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Mechanism of action of cholinesterase inhibitors in Alzheimer's disease.

Cholinesterase inhibitors, such as physostigmine and tacrine, have lately gained interest as potential drugs in the treatment of Alzheimer's disease. Already in the 1950s, it was discovered that physostigmine and tacrine were potent inhibitors of acetylcholinesterase and butyrylcholinesterase. However, later studies have shown that cholinesterase inhibitors also interact with cholinergic receptors, with sodium and potassium ion channels and effect the uptake, synthesis and release of neurotransmitters. In summary, cholinesterase inhibitors are drugs with many modes of action, which may be of advantage in the treatment of a complex disorder such as Alzheimer's disease.

Acetylcholine↗

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia.

OBJECTIVE: To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). METHOD: MEDLINE (1966--December 2004), PsychINFO (1972--December 2004), EMBASE (1980--December 2004), CINHAL (1982--December 2004), and the Cochrane Collaboration were searched in December 2004. RESULTS: Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. CONCLUSION: Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms--in particular tremor--may limit the utility of cholinesterase inhibitors.

Aged↗

The relationship between cholinesterase inhibition in the chick biventer cervicis muscle and its sensitivity to exogenous acetylcholine.

The effect of physostigmine has been studied on cholinesterase in homogenates of chick biventer cervicis muscles and on the contractile responses of the intact muscles to acetylcholine and carbachol. The concentration of physostigmine required to produce the maximum increase in sensitivity to acetylcholine almost completely inhibited the cholinesterase in muscle homogenates. This concentration of physostigmine had no effect on muscle contractures elicited by carbachol. By taking account of the combined effects of acetylcholine diffusion and enzymic hydrolysis, a quantitative theoretical relationship has been derived between the level of cholinesterase activity in cylindrical muscles and the fractional occupancy of the acetylcholine receptors in these muscles in the presence of different concentrations of exogenous acetylcholine. This theory attributes the thousand-fold increase in sensitivity to exogenous acetylcholine produced by anticholinesterases in chick biventer cervicis muscles largely to an alteration in acetylcholine concentration gradient within the muscle and accounts satisfactorily for the shift in the dose-response curve for acetylcholine which occurs after treatment of the muscles with various concentrations of physostigmine.

Acetylcholine↗

The effects of neostigmine on the response of the rat anococcygeus muscle to field stimulation are not a consequence of cholinesterase inhibition.

Neostigmine (5 X 10(-7) to 5 X 10(-6) M) and physostigmine (10(-5) M) each augment the responses of the rat anococcygeus muscle to field stimulation whereas iso-OMPA (5 X 10(-6) to 5 X 10(-4) M) or BW 62c47 (5 X 10(-7) to 5 X 10(-5) M) do not. At a concentration of 10(-5) M, neostigmine. BW 62c47 and iso-OMPA respectively produced a 48, 50 and 68% inhibition of cholinesterase activity in homogenates of anococcygeus muscle. The ED50 for cholinesterase inhibition by neostigmine (1.4 X 10(-5) M) is approximately 15 fold greater than the ED50 for the augmentation of the response to field stimulation (9.5 X 10(-7) M). It is concluded that the action of neostigmine in augmenting the response of the rat anococcygeus muscle to field stimulation is not a consequence of cholinesterase inhibition even though stimulation of muscarinic receptors is implicated.

Animals↗

A quantitative study of cholinesterase in myoneural junctions from rat and guinea-pig extraocular muscles.

1. Cholinesterase staining of rat and guinea-pig extraocular muscle shows focally and multiply innervated fibres.2. The distribution of cholinesterase activities in the populations of focal endings (from singly innervated fibres) and fine motor endings (from multiply innervated fibres) was determined by a sensitive radiochemical method.3. Focal endings had a greater cholinesterase activity than fine motor endings.4. It is suggested that this difference in enzyme activities is related to the functional difference between twitch and slow fibres in extraocular muscle.

Animals↗

E1j, a quantitative variant at cholinesterase locus 1: immunological evidence.

