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The Power & Poison of Acetylcholinesterase Inhibition (6)

To read the first article in this series, click here.

To read the previous article in this series, click here.

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As described above, the acetylcholinesterase enzyme that breaks down acetylcholine into acetate and choline is the target of the main medication prescribed to alleviate the symptoms of Alzheimer’s disease (AD) patients. In fact, it is the main medication prescribed to them broadly, since all the medical community can do for them presently is manage symptoms.


REVERSIBILITY


Acetylcholinesterase inhibitors are categorized as either reversible or irreversible inhibitors of the enzyme (and also competitive or noncompetitive, but we won’t get into that). They bind to the enzyme acetylcholinesterase and thus inhibit the hydrolysis of acetylcholine, leaving more acetylcholine in the brain. As Alzheimer’s disease patients lose cholinergic neurons as part of the disease progression, higher levels of acetylcholine allow them to better use the neurons that they still have. This yields marginally better cognition.


Irreversible acetylcholinesterase inhibitors phosphorylate the acetylcholinesterase enzyme permanently[1], causing acetylcholine to build up to toxic levels in the nervous system. They lead to a cholinergic crisis involving paralysis and death by asphyxiation, as the afflicted are not able to control muscles involved in breathing. The main classes of man-made irreversible inhibitors are insecticides (e.g. malathion and diazinon[2]) and nerve gasses (e.g. VX and Sarin gas[3]).


HITLER AND SHOKO ASAHARA


Sarin gas, named after the German scientists Gerhard Schrader, Otto Ambros, Gerhard Ritter, and Hans-Jürgen von der Linde, was produced extensively by Nazi Germany during WWII[4]. Despite the lobbying of his staff, Hitler refused to use it on the Allied forces[5]. Historians understand this peculiar compassion to be due to Hitler’s own experience suffering a chemical weapon attack from the British while he served Germany in WWI[6]. Unlike Hitler, members of the Japanese doomsday cult Aum Shinrikyo, led by the self-declared Christ Shoko Asahara[7], took less issue with the weapon. Famously, they used the irreversible acetylcholinesterase inhibitor in the 1995 Tokyo subway attacks that killed over a dozen people and injured thousands of others[8][9].


Thankfully, reversible acetylcholinesterase inhibitors are much less dangerous. Along with Alzheimer’s, they have been used to treat the cognitive impairments associated with paranoid schizophrenia, Parkinson’s disease, Tourette syndrome, and senile dementia. They are also used to induce lucid dreaming[10][11] and play a prominent role in traditional Eastern medicine.


To continue to the next blog post in this series, click here.

To return to an overview of the blog series on the cholinergic system, click here.

[1] Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology, 11(3), 315-335. [2] Sparling, D. W., & Fellers, G. (2007). Comparative toxicity of chlorpyrifos, diazinon, malathion and their oxon derivatives to larval Rana boylii. Environmental Pollution, 147(3), 535-539. [3] Singh, M., Kaur, M., Kukreja, H., Chugh, R., Silakari, O., & Singh, D. (2013). Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. European Journal of Medicinal Chemistry, 70, 165-188. [4] Yanagisawa, N. (2014). The nerve agent sarin: history, clinical manifestations, and treatment. Brain and nerve= Shinkei kenkyu no shinpo, 66(5), 561-569. [5] Ono, R. S. (2014). The Secret Weapons of World War II: An Analysis of Hitler's Chemical Weapons Policy. [6] Ullrich, V. (2014). Adolf Hitler. Singel Uitgeverijen. [7] Asahara, S. (1992). Declaring Myself the Christ: Disclosing the True Meanings of Jesus Christ's Gospel. Aum Publishing Company. [8] Beaton, R., Stergachis, A., Oberle, M., Bridges, E., Nemuth, M., & Thomas, T. (2005). The Sarin gas attacks on the Tokyo subway-10 years later/Lessons learned. Traumatology, 11(2), 103-119. [9] Masuda, N., Takatsu, M., Morinari, H., Ozawa, T., Nozaki, H., & Aikawa, N. (1995). Sarin poisoning in Tokyo subway. The Lancet, 345(8962), 1446-1447. [10] Baird, B., Mota-Rolim, S. A., & Dresler, M. (2019). The cognitive neuroscience of lucid dreaming. Neuroscience & Biobehavioral Reviews. [11] LaBerge, S., LaMarca, K., & Baird, B. (2018). Pre-sleep treatment with galantamine stimulates lucid dreaming: A double-blind, placebo-controlled, crossover study. PloS one, 13(8).

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