venom-painkiller.htm

National Geographic. (n.d.). Geographic Cone Snail. National Geographic.
Retrieved September 5, 2013, from http://animals.nationalgeographic.com/animals/invertebrates/geographers-cone-snail/

Marble Cone Snail [Web Graphic]. (n.d.) Retrieved September 5, 2013 from http://lhs204.stellpflug.com/Period%202/Canutito%20Payan/Marble%20cone%20snail.html

Wikipedia. (n.d.). Conus. Wikipedia. Retrieved September 5, 2013 from
http://en.wikipedia.org/wiki/Conus

Wikipedia. (n.d.). Zinconotide. Wikipedia. Retrieved September 5, 2013 from
http://en.wikipedia.org/wiki/Ziconotide

Ziconotide Acetate [Web Graphic]. (n.d.). Retrieved September 5, 2013 from http://www.chemblink.com/products/107452-89-1.htm

2 thoughts on “Analgesic Properties of …. Snail Venom?

  1. When reading Timothy’s blog post about the analgesic properties of snail venom, I enjoyed noting another of the many unusual places which medicine is derived from. It reminded me of my experiences as a member of an expat family. Due to this, I have been subject to the joy of multiple vaccinations. In particular, when I lived in Japan, it was required for me to have the vaccination for Japanese Encephalitis. This has always stuck in my mind. The reason for this is because my loving parents, in an unsuccessful effort to pacify my dislike for vaccinations, told me that the fluid consisted of pulverized mouse brain. As I had thought, who would have searched for snail venom, I had always wondered how the cure had been found in mouse brain of all places. Therefore I decided to make this the focus of my research. This blog post aims to answer the question: To what extent is the mouse brain based vaccine for Japanese Encephalitis effective?

    Japanese encephalitis (JE) virus is a single-stranded RNA virus and is closely related to viruses such as the West Nile and Saint Louis encephalitis viruses (Hills, Weber & Fischer, n.d.). The transmission of the JE virus is through the infected bite of a Culex mosquito (Hills, Weber & Fischer, n.d.). Due to the difficulty of applying preventative measures, there are an estimated 35,000–50,000 annual cases, in which approximately 20%-30% of patients die, while 30%–50% of survivors have neurologic or psychiatric sequelae (a condition that is the consequence of a previous disease or injury) (Fischer, Lindsey, Staples & Hills, 2010). In order to target this, my family chose to use the inactivated mouse brain derived JE Vaccine (JE-MB). However, while researching I noted that there were now two JE vaccines; the inactivated mouse brain–derived vaccine (JE-MB) and an inactivated Vero cell culture-derived vaccine (IXIARO [JE-VC]). I became interested as to how this related to the effectiveness of the vaccine I had taken in 2001 before IXIARO was available (Fischer, Lindsey, Staples & Hills, 2010).

    First I decided to look at how the vaccine was prepared. “JE-MB is an inactivated vaccine prepared by inoculating mice intracerebrally with the JEV Nakayama-NIH strain” (Fischer, Lindsey, Staples & Hills, 2010). Thimerosal is added as a preservative and is shown below in Figure 1

    http://upload.wikimedia.org/wikipedia/commons/3/3a/Thiomersal-Skeletal-Structure-SVG.svg

    Figure 1: Thiomersal Skeletal Structure

    Thimerosal is a mercury-containing organic compound, around 50% mercury in weight. This made me wonder how safe the vaccine could be if it contains mercury which has theoretical potential for neurotoxicity (Food and Drug Administration, n.d.).” Thimerosal in concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000) has been shown to be effective in clearing a broad spectrum of pathogens” (Food and Drug Administration, n.d.). However, with further research I noted that the total concentration of thimerosal amounted only to 0.007%, a relatively safe level for vaccine use.

