Overcoming inhibitions.

O rganophosphorus 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. 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 of acetylcholine is ended by the enzyme acetylcholinesterase (AChE), which very rapidly hydrolyzes it to acetate ion and choline. The choline is then transported back into the nerve for reuse in the synthesis of acetylcholine. The rapid enzymatic hydrolysis of acetylcholine is important to maintain the fidelity of its signal, so anything that disrupts that process can have important consequences. In some circumstances, inhibition of AChE can have beneficial effects. For example, in the neuromuscular disease myasthenia gravis, an autoimmune response leads to a failure of the nicotinic acetylcholine receptors in the muscle, which results in inadequate signaling by acetylcholine and consequent muscle weakness. Because inhibition of AChE increases the amount and duration of acetylcholine available to stimulate the receptors that are still functional in the muscle, reversible inhibitors of AChE are useful for both diagnosis and treatment of the disease. Reversible AChE inhibitors also are useful for treating glaucoma, paralysis of the smooth muscle in the intestinal tract and urinary bladder; most recently, they have become a treatment for Alzheimer’s disease. Irreversible inhibitors of AChE, on the other hand, present a very different picture. Most of these inhibitors are organophosphorus chemicals developed initially in agriculture as pesticides in Germany in the 1930s. But their potential for use as weapons was soon realized, and by the end of World War II Germany had produced large stockpiles of the nerve agents soman, sarin, and tabun. Fortunately, these were never used. After World War II, both the U.S. and the Soviet Union manufactured large quantities of these agents and others, as well as the weapon systems to deliver them. Widespread use of these weapons by the postwar superpowers did not occur, but limited use of them by others has been documented. For example, Iraq used nerve agents with devastating effects during its war with Iran in the mid-1980s and again in 1988 against its own Kurdish population in northern Iraq. Moreover, in 1994 and 1995, sarin was used in two terrorist attacks in Japan, resulting in 19 deaths and hundreds of serious injuries, including injuries to those initially exposed and to emergency responders and hospital personnel providing treatment. In addition to these deliberate uses as weapons, accidental exposure of farm workers to organophosphorus agents used as pesticides occurs at an alarming rate worldwide, often, but certainly not exclusively, in developing countries (2, 3). Moreover, some of the pesticides sold for home and garden use contain organophosphorus AChE inhibitors, although their use is restricted and there have been long-running attempts to phase them out (4). The manifestations of acute poisoning with organophosphorus AChE inhibitors are largely predictable from the physiological changes brought about by acetylcholine acting on its receptors. These receptors are classified as nicotinic or muscarinic, based initially on the discovery of the natural alkaloids that shared with acetylcholine the ability to activate them (5) but now based on the genes that code for them or their substituent subunits. When AChE is inhibited, the actions of acetylcholine at its receptors and thus at the tissues innervated by cholinergic axons are magnified and prolonged. Excessive inhibition of AChE results in widespread combinations of symptoms due to overstimulation of the muscarinic receptors in the eye (miosis is often among the earliest signs), salivary glands, and smooth muscle of the digestive tract as well as bronchial airway constriction (6, 7). Heart rate would be expected to be markedly decreased by overstimulation of the muscarinic receptors in the heart, but bradycardia may be offset by the effects of hypoxia and generalized excitement that lead to increased heart rate (6). Prolongation of acetylcholine actions at the nicotinic receptors in the neuromuscular junction causes muscle twitching and fasciculation, weakness, and finally paralysis, including failure of the muscles of respiration (6, 7). In addition to these effects on the autonomic nervous system and neuromuscular junction, excessive inhibition of AChE depresses CNS respiratory centers, which appears to contribute to respiratory failure (6, 8), so death after acute exposure to AChE inhibitors is probably attributable to a combination of central and peripheral mechanisms. Seizures are another CNS manifestation