Sera of various phenotypes at serum cholinesterase locus 1, including the newly recognized phenotypes E1 aE1j, E1 uE1j, and E1 fE1J, were studied by immunodiffusion and rocket immunoelectrophoresis. The sera containing the E1j allele show reduced numbers of immunologically active cholinesterase molecules. This finding is consistent with the previously advanced hypothesis that E1j results in reduced numbers of circulating 'usual' (E1u) molecules. Whether this reduction is the result of the low rate of synthesis or of an increased rate of degradation of the cholinesterase remains to be determined.

Alleles↗

Predicting the outcome of cholinesterase inhibitor treatment in Alzheimer's disease.

OBJECTIVE: To investigate the possibility that response to cholinesterase inhibitor therapy could be predicted by easily measurable variables that are known to change as a result of treatment (such as the Mini Mental State Examination), measures of function (such as the instrumental activities of daily living and the social behaviour subscales of the Nurse's Observation Scale for Geriatric Patients), and measures of attention (such as the Digit Symbol Substitution Test; DSST), or that might influence response through structural (for example, age, cerebrovascular disease, medial temporal lobe (MTL) atrophy, hypertension) or chemical (for example, smoking) mechanisms. METHOD: This was a cohort study of 160 consecutive outpatients with probable Alzheimer's disease who commenced cholinesterase inhibitor treatment over a 3 year period in a semi-rural area of Scotland. RESULTS: The overall response rate was 42.1%. Stratification of response between good and poor responders was possible using baseline DSST and a measure of MTL thickness using CT. Among the patients, 60.4% of those above the cut off point for both DSST and MTL thickness (29/48 subjects) were classified as good responders, compared with 6.3% of subjects below the cut off point for both (1/16 subjects). Subjects above the cut off point for both measures were more likely to be classified as good responders than subjects with only one or no values above the respective cut off points (chi(2) = 10.61, df = 1, p = 0.001) CONCLUSIONS: The DSST and a measure of MTL thickness derived from CT scanning may be useful in improving the prediction of response to cholinesterase inhibitors in subjects with AD. Subjects with low DSST scores and more severe MTL atrophy are unlikely to respond to treatment. These preliminary data justify a prospective trial of the usefulness of our suggested predictive measures.

Activities of Daily Living↗

Enhanced heart rate variability and baroreflex index after stress and cholinesterase inhibition in mice.

Experiments tested the effect of stress coupled with cholinesterase inhibition on blood pressure, heart rate, baroreflex index, and variability in time and frequency domain in conscious mice. The objective was to determine whether cholinergic systems interact with stress to alter cardiovascular responses. Male C57BL/6J mice with arterial catheters were exposed to 3-day treatments: 1) intermittent shaker stress, 2) pyridostigmine (10 mg.kg(-1).day(-1)); or 3) combined pyridostigmine and stress. Pyridostigmine reduced blood cholinesterase (-33%) with no added effects of stress. Twenty-four-hour blood pressure recordings showed that there were no differences in blood pressure and heart rate with the treatments. Pulse interval standard deviation was greatly increased in the pyridostigmine/stress group compared with stress or pyridostigmine groups (11.0 +/- 1.4, 5.0 +/- 0.9, and 7.5 +/- 0.9 ms, respectively). Spectral analysis showed two distinct components for pulse interval variability (low and high frequency). Variability in the low-frequency range was greatly enhanced in the pyridostigmine/stress group, seen as a doubling of the power (9.5 +/- 1.7, 3.3 +/- 0.9, and 5.0 +/- 0.6 ms for pyridostigmine/stress, stress and pyridostigmine groups, respectively). Baroreflex sensitivity was also increased in the pyridostigmine/stress group (3.6 +/- 0.5 compared with 1.8 +/- 0.3 and 1.7 +/- 0.5 ms/mmHg in the stress and pyridostigmine groups, respectively). There was no difference in blood pressure variability or its spectral components. Results demonstrate that there are potent interactions between a mild stressor and cholinesterase inhibition seen as an accentuation of low-frequency variability in pulse interval time series, probably associated with baroreflex input and autonomic drive.

Animals↗

Cholinesterase activity in some human lymphatic organs.

