Effects Of Acetylcholinesterase Inhibitors Research Articles

ACC/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Chronic Heart Failure

Table of Contents 1. Uses for HF Data Standards 1892 2. Balance Between Focus and Comprehensiveness 1893 3. Balance Between “Primary” and “Summary” Data Elements 1893 4. Variety of Disease States Leading to HF 1893 5. Acute and Chronic Care, Inpatient and Outpatient Care Venues 1893 6. Therapy for HF 1893 7. Outcomes Assessment for HF 1893 1. III. HF Clinical Data Standards Elements and Definitions 1893 The American College of Cardiology (ACC) and the American Heart Association (AHA) recognize …

Expression and production of two selected beta-chemokines in peripheral blood mononuclear cells from patients with Alzheimer's disease

MCP-1 and RANTES are molecules that regulate monocyte and T-lymphocyte recruitment towards sites of inflammation. We sought to evaluate the role of these chemokines in Alzheimer's disease (AD), and the effect of acetylcholinesterase inhibitor (AchEI) therapy on their release from peripheral blood mononuclear cells (PBMC). MCP-1 and RANTES mRNA expressions were determined by RT-PCR and the amount of secreted chemokines was assayed using specific ELISA methods from purified PBMC from each AD patients ( n=40) at the time of enrolment (T0) and after 1 month of treatment with AchEI (T1) and from 20 healthy age and sex-matched subjects (HC). We found that expression and production of MCP-1 in AD patients was significantly lower than in HC subjects. After 1 month of therapy with AchEI (Donepezil ®), MCP-1 levels increased in each patient. However, higher levels were detected for RANTES in AD patients compared to control subjects and in AD patients treated with Donepezil. MCP-1 and RANTES have a compensatory role in balancing the impaired mechanisms involved in immune response during ageing. Our present findings suggest that these two chemokines are both involved in AD pathogenesis and might reflect different states of activation and/or responsiveness of PBMC from AD patients, contributing to the impaired of the peripheral immune system in these patients.

Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice.

A primary therapeutic strategy for Alzheimer's disease includes acetylcholinesterase (AChE) inhibitors with the goal of enhancing cholinergic transmission. Stimulation of muscarinic acetylcholine receptors (mAChRs) by elevated levels of ACh plays a role in the effects of AChE inhibitors on cognition and behavior. However, AChE inhibitors only demonstrate modest symptomatic improvements. Chronic treatment with these drugs may cause mAChR downregulation and consequently limit the treatment efficacy. AChE knockout (-/-) mice were utilized in this study as a model for investigating the effects of selective, complete, and chronic diminished AChE activity on mAChR expression and function. In AChE -/- mice, the M(1), M(2), and M(4) mAChRs showed strikingly 50 to 80% decreased expression in brain regions associated with memory. In addition, mAChRs showed decreased presynaptic, cell surface, and dendritic distributions and increased localization to intracellular puncta. Furthermore, mAChR agonist-induced activation of extracellular signal-regulated kinase, a signaling pathway associated with synaptic plasticity and amyloidogenesis, is diminished in the hippocampus and cortex of AChE -/- mice. Therefore, chronic diminished ACh metabolism produces profound effects on mAChR expression and function. The alterations of mAChRs in AChE -/- mice suggest that mAChR downregulation may contribute to the limited efficacy of AChE inhibitors in Alzheimer's disease treatment.

