Alzheimer disease cholinergic stimulants

Whitehouse PJ, Price DL, Clark AW, et al Alzheimer disease evidence for selective loss of cholinergic neurons in the nucleus basahs. Ann Neurol 10 122-126, 1981 Whitehouse PJ, Price DL, Struble RG, et al Alzheimer s disease and senile dementia—loss of neurons in the basal forebrain. Science 215 1237-1239, 1982 Whitehouse PJ, Hedreen JC, White CL, et al Basal forebrain neurons in dementia of Parkinson s disease. Ann Neurol 13 243-248, 1983 Whitehouse P, Martino A, Antuono P, et al Nicotinic acetylcholine binding sites in Alzheimer s disease. Brain Res 371 146-151, 1986 Whitehouse PJ, Martino AM, Marcus KA, et al Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 45 722-724, 1988 Whitton PS, Sama GS, O Connell MT The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal diasylates in vivo. Neuropharmacology 39 1-4, 1991 Whitworth P, Kendall DA Lithium selectively inhibits muscarinic receptor-stimulated inositol tetrakisphosphate accumulation in mouse cerebral cortex slices. J Neurochem 51 258-265, 1988... 

Mufson EJ, Cochran E, Benzing W, et al Galaninergic innervation of the cholinergic vertical limb of the diagonal band (Ch2) and bed nucleus of the stria terminahs in aging, Alzheimer s disease and Down s syndrome. Dementia 4 237-250, 1993 Muhlbauer HD The influence of fenfluramine stimulation on prolactin plasma levels in lithium long-term-treated manic-depressive patients and healthy subjects. Pharmacopsychiatry 17 191-193, 1984... 

The toxins that inhibit the AChE are called anticholinesterase (anti-ChE) agents. They cause acetylcholine to accumulate in the vicinity of cholinergic nerve terminals, and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems (Long, 1963). Nevertheless, several members of this class of compounds are widely used as therapeutics agents others that cross the blood-brain barrier have been approved or are in clinical trial for the treatment of Alzheimer s disease. 

In the 1950s, tacrine was used experimentally to reverse cholinergic coma in animals. In the 1960s, tacrine was used to reverse the effects of phencyclidinelike drugs. It was also marketed for many years as a respiratory stimulant. In 1993, the Food and Drug Administration approved tacrine for the treatment of symptoms of mild to moderate Alzheimer s disease. 

In the case of Alzheimer s disease, disease modifying therapy may involve therapeutic approaches designed to modify the basic pathogenetic mechanisms of AD. In particular, (3-amyloid appears to produce dysfunction of nicotine-stimulated release of acetylcholine and dopamine (Itoh et al., 1996) and other cholinergic dysfunction which can to some extent be ameliorated by nicotine administration (Maurice et al., 1996). It has been shown that nicotine may act to inhibit the deposition of -amyloid in vitro (Salomon et al., 1996) by impairing the aggregation of (3 42 peptide into p-pleated sheets. It appears that nicotine may bind to and stabilize the a-helical structure of the P-peptide. Nicotine appears to inhibit P-amyloid toxicity in rat cortical neurons (Kihara et al., 1997 Zamani et al.,... 

Tacrine (9-amino-1,2.3,4-tetrahydroacride hydrochloride hydrate) is a cholinesterase inhibitor of potential use in Alzheimer s disease, based on the ability to facilitate cholinergic function in the CNS via direct stimulation of M- and N-receptors through inhibition of AChE (Avery et al, 1997 Newhouse et uL, 1997). Since ACh plays a fundamental role in visual function (Famiglictti, 1983 Hutchins, 1987 Ross et al, 1985), and because some visual. symptoms and optic nerve degeneration occur in Alzheimer s disease patient-s (Hinton et al., 1986) and the decrease in ACh found in the CNS may also occur in the retina (Strenn et ai, 1991), it was considered appropriate by Alhomida et al, (2000) to investigate the effects of tacrine on human retinal AChE activity. In vitro studies on human retinal homogenates showed a concentration-dependent inhibition of AChE activity by tacrine, with an... 

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