    Then why were there two vaccines available for Japanese encephalitis? In what way was JE-VC superior to JE-MB? I discovered with further reading that the post-marketing surveillance carried out by the Chinese Centre for Drug Evaluation during 2009–2012 indicated 6024 adverse events following immunization (AEFI) (Fischer, Lindsey, Staples & Hills, 2010). “The JE-MB vaccine has been associated with serious yet rare AEFI’s such allergic hypersensitivity reactions. Due to this, JE-VC was licensed on the basis of its ability to induce JEV-specific neutralizing antibodies, which is thought to be a reliable method and has a much less significant frequency of adverse AEFI’s (Fischer, Lindsey, Staples & Hills, 2010; World Health Organization, n.d.). It became apparent that this question was more convoluted than it seemed when looking at the age of the recipient. A report stated that the JE-MB vaccine was recommended for travelers aged ≥1 year. “However, in March 2009, the FDA approved a new inactivated Vero cell culture-derived JE vaccine (JE-VC) for people over the age of 17 years.” (Fischer, Lindsey, Staples & Hills, 2010). Although the JE-VC vaccine is the safer alternative in terms of adverse side-effects, JE-MB remains the only JE vaccine approved for use in children in the United States.

    Therefore, to answer the question: to what extent is the mouse brain based vaccine for Japanese Encephalitis effective, we must look at multiple age perspectives. It is clear that the JE-VC vaccine is superior in terms of safety due to its lack of side effects and traces of mercury; nevertheless the age restrictions deem that for children under the age of 17, the JE-MB vaccine is the safer choice. The broader implications of this are that as there are still flaws in the two vaccines available, there is still room for scientific research into a safer vaccine, thus decreasing the mortality rate. If a cure can be found in mouse brains and snail venom, scientists should definitely continue to look in strange places.

    References

    Fischer, M., Lindsey, N., Staples, E. & Hills, S. (2010). Morbidity and Mortality Weekly Report (MMWR). Center for Disease Control and Prevention. Retrieved from http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5901a1.htm

    Food and Drug Administration. (n.d.) U.S. Food and Drug Administration: Protecting and Promoting Your Health. U.S. Department of Health & Human Sciences. Retrieved from http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228

    Hills, S., Weber, I. & Fischer, M. (n.d.) Chapter 3: Infectious Diseases Related To Travel. Center for Disease Control and Prevention. Retrieved from http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/japanese-encephalitis

    World Health Organization. (n.d.). Safety profile of Japanese encephalitis vaccines. World Health Organization. Retrieved from http://www.who.int/entity/vaccine_safety/committee/topics/japanese_encephalitis/Jun_2013/en/index.html

  2. Lately, my mom has made me to eat worms in order to cure my aggravated asthma. However, these aren’t just any normal worms, they are a larva of ghost moth that has been infected and killed by the fungus Ophiocordyceps sinensis. According to Tibetan legend, they have amazing healing properties and have been “known” to cure things such as asthma and even cancer and give increased energy and endurance. Needless to say, I didn’t believe my mom at first, everyone knows that as of yet cancer is incurable and the same goes for my asthma. I was determined to prove her wrong so I went online to find all of the credible sources that I could to enlighten her. Strangely enough, I found that there was great scientific interest in this worm that I was about to ingest and I remembered another super wacky story coming from Tim’s blog post about the analgesic properties of a venomous Snail. So I wanted to dig deep into the background of this worm and exactly how this worm was supposed to cure my incurable “asthma”.

    What I first found and heard from my mom about these worms was extremely bizarre. They are only found in the highlands of Tibet within the altitudes of 3,000m and 5,000m above sea level. Another thing was that the parasitic fungus O. Sinensis actually germinates inside of the living larva, killing it and leaving only the exoskeleton intact. Then, come spring a brown stalk called the stroma “erupts” from the larva’s head, killing it. Thus tricking the Tibetans into calling it “summer grass, winter worm”. Even more strange is that all attempts at farming this fungus have failed, meaning that this fungus can only be found in tibet. (Finkel M, 2012)

