Lecture 13 - Neurotoxicity Flashcards

Question

In silico neurotoxicity assessment: peripheral neuropathy

Answer 1

Various approaches; may be combined (e.g., ‘on-a-chip’; multi-electrode arrays): Functional readouts Electrophysiological recordings Live cell calcium imaging Live cell fluorescence imaging Neurotransmitter release Morphological readouts Dendritic spine morphology and density Neurite outgrowth and synapse density Cell viability Biomarkers of neurotoxicity There is also the option to knock-down receptor targets to investigate mechanism of action of drug-induced neurotoxicity.

Answer 2

Hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to non-noxious stimuli) are generally associated with sensory neuropathy (which takes >24 h to develop; e.g. paclitaxel).Examples of some tests used:

Answer 3

Irreversible organophosphate acetylcholinesterase inhibitors have been developed as chemical warfare agents. These are classified as weapons of mass destruction by the United Nations. All stockpiles of such agents were supposedly destroyed under a multilateral treaty in 1993. Clearly this didn’t happen, and these agents have made an unwelcome reappearance on the world stage in recent years.

Answer 4

The chemical warfare agents about to be described are potent, irreversible inhibitors of acetylcholinesterase, forming covalent bonds. Acetylcholine is the primary neurotransmitter in motor neurones to the skeletal muscles and diaphragm (released at the neuromuscular junction). Acetylcholine is also the primary neurotransmitter at ganglia (synapses) of the autonomic nervous system, which execute ‘unconscious’ functions (e.g., maintenance of smooth muscle tone, including in the cardiovascular system, airways, bladder, and gastrointestinal tract; heart rate; exocrine glands, etc., etc.). It is also the primary neuroeffector for the parasympathetic arm of the autonomic nervous system. Acetylcholine is also a neurotransmitter in the central nervous system. Acetylcholine also has non-neurotransmitter roles elsewhere in the body. Acetylcholine released by neurones is broken down by acetylcholinesterase; if this enzyme is inhibited, the consequences are widespread, and can be lethal.

Answer 5

All organophosphate agents (pesticides and chemical warfare agents) bind irreversibly to the esteratic site.

Answer 6

These are chemical warfare agents developed in Germany from 1936 (tabun) onwards (cyclosarin post-war in 1949). Tabun, sarin and soman were stockpiled but never used by the German military. Producing or stockpiling such agents was banned by the 1993 Chemical Weapons Convention. As of December 2015, most of the stockpiles had been destroyed.

Answer 7

Following World War II the USA and Soviet Union stockpiled these agents. In 1988 Iraq used sarin, cyclosarin and tabun in an aerial attack on Kurdish civilians in Halabja, killing 5,000 people. In 1994 a religious sect released sarin into the atmosphere in central Matsumoto, killing 7 people and affecting ~600 others. The following year, the same group released sarin on the Tokyo underground, killing 13 people. From 2013 onwards there were reports of use of sarin against civilians in the conflict in Syria.

Answer 8

VX is a chemical warfare agent developed in the UK in the 1950s (inadvertently, from a pesticide programme at ICI) VX is short for ‘Venomous Agent X’ More potent than sarin. It is readily absorbed via the skin. It was stockpiled by the USA, Soviet Union, Syria and North Korea. Stockpiles were ordered to be destroyed under a multilateral treaty in 1993. On 13 February 2017, Kim Jong-nam, half-brother of North Korean leader Kim Jong-un, died after a liquid containing VX was thrown in his face in Kuala Lumpur International Airport in Malaysia.

Answer 9

‘Novichok’ (‘newbie’) is a term applied to a series of nerve agents developed by the Soviet Union and Russia between 1971 and 1993. A fourth generation chemical warfare agent. May be a binary agent (synthesized in situ by mixing two safer precursors). Up to 8 times more potent than VX, and readily absorbed via the skin. On 04 March 2018, A-234 was used in an attack in Salisbury in an assassination attempt on former GRU officer Sergei Skripal and his daughter Yulia. They ended up on life support in intensive care but eventually recovered. A police officer (Detective Sergeant Nick Bailey) who attended became seriously ill and was also hospitalised. Large areas of the town had to be decontaminated. A total of 24 emergency services vehicles used had to be buried in landfill sites. A few weeks later, Charlie Rowley and Dawn Sturgess were found unconscious several miles from the Salisbury poisoning site. Dawn Sturgess died as a result of the poisoning. On 20 August 2020, the Russian opposition politician Alexei Navalny fell ill during an internal flight. He was hospitalised and ventilated after falling into a coma. After a few days he was allowed to be sent to Charité Hospital in Berlin for further treatment. They discovered he had been poisoned with Novichok.

Lecture 13 - Neurotoxicity Flashcards

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