(1) Cholinesterase activity was investigated in some human lymphatic organs (palatine tonsil, 'normal' spleen, 'bilharzial' spleen, thymus, lymph node and appendix) using GOMORI'S modification of KOELLE and FRIEDENWALD'S thiocholine iodide method, hydrolyzing acetylthiocholine iodide and butyrylthiocholine iodide. (a) Acetyl- and butyrylcholinesterases seemed to be different enzymes; but when they have the same pattern of activity, the latter generally offers a weaker reaction. (b) All the lymphatic follicles of the tonsil, those found in the cortex of the cervical lymph nodes as well as those present in the appendix, were stainable with both acetyl- and butyrylcholinesterase. (c) Acetylcholinesterase activity was not demonstrated in the Malpighian bodies of the 'normal' spleen, but the reaction was strongly present in the blood vessels (including the central arterioles) as well as in the capsule and the different components of the trabecular system. (d) In 'bilharzial' splenomegaly a relatively strong activity started to appear in the Malpighian corpuscles, manifested as a brownish precipitate in their centres. Also some patchy positive areas began to make their appearance in the tissue of the red pulp and had a particular arrangement around the Malpighian corpuscules, in such a way as to 'wall them off' from the tissue of the red pulp. (e) In the thymus no acetylcholinesterase activity was encountered, except in Hassal's corpuscles and in the trabeculae between the thymic lobules. (2) The data obtained in this work were discussed in relation to previous works in other laboratories and it seems that a species difference exists. (3) Cholinesterases may be present in the lymphatic tissue in order to get rid of some potentially toxic esters resulting from the necrobiotic phenomena accompanying the high mitotic activity found especially in the germinal centres of the lymphoid follicles. (4) There are many unanswered questions about the coexistence of the phosphatases and cholinesterases in the same places; their concomitant association in the lymphatic tissue may represent a special case within the framework of a more general mechanism.

Acetylcholinesterase↗

Cholinesterase activity in sensory-nerve endings, capillaries and motor end plates of the facial skin of the brush-tailed possum (Trichosurus vulpecula).

The facial skin of two adult and one 50-day-old pouch animal of the marsupial mammal Trichosurus vulpecula was removed after the animals has been suitably anesthetized and perfused for electron microscopy. Small blocks of tissue (1 x 0.5 mm) were cut and incubated in acetylthiocholine iodide substrate for cholinesterase studies. The blocks were then subsequently postfixed in osmium tetroxide. Thin sections were cut and stained with lead acetate. Specific cholinesterase was found within the nerves of both the adult and the 50-day-old pouch animal, and in the motor end plates. Nonspecific cholinesterase was present in pinocytotic vesicles and interlamellar spaces of terminal Schwann cells associated with nerve end organs in the adult, and in the same areas in Schwann cells of nonmyelinated nerves in the pouch animal. It was also present in the pinocytotic vesicles of the capillary endothelium.

Animals↗

Detection of the plasma cholinesterase K variant by PCR using an amplification-created restriction site.

Ten individuals registered at the Danish Cholinesterase Research Unit were examined at the DNA level for the presence of the K allele of plasma cholinesterase, using amplification-created restriction sites (ACRSs). A further nine members of a family registered at the unit were tested for mutations of the K and atypical variants. The frequency of the K allele was calculated from examination of normal material from 25 individuals, representing 50 random alleles. The results show that the ACRS method successfully demonstrates the presence of the K variant, whose frequency in the Danish population was found to be 0.18. We conclude that this technique is a reliable and rapid non-radioactive diagnostic assay for detecting the plasma cholinesterase K variant.

Alleles↗

Aggressive behavior following exposure to cholinesterase inhibitors.

The authors report four instances of significant, essentially unprovoked aggressive behavior, including two homicides, following exposure to cholinesterase inhibitors. No subject had a history of violent behavior, antisocial personality, or major psychiatric or neurologic disorder. After anticholinesterase exposure ceased, all showed sincere remorse for their actions, and none has since engaged in aggressive or psychopathologic behavior. Well-controlled experimentation in animals suggests that enhanced activation of hypothalamic cholinergic receptors may underlie aggressive behavior in humans exposed to cholinesterase inhibitors. A relationship between cholinesterase inhibitors and aggression has important implications for public health, raising the possibility of unappreciated neurotoxic influences on behavior.

Adult↗

Measurement of erythrocyte acetylcholinesterase and plasma cholinesterase activity by a differential pH technique.