Nimodipine Affects the Microcirculation and Modulates the Vascular Effects of Acetylcholinesterase Inhibition

The present investigation was undertaken in order to study whether microvascular effects of the calcium antagonist nimodipine induces changes that can explain an increased detoxification of the highly toxic cholinesterase inhibitor soman. Anaesthetised, tracheotomised and artificially ventilated rats were treated intra-peritoneally (ip) with nimodipine, 10 mg kg-1 or vehicle followed one hour later by the exposure to 45 μg kg-1 soman (iv). Nimodipine per se induced a vasodilation in the intestine, myocardium and other muscles. In the abdominal skin soman elicited a significant vasoconstriction that was turned into an increased blood flow after nimodipine pre-treatment. A slight vasoconstriction in diaphragm of soman intoxicated rats was turned into a significant vasodilation by nimodipine pre-treatment. In the intestinal parts no effect of soman was detected. However, in nimodipine pretreated animals soman induced a significant vasoconstriction. The capacity of soman detoxifying processes, i.e. enzymatic hydrolysis and covalent binding to different esterases, is unequally distributed throughout the body.Together with the knowledge of the detoxifying processes of cholinesterase inhibition the results support our theory, that nimodipine alters the peripheral blood flow in a beneficial way resulting in improved detoxification ability.

The effect of acetylcholinesterase-inhibition on depolarization-induced GABA release from rat striatal slices

The severity of poisoning after intoxication with the acetylcholinesterase (AChE) inhibitor soman has been shown to be positively correlated with GABA release in rat striatum. Since most of the neurons in striatum and striatal projection regions use GABA as transmitter, it is still unclear, whether an increase of extracellular GABA in this region results from enhanced activation of these projections or is due to the local effect of AChE inhibition. In this study, the modulation of depolarization-induced increase in GABA concentration by soman was determined in the superfusate of rat striatal slices. Soman and neostigmine increased GABA concentration in the superfusate dose dependently. This increase was exerted through M-cholinoceptors as it could be blocked by atropine and enhanced by application of the muscarinic agonists pilocarpine or oxotremorine. These results clearly indicate that AChE inhibition by soman in rat striatum can directly lead to enhanced release of GABA through M-cholinoceptors.

Novel Uses of Donepezil

Two recent small studies demonstrate effects of acetylcholinesterase inhibitors in populations other than patients with a primary diagnosis of

Nicotinic receptor modulation: advantages for successful Alzheimer's disease therapy.

Galantamine is a modest acetylcholinesterase inhibitor (AChEI) that is also an allosteric potentiating ligand (APL) of nicotinic acetylcholine receptors (nAChRs). In this report, these two effects are shown to be dependent upon each other using a realistic computer model of the cholinergic synaptic cleft. The model is based upon realistic estimates of the anatomy of a neuronal synapse, the kinetic states of pre- and postsynaptic nAChRs, and the acetylcholinesterase enzyme. The number of open postsynaptic nAChRs per action potential is a measure of cholinergic neurotransmission. Using mathematical equations and published data, the effect of the AChEI and APL actions of galantamine is quantitatively described and compared to the effects of pure AChEIs. The model shows that galantamine--compared to similar concentrations of pure AChEIs--is able to compensate for its somewhat modest effect on the cholinesterase enzyme with its allosteric modulatory effects that include the additional benefit of a lower degree of receptor desensitization.

Effects of acetylcholinesterase inhibitors on the metabolism of amyloid precursor protein in vitro

Effects of acetylcholinesterase inhibitors on the metabolism of amyloid precursor protein in vitro

Amyloid precursor protein in platelets of patients with Alzheimer's disease: Biological effect of acetylcholinesterase inhibitors (donepezil) treatment

Amyloid precursor protein in platelets of patients with Alzheimer's disease: Biological effect of acetylcholinesterase inhibitors (donepezil) treatment

Fatigability of rat hindlimb muscles after acute irreversible acetylcholinesterase inhibition.

