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From Proteopedia

Botulinum Neurotoxin

Function

Clostridium botulinum is a rod-shaped, spore-forming bacteria that is highly pathogenic.^[1] These bacteria are prevalent in soils, sediments, and aquatic environments. The botulinum toxins decrease or prevent nerve function which leads to respiratory and muscular paralysis. The spores within the C. botulinum grow an abundance of active bacteria and transform into neurotoxins to produce or Botulinum Toxin. Botulinum Neurotoxin is one of the most toxic proteins known to exist.

Types of Botulinum Neurotoxins

Botulinum Neurotoxins A^{[2] [3]}is the first type of toxin to be introduced into the cosmetic world with the abbreviated name, Botox. Botox is mainly used for treating facial imperfections, muscle spasms, and other conditions like chronic migraines, dystonia, blepharospasms, diabetic neuropathy, spinal cord injury, epicondylitis incontinence, hyperhidrosis, and many more. The mechanism of action for type A: Consists of a heavy chain (100 kDa) and light chain (50 kDa) which are linked together by a single disulfide bond. It is a 150- kDa molecular weight protein that inhibits the release of acetylcholine by blocking the neuromuscular communications and transmissions on motor and sympathetic nerve terminals. The heavy chain binds at the pre-synaptic surface of cholinergic neurons. They bind one way and are irreversible. Endocytosis allows for the toxin receptor- complex to be sent into the cell after binding. The botulism toxin enters the cytoplasm after the disulfide bond between the two chains is broken. The light chain interacts with SNAP-25 (needed for binding/ attachment and release of ACH from vesicles) specifically at the nerve terminal to prevent binding of acetylcholine vesicles with the cell membrane. ^[4]

Produced through the process of fermentation to block acetylcholine release for the treatment of dystonia and sialorrhea. Mechanism of Action for Type B: Binds and cleaves VAMP- which is part of the protein complex that is known for docking and fusion of the presynaptic membrane to the synaptic vesicles.

Generates apoptotic cell death in cerebellar (area in the brain that is responsible for coordination and balance) neurons acting in birds mostly but can also be seen in some mammals and fish

Botulinum Neurotoxin type D: Causes a periodic onset of the fatal disease, botulism. This occurs mostly in horses and cattle and is rarely found in humans. The mechanism of action for Type D: Inhibits the discharge of TNF from monocytes.^[5]

Botulinum neurotoxin type D/C: Attaches and efficiently enters into the neurons that lack complex gangliosides. Complex glycosphingolipids are acidic glycosphingolipids that have sialic acid groups. Type D/C recognizes the sialic acid only but no other gangliosides' moieties.

Disease

There are four types of botulism that are associated with the bacteria, Clostridium botulinum. These include food, wound, infant, and inhalation botulism.

Food botulism includes toxins in food that have not been correctly processed and is often found in jarred, canned, or fermented food items. Symptoms include flaccid paralysis which leads to respiratory failure. Symptoms start as early as 12-36 hours and include fatigue, weakness, vertigo, blurred vision, dry mouth, difficulty swallowing, and speaking. Vomiting, diarrhea, constipation, and abdominal swelling may also occur. The disease can progress to the weakness of the neck and arms, after which the respiratory and lower body muscles are affected. There is no fever and no loss of consciousness.^[6]

Wound botulism is very rare, in an area that lacks oxygen/ anaerobic environment, the spores of the bacteria get inside the wounds and are able to reproduce. Symptoms of wound botulism are very simar to that of food botulism however, symptoms will appear around two weeks of exposure. This occurs in individuals who abuse drugs. ^[6]

Infant botulism occurs in patients who are under six months of age. Babies get this when they ingest C. botulism spores which evolve and germinate in the stomach region to produce toxins.​​ This does not occur in children over 6 months due to natural defenses in the intestines that develop over time. Children may exhibit symptoms of constipation, loss of appetite, weakness, altered cry, and a striking loss of head control.^[6]

Inhalation botulism is due to the inhalation of aerosolized botulinum toxin. Inhalation botulism is rare but the lethal dose is around 2 nanograms of toxin per kilogram of the human weight. After inhalation, the symptoms will begin to show after one to three days which leads to muscular paralysis and respiratory paralysis ^[6]

Treatment

How Botox is being used to treat migraines? A migraine is a severe headache that results in throbbing pain or a pulsing sensation on one side of the head. It can last from hours to days and is followed by multiple symptoms such as nausea, vomiting, and sensitivity to light and sound. In recent studies, it was found that Botulinum neurotoxins A or Botox is being used to stop migraine signals and leading factors that result in a migraine. A medical professional uses Botox to inject into seven specific areas around the head and surrounding the neck. Those areas include the forehead, bridge of the nose, temples, neck, back of the head, and above the shoulder blades in the upper back, leading to around thirty-one injections within each treatment. Typically a person with a migraine would get nearly 4 treatments per year.

