Russian spy: Novichok. How does this nerve agent work?

Apparently, this week, the Russian government poisoned a former spy and his daughter using Novichok in the UK. As a response, many countries have decided to expel Russian diplomats. I was curious to know more about the nerve agent that was used in this poisoning, so I am writing a short post about the mechanism of action of Novichok.

Novichok acts on the cholinergic system. Acetylcholine (ACh) is involved in a diverse number of functions both in the central (CNS) and peripheral nervous system (PNS). In the PNS, acetylcholine is vital for muscular function because it is released by motor neurons at the neuromuscular junction to activate the muscles. In addition, acetylcholine works in the autonomic nervous system, which controls functions not consciously directed such as our breathing, heartbeat, and digestive system. In the CNS, acetylcholine is a neuromodulator that participates in cognitive functions (Fig. 1). Fun fact: cholinergic neurons die in the hippocampus in Alzheimer’s disease, so some drugs (e.g., galantamine) target AChE in order to increase acetylcholine and alleviate memory problems.

gr1
The major cholinergic pathways in the brain. Source: https://doi.org/10.1016/S0166-2236(98)01361-7

Novichok inhibits the enzyme acetylcholinesterase (AChE). This enzyme is responsible for the breakdown of the neurotransmitter acetylcholine. As a result, there is a build-up of ACh in our system. In the PNS, the muscles are hyperactivated because ACh depolarizes the postsynaptic muscle fibers and puts them in a sort of “pause” state because the cells enter a refractory period. Ultimately, the build-up of ACh leads to neuromuscular paralysis. Because we need muscles to breath, our breathing is messed up. Moreover, acetylcholine acts on a different type of receptors in the heart, which cause a decrease in the heart rate as ACh builds up. In the case of the CNS, the major result of ACh build-up is convulsions, loss of consciousness, and coma. Finally, our pupils’ size is modulated by acetylcholine. In fact, some antagonists of acetylcholine are used to dilate the pupils and make them look “pretty”. In this case, because Novichok increases acetylcholine, the pupils are constricted.

Novichok
Novichok inhibits the enzyme that breaks down acetylcholine (AChE). As a result, ACh builds up in the system. Source: https://www.ncbi.nlm.nih.gov/books/NBK11143/

The antidote for Novichok and other nerve agents is a combination of anticholinergic drugs. This type of drugs prevent acetylcholine from acting on its receptors, so they allow our system to recover from the toxicity of ACh build-up. Unfortunately, Novichok and other similar nerve agents are very potent and they act very fast. If you have ever seen an insect dying from an insecticide, you might understand how these nerve agents work. In fact, insecticides and pesticides use the same concept of attacking the cholinergic system to kill animals.

Final note: I think it is crazy how a single neurotransmitter can have such a drastic effect on our system. It’s almost like if it were our Achilles heel.

 

Further readings:

http://www.bbc.com/news/world-europe-43377698

https://www.ncbi.nlm.nih.gov/books/NBK11143/

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