Overcoming Inhibitions

COMMENTARY Overcoming inhibitions Kenneth J. Kellar* Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20057 rganophosphorus nerve weapons, accidental exposure of farm agents and pesticides (Fig. 1) workers to organophosphorus agents markedly increase the amount used as pesticides occurs at an alarming and duration of the action of rate worldwide, often, but certainly not Oacetylcholine at all of the synaptic sites exclusively, in developing countries (2, where it acts, resulting in overstimula- 3). Moreover, some of the pesticides tion of critical processes that can lead Fig. 1. The general structure of many organo- sold for home and garden use contain to incapacitation, muscle paralysis, and phosphorus compounds, which present a threat as organophosphorus AChE inhibitors, al- death. In a recent issue of PNAS, Albu- nerve agents and in agricultural use as pesticides. though their use is restricted and there querque et al. (1) reported that a drug All of these compounds have the potential to irre- have been long-running attempts to already in use for treating Alzheimer’s versibly inhibit AChE, which is crucial to normal phase them out (4). disease provides remarkable protection acetylcholine neurotransmission. The manifestations of acute poisoning against death and neuronal damage with organophosphorus AChE inhibitors from exposure to some of the most po- are largely predictable from the physio- tent nerve agents known. immune response leads to a failure of logical changes brought about by acetyl- Acetylcholine is a workhorse neuro- the nicotinic acetylcholine receptors in choline acting on its receptors. These transmitter. It does the heavy lifting at the muscle, which results in inadequate receptors are classified as nicotinic or the neuromuscular junction, where mo- signaling by acetylcholine and conse- muscarinic, based initially on the discov- tor axons signal our voluntary muscles quent muscle weakness. Because inhibi- ery of the natural alkaloids that shared to contract by releasing acetylcholine, tion of AChE increases the amount and with acetylcholine the ability to activate and it signals the ganglia of our auto- duration of acetylcholine available to them (5) but now based on the genes nomic nervous system, which in turn stimulate the receptors that are still that code for them or their substituent regulate our blood pressure and heart functional in the muscle, reversible in- subunits. When AChE is inhibited, the rate, respiration, digestive processes, hibitors of AChE are useful for both actions of acetylcholine at its receptors visual accommodation, crucial aspects diagnosis and treatment of the disease. and thus at the tissues innervated by of our sexual function, and other physio- Reversible AChE inhibitors also are cholinergic axons are magnified and logical processes. In many cases, these useful for treating glaucoma, paralysis of prolonged. Excessive inhibition of AChE effects are triggered by the release of the smooth muscle in the intestinal tract results in widespread combinations of acetylcholine at the end organ. Acetyl- and urinary bladder; most recently, they symptoms due to overstimulation of the choline even initiates the release of epi- have become a treatment for Alzhei- muscarinic receptors in the eye (miosis nephrine from our adrenal glands to mer’s disease. is often among the earliest signs), sali- prepare us for self-preserving extraordi- Irreversible inhibitors of AChE, on vary glands, and smooth muscle of the nary activity (the ‘‘fight or flight’’ re- the other hand, present a very different digestive tract as well as bronchial air- sponse). Moreover, acetylcholine is a picture. Most of these inhibitors are or- way constriction (6, 7). Heart rate would fundamental neurotransmitter in the ganophosphorus chemicals developed be expected to be markedly decreased CNS, where it is critically involved in initially in agriculture as pesticides in by overstimulation of the muscarinic functions related to cognition and Germany in the 1930s. But their poten- receptors in the heart, but bradycardia behavior, in some cases by modulating tial for use as weapons was soon real- may be offset by the effects of hypoxia release of other neurotransmitters, in- ized, and by the end of World War II and generalized excitement that lead to cluding glutamate, GABA, norepineph- Germany had produced large stockpiles increased heart rate (6). Prolongation of rine, and dopamine. of the nerve agents soman, sarin, and acetylcholine actions at the nicotinic The life cycle of acetylcholine, like tabun. Fortunately, these were never receptors in the neuromuscular junction that of all neurotransmitters, includes used. After World War II, both the U.S. causes muscle twitching and