How Botox is being used to treat cervical dystonia? This disease is also known by the name Spasmodic Torticollis, in which the neck muscles involuntarily contract. The neck contraction causes the head to twist or move to the side, and tilt forward/backward uncontrollably. Jerking movement could be chin toward the shoulder, ear toward the shoulder, chin straight up, chin straight down. Botox can be a temporary treatment by preventing the nerve signals that cause the spontaneous muscle spasms from getting to the dystonic muscles thus putting a stop to the involuntary spasms.^[7]

How Botox is being used to treat sialorrhea? Sialorrhea is the production of excessive saliva or the act of drooling involuntarily. This problem is mostly found in neurologically affected children such as cerebral palsy patients and in adults who have been diagnosed with Parkinson's disease. In some cases, excessive salivation may be present in patients who have had a stroke. This is most commonly caused by an inability to have full control of the oral and facial muscles. Botox is injected into the salivary glands to temporarily decrease saliva output. ^[8]

How is Botox used in the cosmetic world? A greater majority of the time, Botox is inserted into the skin via a syringe. Cosmetic procedures are the most common use of Botox applications. Once the liquid botox is inserted into the skin, the muscle contracts and is unable to move. Botox can be used for facial wrinkles, frown lines, forehead lines, top of the nose (bunny lines), etc. to improve or enhance facial features. ^[9]

Structural highlights

Consists of a which are linked together by a single disulfide bond. It is a 150- kDa molecular weight protein that inhibits the release of acetylcholine by blocking the neuromuscular communications and transmissions on motor and sympathetic nerve terminals. The heavy chain binds at the pre-synaptic surface of cholinergic neurons. They bind one way and are irreversible. Endocytosis allows for the toxin receptor- complex to be sent into the cell after binding. The botulism toxin enters the cytoplasm after the disulfide bond between the two chains is broken. The light chain interacts with SNAP-25 (needed for binding/ attachment and release of ACH from vesicles) specifically at the nerve terminal to prevent binding of acetylcholine vesicles with the cell membrane.

"Botulinum toxin is a that acts on vulnerable cells to cleave polypeptides that are essential for exocytosis"^[10] Botulinum toxin Type 1 or Botox contains two modules: the (residues 441-875) and the C-terminal receptor-binding domain ()^[11]

References

1. ↑ Lakna. (2018, July 16). Difference between spore-forming bacteria and non-spore-forming bacteria. Pediaa.Com. Retrieved April 27, 2022
2. ↑ Naumann M, Jankovic J: Safety of botulinum toxin type A: A systematic review and meta-analysis. Curr Med Res Opin. 2004 Jul;20(7):981-90. doi: 10.1185/030079904125003962. [Article]
3. ↑ Product Monograph: Botox (Clostridium botulinum type A neurotoxin complex ) powder for injectable solution [Link]https://pediaa.com/difference-between-spore-forming-bacteria-and-non-spore-forming-bacteria
4. ↑ Patil S, Willett O, Thompkins T, Hermann R, Ramanathan S, Cornett EM, Fox CJ, Kaye AD. Botulinum Toxin: Pharmacology and Therapeutic Roles in Pain States. Curr Pain Headache Rep. 2016 Mar;20(3)http://dx.doi.org/10.1007/s11916-016-0545-0
5. ↑ Pellett, S., Tepp, W. H., Scherf, J. M., Pier, C. L., & Johnson, E. A. (2015). The activity of botulinum neurotoxin type D (strain 1873) in human neurons. Toxicon: official journal of the International Society on Toxinology, 101, 63–69. https://doi.org/10.1016/j.toxicon.2015.04.015
6. ↑ ^{6.0 6.1 6.2 6.3} World Health Organization. (2018, January 10). Botulism. World Health Organization. Retrieved May 2, 2022, from https://www.who.int/news-room/fact-sheets/detail/botulism
7. ↑ Mayo Foundation for Medical Education and Research. (2021, September 3). Cervical dystonia. Mayo Clinic. Retrieved April 27, 2022, from https://www.mayoclinic.org/diseases-conditions/cervical-dystonia/symptoms-causes/syc-20354123
8. ↑ Oliveira, Ademar Francisco de Filho et al. “Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review.” Einstein (Sao Paulo, Brazil) vol. 14,3 (2016): 431-434. doi:10.1590/S1679-45082016RB3594
9. ↑ How botox® is injected. The Cosmetic Skin Clinic. (2021, November 2). Retrieved April 27, 2022, from https://www.cosmeticskinclinic.com/advice-centre/how-botox-is-injected
10. ↑ Simpson, L. L., Maksymowych, A. B., & Hao, S. (2001). The role of zinc-binding in the biological activity of botulinum toxin. The Journal of biological chemistry, 276(29), 27034–27041. https://doi.org/10.1074/jbc.M102172200
11. ↑ Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol. 1998 Oct;5(10):898-902.

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