The use of cholinomimetic drugs in the treatment of Alzheimer’s disease
In addition to the accumulation of senile plaques (abnormal beta amyloid containing proteins) and neurofibrillary tangles (modified microtubular associated proteins) which characterize the disease, the most consistent neuropathological finding in patients with Alzheimer’s disease is a degeneration of the projections from the main cholinergic cell body which comprise the nucleus basalis of Meynert. The degenerative changes involve the loss of M1 and M2 receptors and a reduction in the activity of choline acetyltransferase (CAT), the rate-limiting enzyme for the synthesis of acetylcholine. The reduction in CAT and the associated neuronal loss in the basal forebrain are the most consistent correlates of cognitive impairment seen in Alzheimer’s disease. The treatment strategies are primarily aimed at increasing cholinergic transmission. These include the centrally acting reversible inhibitors of acetylcholinesterase such as tacrine, donepezil, rivastigmine, galanthamine and metrofinate. Physostigmine has also been used but its efficacy and peripheral side effects have limited its widespread clinical use. Such drugs have beneficial effects in about 40% of patients; the patients show an improved score in several tests of cognitive function. However, even in those patients who do show some improvement following the administration of these drugs at an early stage in the development of the disease, the benefit is limited to approximately 18 months. Furthermore gastrointestinal side effects are often problematic. Nicotinic receptors Following studies of the actions of specific agonists and antagonists on the nicotinic receptors from skeletal muscle and sympathetic ganglia, it was soon apparent that not all nicotinic receptors are the same. The heterogeneity of the nicotinic receptors was further revealed by the application of molecular cloning techniques. This has led to the classification of nicotinic receptors into N-m receptors and N-n receptors, the former being located in the neuromuscular junction, where activation causes end-plate depolarization and muscle contraction, while the latter are found in the autonomic ganglia (involved in ganglionic transmission), adrenal medulla (where activation causes catecholamine release) and in the brain, where their precise physiological importance is currently unclear. Of the specific antagonists that block these receptor subtypes, and which have clinical applications, tubocurarine and related neuromuscular blockers inhibit the N-m type receptor while the antihypertensive agent trimethaphan blocks the N-n receptor. In contrast to the more numerous muscarinic receptors, much less is known about the function of nicotinic receptors in the brain. In addition totheir distribution in the neuromuscular junction, ganglia and adrenal medulla, nicotinic receptors occur in a high density in the neocortex. Nicotinic receptors are of the ionotropic type which, on stimulation by acetylcholine, nicotine or related agonists, open to allow the passage of sodium ions into the neuron. There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain. In Alzheimer’s disease it would appear that there is a selective reduction in the nicotinic receptors which contain the alpha 3 and 4 sub-units.Unlike the muscarinic receptors, repeated exposure of the neuronal receptors to nicotine, both in vivo and in vitro, results in an increase in the number of receptors; similar changes are reported to occur after physostigmine is administered directly into the cerebral ventricles of rats. These changes in the density of the nicotinic receptors are accompanied by an increased release of acetylcholine. Following the chronic administration of physostigmine, however, a desensitization of the receptors occurs. Functionally nicotinic receptors appear to be involved in memory formation; in clinical studies it has been shown that nicotine can reverse the effects of scopolamine on short-term working memory and both nicotine and arecholine have been shown to have positive, though modest, effects on cognition in patients with Alzheimer’s disease.
In addition to the accumulation of senile plaques (abnormal beta amyloid containing proteins) and neurofibrillary tangles (modified microtubular associated proteins) which characterize the disease, the most consistent neuropathological finding in patients with Alzheimer’s disease is a degeneration of the projections from the main cholinergic cell body which comprise the nucleus basalis of Meynert. The degenerative changes involve the loss of M1 and M2 receptors and a reduction in the activity of choline acetyltransferase (CAT), the rate-limiting enzyme for the synthesis of acetylcholine. The reduction in CAT and the associated neuronal loss in the basal forebrain are the most consistent correlates of cognitive impairment seen in Alzheimer’s disease. The treatment strategies are primarily aimed at increasing cholinergic transmission. These include the centrally acting reversible inhibitors of acetylcholinesterase such as tacrine, donepezil, rivastigmine, galanthamine and metrofinate. Physostigmine has also been used but its efficacy and peripheral side effects have limited its widespread clinical use. Such drugs have beneficial effects in about 40% of patients; the patients show an improved score in several tests of cognitive function. However, even in those patients who do show some improvement following the administration of these drugs at an early stage in the development of the disease, the benefit is limited to approximately 18 months. Furthermore gastrointestinal side effects are often problematic. Nicotinic receptors Following studies of the actions of specific agonists and antagonists on the nicotinic receptors from skeletal muscle and sympathetic ganglia, it was soon apparent that not all nicotinic receptors are the same. The heterogeneity of the nicotinic receptors was further revealed by the application of molecular cloning techniques. This has led to the classification of nicotinic receptors into N-m receptors and N-n receptors, the former being located in the neuromuscular junction, where activation causes end-plate depolarization and muscle contraction, while the latter are found in the autonomic ganglia (involved in ganglionic transmission), adrenal medulla (where activation causes catecholamine release) and in the brain, where their precise physiological importance is currently unclear. Of the specific antagonists that block these receptor subtypes, and which have clinical applications, tubocurarine and related neuromuscular blockers inhibit the N-m type receptor while the antihypertensive agent trimethaphan blocks the N-n receptor. In contrast to the more numerous muscarinic receptors, much less is known about the function of nicotinic receptors in the brain. In addition totheir distribution in the neuromuscular junction, ganglia and adrenal medulla, nicotinic receptors occur in a high density in the neocortex. Nicotinic receptors are of the ionotropic type which, on stimulation by acetylcholine, nicotine or related agonists, open to allow the passage of sodium ions into the neuron. There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain. In Alzheimer’s disease it would appear that there is a selective reduction in the nicotinic receptors which contain the alpha 3 and 4 sub-units.Unlike the muscarinic receptors, repeated exposure of the neuronal receptors to nicotine, both in vivo and in vitro, results in an increase in the number of receptors; similar changes are reported to occur after physostigmine is administered directly into the cerebral ventricles of rats. These changes in the density of the nicotinic receptors are accompanied by an increased release of acetylcholine. Following the chronic administration of physostigmine, however, a desensitization of the receptors occurs. Functionally nicotinic receptors appear to be involved in memory formation; in clinical studies it has been shown that nicotine can reverse the effects of scopolamine on short-term working memory and both nicotine and arecholine have been shown to have positive, though modest, effects on cognition in patients with Alzheimer’s disease.
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