We describe a new electrochemical method for the determination of erythrocyte acetylcholinesterase activity (EC 3.1.1.7) and plasma cholinesterase (EC 3.1.1.8) activity, based on the measurements of pH variation due to release of acetic acid from acetylcholine. The major advantages of the differential pH procedure are simplicity, high reproducibility, no need for pre-treatment of samples, automatic correction of sample blanks, and speed and direct measurement of enzymatic reaction. The proposed methods are linear up to 7400 U/L at 30 degrees C and correlate well with the manual spectrophotometric method of Ellman for plasma cholinesterase and for washed erythrocytes. We adapted the same technique for the determination of erythrocyte cholinesterase using whole blood as sample and quinidine sulphate as inhibitor of pseudocholinesterase.

Acetylcholinesterase↗

Role of cholinesterase inhibitors in Parkinson's disease and dementia with Lewy bodies.

This article reviews the cholinergic changes in Parkinson's disease and dementia (PDD) and dementia with Lewy bodies (DLB), their potential clinical implications, and the available evidence for cholinesterase inhibitors in the treatment of PDD and DLB. Marked neuronal loss of cholinergic nuclei, reduced cholinergic markers in the neocortex, hippocampus, and selected thalamic nuclei, and receptor changes have been reported. One large and 2 small placebo-controlled trials and nearly 20 open-label studies suggest that cholinesterase inhibitors have a positive effect on cognition, psychiatric symptoms, and global function in patients with DLB and PDD. The treatment is well tolerated in most patients without any apparent worsening of extrapyramidal motor features. Given the high risk of severe sensitivity reactions and increased risk of cerebrovascular incidents during treatment with neuroleptics, more clinical trials of cholinesterase inhibitors are encouraged to establish their precise role in DLB and PDD.

Cholinesterase Inhibitors↗

Plasma cholinesterase: gene and variations.

The traditional tests that have been used for the past 30 yr to determine plasma cholinesterase phenotype--measurement of esterase activity with a variety of substrates, dibucaine inhibition, fluoride inhibition, and Ro2-0683 inhibition--are inadequate for identifying some variants of this enzyme and leave many cases of prolonged response to succinylcholine unexplained. The application of the techniques of molecular genetics has permitted precise identification of plasma cholinesterase variants and has resulted in the discovery of previously unrecognized variants. It is now possible, in cases of prolonged response to succinylcholine resulting from genetically determined alterations in plasma cholinesterase, to ascertain the nature of the mutations in the alleles, and from them to deduce the structural changes in the enzymes responsible for the impairment in drug metabolism.

Butyrylcholinesterase↗

Ipratropium in patients with COPD receiving cholinesterase inhibitors.

Three patients with chronic obstructive lung disease (COPD) and myasthenia gravis whose pulmonary symptoms were worsened by therapy with cholinesterase inhibitors were improved by inhaled ipratropium bromide. Two had increases in FEV1 (19 percent, 35 percent) and specific conductance (106 percent, 81 percent) and reductions in dyspnea. The third had no change in airflow with ipratropium, but improved due to decreased bronchial secretions which had limited the use of cholinesterase inhibitors. In contrast, beta agonist bronchodilators had no effect in any of these patients. This experience suggests that ipratropium may be the bronchodilator drug of choice in patients with obstructive lung disease aggravated by cholinesterase inhibitors.

Administration, Inhalation↗

The C-terminal T peptide of cholinesterases: structure, interactions, and influence on protein folding and secretion.

Mammalian cholinergic tissues mostly express the T splice variant of acetylcholinesterase, in which the catalytic domain is associated with a C-terminal peptide of 40 residues, called the t peptide (Massoulié, 2002). Homologous t peptides exist in all vertebrate cholinesterases, acetylcholinesterases (AChEs), and butyrylcholinesterases (BChEs): they contain a series of seven conserved aromatic residues, including three tryptophans, and a cysteine at position-4 of their C-terminus. The major AChE isozyme of the nematode Caenorhabditis elegans also contains a similar peptide. Although the C-terminal t peptides do not seem to affect the catalytic activity of cholinesterases, they determine their physiological function, because they allow cholinesterase subunits of type T to form oligomers and to associate with structural anchoring proteins. When reduced to their catalytic domain, AChE subunits without a t peptide are active but remain monomeric and soluble.

Amino Acid Sequence↗