The purpose of this study was to investigate the functional impact of acute irreversible inhibition of acetylcholinesterase (AChE) on the fatigability of medial gastrocnemius and plantaris muscles of Sprague-Dawley rats. After treatment with methanesulfonyl fluoride (a lipid-soluble anticholinesterase), which reduced their AChE activity by >90%, these muscles were subjected to an in situ indirect stimulation protocol, including a series of isolated twitch and tetanic contractions preceding a 3-min fatigue regimen (100-ms trains at 75 Hz applied every 1.5 s). During the first minute of the fatigue regimen, the effects of AChE inhibition were already near maximal, including marked reductions in peak tension and the force-time integral (area), as well as a decrement of compound muscle action potential amplitudes within a stimulus train. Neuromuscular transmission failure was the major contributor of the force decreases in the AChE-inhibited muscles. However, despite this neuromuscular transmission failure, muscles of which all AChE molecular forms were nearly completely inhibited were still able to function, although abnormally, during 3 min of intermittent high-frequency nerve stimulation.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

Kinetics of muscarinic reduction of IsAHP in hippocampal neurons: effects of acetylcholinesterase inhibitors.

The present experiments were designed to elucidate the time frame in which an evoked cholinergic impulse decreases the Ca2+-dependent K+ current (IsAHP) in hippocampal CA1 neurons, and to determine to what extent acetylcholinesterase (AChE) inhibitors enhance the efficacy of the cholinergic impulse. Whole cell voltage-clamp recordings were performed on hippocampal CA1 neurons of rat brain slices and IsAHPs were evoked by constant depolarizing pulses. Cholinergic afferent fibers in stratum oriens were stimulated electrically and the time interval between the afferent stimulus and the depolarizing pulse was varied from 1 to 30 s. In slices perfused with the standard external medium, the afferent stimulus caused a profound decrease in the following IsAHP only when the stimulus preceded the depolarizing pulse by 1-2 s. The stimulus was without effects on the IsAHP when applied >/=5s before the depolarizing pulse. The effects of the afferent stimulus were greatly enhanced in CA1 neurons exposed to the catalytic AChE inhibitors neostigmine, physostigmine, or 9-amino-1,2,3, 4-tetrahydro-acridine. A substantial decrease in the IsAHP was observed even when the stimulus preceded the depolarizing pulse by >/=30 s. However applications of peripheral site AChE inhibitors decamethonium and propidium caused only minor or no enhancement of the IsAHP reduction after the afferent stimulus. We suggest in physiological conditions that muscarinic modulation of ionic conductances of CNS neurons has a limited time course after a cholinergic impulse and that the modulation is greatly enhanced and prolonged when catalytic activities of AChEs are suppressed pharmacologically.

Effect of Physostigmine and Verapamil on Active Avoidance in an Experimental Model of Alzheimer's Disease

The present study was performed to investigate and compare the effect of acetylcholinesterase inhibitor, physostigmine (0.045, 0.060 and 0.075 mg/kg sc, 30 min before the tests) and Ca-antagonist, verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg sc, 30 min before the tests), on two-way active avoidance (AA) learning (acquisition and performance) in nucleus basalis magnocellularis (NBM)-lesioned rats. Bilateral electrolytic lesions of NBM induced significant decrease of acquisition and performance of AA responses in rats. Physostigmine (0.060 mg/kg) significantly improved only acquisition of AA, while verapamil (2.5 and 5.0 mg/kg) significantly improved both type of AA behavior in NBM-lesioned rats. These results suggest that altered calcium homeostasis might play significant role in pathogenesis of experimental induced Alzheimer's disease (AD) and that administration of calcium antagonist such as verapamil might successfully ameliorate disturbances of learning and memory appeared after lesions of NBM.

Open Field Behavior in Nucleus Basalis Magnocellularis-Lesioned Rats Treated with Physostigmine and Verapamil