    Although this was all very impressive, I wanted to know exactly what inside of this O. Sinensis was and how it interacted on our bodies. First of all, the method of taking this medicine is to boil the worms in hot water, essentially creating a “tea” then drinking the tea and chewing and consuming the worm, stalk and all. According to an investigative study by Xiao. LW & Yi JY, O. Sinensis contains an active ingredient called Cordycepin. From my prior knowledge, I can deduce that Cordycepin has a number of functional groups. Two alcohol groups (-OH), 1 primary Amine group (R-NH2) and one ether group (R-O-R). It has a non-polar shape and alcohol groups so it is probably soluble in water, which leads me to believe that this could be a reason as to why my mom boils it in water first. However that is just my own speculation. According to Traditional Chinese medicine, Cordycepin is “believed” but not proven, to nourish the lungs and kidney’s. However, more recent and quantitative studies have shown that cordycepin does have many pharmacological effects such as: immunomodulating (an adjustment of the body’s immune response to be either suppressed or excited), hypocholesterolemic, hypoglycemic (an agent that lowers blood glucose levels, associated with diabetics), anti-tumor, anti-oxidation and anti-aging activities. Probing deeper, I discovered a study that investigated how cordycepin interacted inside of our bodies. According to Wong YY et al. 2009, corycepin is also known as 3’-Deoxyadenosine, a polydenylation inhibitor. Polydenylation is the addition of a poly(A) tail to a primary transcript RNA, the purpose of the poly(A) tail is to protect the mRNA molecule from enzymatic degradation in the cytoplasm. Like the term “polydenylation inhibitor” suggests, corcycepin inhibits the polydenylation process by reducing the length of poly(A)tails. The study did not state any correlation between this property and the previously stated pharmacological effects, suggesting that we know relatively little about corycepin. The study stated many more bodily interactions of corycepin however at my current level I am unable to understand them.

    Picture 2: http://en.wikipedia.org/wiki/File:Cordycepin.svg
    Skeletal structure of Cordycepin, active ingredient in O. sinesis.

    When I read through the long list of pharmacological effects that Cordycepin had on our bodies, I was stunned. Mom was right again. The medical and health implications of this are big. It demonstrates hypoglycemic properties that could be used to help out type 1 diabetics. Anti-tumor properties? That will help with cancer patients. Anti-oxidation and anti-again activities? Who doesn’t want to look younger? The economic implications are also significant, as more and more people (like myself) are starting to hear about this miracle remedy, the market for these worms has increased exponentially. According to Barbara Demick of the LA times, in the year 2007 china exported $43 million worth of the larva fungus and is enabling the relatively poor Tibetan nomads to earn a larger wage and to live a more comfortable lifestyle. However, a recent investigation by Elizabeth Snouffer shows that over-farming of these worms is increasing and that in 10 years time, there might not be any more Golden worms to eat anymore. I am personally excited for the increased research going into the use and function of Cordycepin, all of the claimed health benefits sprouting from this larva could maybe one day tackle many of the deep health problems we face today.

    References List:

    1.Finkel, M. (2012). Tibetan Gold. Retrieved Jan 22 from: http://ngm.nationalgeographic.com/2012/08/tibetan-mushroom/finkel-text

    2. Xiao, LW.,Yi, JY. (2011). Host insect species of Ophiocordyceps sinensis: A review. Retrieved Jan 21 from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175130/

    3. Demick, B. (2008). In Tibet, a worm worth its weight in gold. Retrieved Jan 22 from: http://www.latimes.com/news/nationworld/world/asia/la-fg-worm27-2008jun27,0,1106221.story#axzz2r1uhkkaj Barbara Demick

    4. Snouffer, E. (2013) Parasitic caterpillar fungus in decline. Retrieved Jan 22 from: http://www.scmp.com/lifestyle/health/article/1197235/parasitic-caterpillar-fungus-decline

    5. Wong YY, et al. (2009). Cordycepin Inhibits Protein Synthesis and Cell Adhesion through Effects on Signal Transduction. Retrieved Jan 21 from: http://www.jbc.org/content/285/4/2610.full

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