fasciculation, synthesis in cells that have the necessary and the Soviet Union manufactured weakness, and finally paralysis, including specialized enzyme(s), release from large quantities of these agents and oth- failure of the muscles of respiration (6, those cells, activation of its specific re- ers, as well as the weapon systems to 7). In addition to these effects on the ceptors on the target tissues, and finally deliver them. Widespread use of these autonomic nervous system and neuro- a mechanism to end its action. The ac- weapons by the postwar superpowers muscular junction, excessive inhibition tion of acetylcholine is ended by the en- did not occur, but limited use of them of AChE depresses CNS respiratory zyme acetylcholinesterase (AChE), by others has been documented. For centers, which appears to contribute to which very rapidly hydrolyzes it to ace- example, Iraq used nerve agents with respiratory failure (6, 8), so death after tate ion and choline. The choline is then devastating effects during its war with acute exposure to AChE inhibitors is transported back into the nerve for re- Iran in the mid-1980s and again in 1988 probably attributable to a combination use in the synthesis of acetylcholine. against its own Kurdish population in of central and peripheral mechanisms. The rapid enzymatic hydrolysis of ace- northern Iraq. Moreover, in 1994 and Seizures are another CNS manifestation tylcholine is important to maintain the 1995, sarin was used in two terrorist at- fidelity of its signal, so anything that tacks in Japan, resulting in 19 deaths disrupts that process can have important and hundreds of serious injuries, includ- Conflict of interest statement: No conflicts declared. consequences. In some circumstances, ing injuries to those initially exposed See companion article on page 13220 in issue 35 of volume inhibition of AChE can have beneficial and to emergency responders and hospi- 103. effects. For example, in the neuromus- tal personnel providing treatment. In *E-mail: [email protected]. cular disease myasthenia gravis, an auto- addition to these deliberate uses as © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606052103 PNAS ͉ September 5, 2006 ͉ vol. 103 ͉ no. 36 ͉ 13263–13264 Downloaded by guest on September 26, 2021 of AChE inhibition (6, 9). It is not clear becomes particularly important when use in Alzheimer’s disease, as a treat- whether these seizures are related to the organophosphorus compound in ment for organophosphorus exposure. overstimulation of acetylcholine pathways question is soman, because soman- In combination with atropine, galan- in the brain or are sequelae of hypoxia, inhibited AChE undergoes the aging tamine demonstrated higher efficacy but in their worst form they can lead to process in just minutes. than pyridostigmine in protecting guinea neuronal damage and contribute to death With that rationale in mind, pyri- pigs against the lethal effects of organo- and potentially to disability in the survi- dostigmine appears to be a logical addi- phosphorus AChE inhibitors. The pro- vors of exposure. tion as a pretreatment to prevent muscle tection by galantamine was demonstrated Acute exposure to organophosphorus paralysis. But pyridostigmine is a against the nerve agents soman and AChE inhibitors is treated with the charged, quaternary amine molecule sarin as well as against paraoxon, the that doesn’t cross the blood–brain bar- muscarinic receptor antagonist atropine active metabolite of parathion, an agri- rier, so it doesn’t protect the AChE in in sufficient doses to maintain block of cultural pesticide that only recently was peripheral and CNS receptors, with ben- the CNS. In fact, for many years, the use of reversible AChE inhibitors that phased out of use in the U.S. Perhaps zodiazepines to prevent convulsions, more remarkable, galantamine protected and with agents such as pralidoxime (2- guinea pigs even when administered 5 PAM), which can prevent the ‘‘aging’’ When acetyl- min after exposure to soman, the organ- process, during which organophosphorus ophosphorus agent that causes the fast- compounds phosphorylate the enzyme, cholinesterase is est aging of AChE. Another exciting rendering it irreversibly inhibited (6, 7). finding of these studies is that, although The half-time for this aging process var- atropine alone did not protect guinea ies from Ϸ2 min for soman to several inhibited, the actions pigs against soman-induced neurodegen- hours for other organophosphorus com- of acetylcholine at its eration in brain, galantamine in combi- pounds, including sarin and tabun [the nation with atropine did, even when compounds used in agriculture and receptors are magnified households cause less aging of AChE administered

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