Overcoming inhibitions
- Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20057
Organophosphorus nerve agents and pesticides (Fig. 1) markedly increase the amount and duration of the action of acetylcholine at all of the synaptic sites where it acts, resulting in overstimulation of critical processes that can lead to incapacitation, muscle paralysis, and death. In a recent issue of PNAS, Albuquerque et al. (1) reported that a drug already in use for treating Alzheimer's disease provides remarkable protection against death and neuronal damage from exposure to some of the most potent nerve agents known.
The general structure of many organophosphorus compounds, which present a threat as nerve agents and in agricultural use as pesticides. All of these compounds have the potential to irreversibly inhibit AChE, which is crucial to normal acetylcholine neurotransmission.
Acetylcholine is a workhorse neurotransmitter. It does the heavy lifting at the neuromuscular junction, where motor axons signal our voluntary muscles to contract by releasing acetylcholine, and it signals the ganglia of our autonomic nervous system, which in turn regulate our blood pressure and heart rate, respiration, digestive processes, visual accommodation, crucial aspects of our sexual function, and other physiological processes. In many cases, these effects are triggered by the release of acetylcholine at the end organ. Acetylcholine even initiates the release of epinephrine from our adrenal glands to prepare us for self-preserving extraordinary activity (the “fight or flight” response). Moreover, acetylcholine is a fundamental neurotransmitter in the CNS, where it is critically involved in functions related to cognition and behavior, in some cases by modulating release of other neurotransmitters, including glutamate, GABA, norepinephrine, and dopamine.
The life cycle of acetylcholine, like that of all neurotransmitters, includes synthesis in cells that have the necessary specialized enzyme(s), release from those cells, activation of its specific receptors on the target tissues, and finally a mechanism to end its action. The action …
*E-mail: kellark{at}georgetown.edu
