General Neuroscience

Drugs and Toxicology

Chiara Di Censo


Abstract

Drugs have always attracted human attention. Drugs have a central role in human evolution thanks to their therapeutic potential to help humans cope with illnesses and disease. However, drugs can also have very serious negative effects on health due to their capacities to influence human physiology. This article discusses the influences of several drugs on the fields of toxicology and medicine.

 

MPTP

     MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a molecule that can be produced through the synthesis of meperidine, more commonly known as MPPP. While MPPP is an opioid drug and shows the same properties as morphine, MPTP has no psychoactive effects despite being a potent neurotoxin. As a lipophilic drug, MPTP enters easily into the brain by passing through the Blood Brain Barrier, being later processed by MAO-B of glial cells into the cation MPP+. However, this compound is highly toxic to the  dopaminergic neurons in the pars compacta of the Substantia Nigra.

     As a major player in the progression of Parkinson's disease research, MPTP and its toxicity have been heavily investigated since its accidental synthesis in 1976. Barry Kinston, a chemical graduate student of Maryland, synthesized MPTP for the first time in 1976. Kinston attempted to produce MPPP, but a contamination led to MPTP synthesis. Barry injected himself with the manufactured substance, and within three days, had developed early Parkinsonian symptoms. This sparked a strong interest in the scientific community, where MPTP later became crucial in major developments in understanding the mechanisms behind Parkinson’s disease.

     Subsequently, MPTP’s Parkinsonian manifestations inspired further study into the mechanisms behind its neurotoxicity. In 1982, six young persons were diagnosed with Parkinson’s disease in Santa Clara County, California. The neurologist J. William Langston along with the NIH recognised the real cause of such common cases. All the patients had taken MPPP contaminated with MPTP, which generates Parkinsonian symptoms. The treatment with LevoDOPA helped mitigate the paralysis and tremors of PD. Despite the previous study on rats failing, Langstone wanted to test the substance on primates, in order to clarify the neurotoxic effects of MPTP. The neurologist found the relationship between the loss of dopaminergic neurons and the injection of MPTP, and subsequently published the results in the book The Case of Frozen Addicts.

 

Tetrodotoxin

     Tetrodotoxin (TTX) is a strong neurotoxin produced by pufferfishes so that they are easily able to break shells. However, triggerfish, ocean sunfish, some species of octopus, and several bacteria like Pseudoalteromonas and Pseudomonas carry tetrodotoxin. The substance was isolated for the first time by the Japanese scientist Yoshizumi Tahara in 1909, while in 1964 Toshio Narahashi and John Moore described the action mechanism of tetrodotoxin, using a particular technique called sucrose gap of voltage clamp.  

     Tetrodotoxin is approximately 100 times more effective than Potassium cyanide. The median  mice lethal dose is 334 µg per kg, whereas the lethal dose of box jellyfish venom reaches only 5 µg per kg. The toxic reaction occurs when tetrodotoxin is taken from ingestion, injection, or inhalation.

     The molecule blocks the voltage-gated sodium channel; as a result, sodium ions cannot flow into the cell membrane, and the action potential is disrupted. Tetrodotoxin acts on both the peripheral and central nervous system. The muscles are unable to receive the neural impulses so the victim who has taken tetrodotoxin is totally paralyzed. Moreover, the substance affects respiratory and vasomotor nuclei in medulla oblongata causing respiratory failure and hypotension. Early symptoms arise within about 20 minutes of ingestion. Victims experience paraesthesia of tongue and extremities, hyper-salivation, sweating, headaches, incoordination, tremors, paralysis, cyanosis, aphonia, dysphagia, and even seizures. Nausea, vomiting, diarrhoea, and abdominal pain can often occur and death due to respiratory failure is possible. Victims are often conscious before death and sometimes may even fall into a coma.

    Unfortunately, there is not an antidote capable of treating the toxic reaction from tetrodotoxin. Gastric lavage may be helpful for patients who have ingested a life-threatening dose of tetrodotoxin. In other cases, the patient needs controls of respiratory and cardiovascular system and glycaemia level.

 

Tetrodotoxin and Pop Culture

     Tetrodotoxin is also considered to have a role behind the myth of zombies. Between 1982 and 1984, Dr. Wade Davis conducted a study on TTX’s potential for creating zombies in Haiti. The doctor was particularly interested in the case of Clairvius Narcisse, who had been seen in a Haitian village after he was declared death. It turns out that Narcisse was poisoned from TTX, and although totally paralyzed, he remained conscious while he was being pronounced dead.

     After some research, Davis asserted that an obscure technique called bokor had the ability to create “zombies”. The bokor used a particular mixture of several substances such as natural toxins and tetrodotoxin. As a result, victims were paralyzed by TTX but remain conscious. Sometime they managed to survive to toxic reaction but appeared completely dead so doctors would declare them dead and proceed with burials. By then, presuming they had not been killed by the toxins,  the toxic effects wore off, and the victim would resume normal activity. This would, naturally, scare other villagers as they had just seen the victim pronounced dead.

 

Tetraethylammonium

     Tetraethylammonium (TEA) is a quaternary ammonium cation, commonly known for its blockage of voltage-gated K+ channels, the characteristic that determines its neurotoxicity. TEA inhibits autonomic ganglia, voltage-gated Ca2+ channels and nicotinic acetylcholine receptors as well. Because of its action on autonomic ganglia, TEA causes vasodilatation and represents an effective drug for treating serious peripheral vascular disease. However, the collateral toxic effects of the drug, such as death in some patients, have prevented this drug from becoming a commonly used therapy.

     Several studies on dogs and mice reported that TEA causes muscle paralysis through its action on neuromuscular junctions. As a result, when the diaphragm is affected, respiratory failure and even death may occur. In humans, typical symptoms from ingestion are a dry mouth and reduced gastrointestinal secretion and motility due to the inhibition of autonomic nervous system.

     Tetraethylammonium has a crucial utility for research in neuroscience. The molecule blocks specifically voltage-gated potassium channel, allowing neurosciences to study the real response of other ion channels. Furthermore, TEA can relieve symptoms of Parkinson’s disease by improving motor learning and reducing the progression of the disease.


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Chiara Di Censo

Chiara Di Censo


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