The present study was done to investigate and compare the effect of acetylcholinesterase inhibitor, physostigmine (0.030, 0.045, 0.060 and 0.075 mg/kg sc) and Ca-antagonist, verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg sc) on open field behavior in male Wistar rats with bilateral electrolytic lesions of nucleus basalis magnocellularis (NBM). NBM-lesions produced a significant increase and decrease of ambulation and number of inner squares entered, and defecation, respectively, with no influence on grooming in rats exposed to novel environment. Physostigmine and verapamil in all tested doses, given 30 min before the test did not affect the open field behavior in control animals. In contrast to that, physostigmine (0.045, 0.060 and 0.075 mg/kg) and verapamil (2.5 and 5.0 mg/kg) significantly reduced ambulation and number of inner squares entered in NBM-lesioned rats. Also, physostigmine in a dose of 0.060 mg/kg significantly decreased defecation and in doses of 0.060 and 0.075 mg/kg the grooming, as well. On the other hand, verapamil only in a dose of 2.5 mg/kg significantly increased defecation. It could be concluded that lesions of NBM in rats induced disturbances in the open field behavior, which might be successfully ameliorate by physostigmine and verapamil treatment.

Effect of acetylcholinesterase inhibition on behavior is age-dependent in freely moving Aplysia

The significance of age-dependent changes in acetylcholinesterase (AChE) activity level is poorly understood. Reported here is one approach to understand AChE's function as it relates to age: to investigate how inhibition of AChE affects behavior in freely moving Aplysia of two age groups, mature and old. The siphon/gill withdrawal reflex (S/GWR) and gill pumping movement (GPM) were examined to assay the effects of AChE inhibition by BW284c51, a specific and reversible AChE inhibitor. In mature Aplysia AChE inhibition by 2 μM and 5 μM of BW284c51 resulted in a significantly shortened S/GWR duration, and in suppression of habituation and dishabituation. In old animals, AChE inhibition by 2 μM of BW284c51 did not affect S/GWR and only dishabituation was suppressed by inhibition by 5 μM of BW284c51. AChE inhibition reduced the GPM rate significantly only in mature animals. AChE inhibition did not alter the decrement in GPM rate which is regularly observed in both age groups during repetitive exposure to acidified sea water. Thus both S/GWR and GPM were affected by AChE inhibition, and a significant age effect on the two behaviors was observed. Comparisons of the results of AChE inhibition which would elevate acetylcholine (ACh) levels with those of carbachol administration revealed that AChE inhibition affects both cholinergic and non-cholinergic mechanisms underlying the two behaviors.

Non-reactivating effects of HI-6 on hippocampal neurotransmission.

Effects of the oxime HI-6, unrelated to reactivation of acetylcholinesterase (AChE), on field potentials in the dentate gyrus of the rat hippocampus following AChE inhibition, were investigated both in vitro and in vivo. In hippocampal slices, AChE inhibition decreased the perforant path evoked population spike amplitude (PSA). This effect could be prevented by pre-incubation of the slices with atropine (0.1-1 microM) or with the M1 muscarinic receptor antagonist pirenzepine (1 microM). A similar preventive effect was found after pre-incubation with the GABAA antagonist picrotoxin (20 microM), suggesting that the effects of AChE inhibition in vitro may be due to an enhancement of GABAergic inhibitory activity via activation of M1-muscarinic receptors. The effects of AChE inhibition in vivo were variable; both increases and decreases of the PSA were found. Following AChE inhibition, HI-6 increased the PSA dose-dependently, both in the in vivo and in the in vitro hippocampus. At higher oxime doses the perforant path stimulation elicited multiple population spikes. The effects of the oxime were presumably not mediated by an antagonism of cholinergic receptors, since they could not be mimicked with cholinergic antagonists like atropine, mecamylamine or gallamine. Further testing of the nature of the HI-6 effect in hippocampal slices in vitro, using a paired antidromic-orthodromic stimulation protocol, showed that HI-6 may interfere with GABAergic inhibition.

The effects of acetylcholinesterase inhibitors on acetylcholinesterase in senile plaque: S. Nakamura, M. Yukawa and Y. Mimori. Third Dept of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minamiku, Hiroshima 734, Japan

As a long-acting acetylcholinesterase inhibitor (CI) with peripheral and central effects, tetrahydroaminoacridine (THA) has been extensively studied since 1981, for its potential efficacy as a symptomatic treatment for Alzheimer's disease (AD). This strategy is a part of an ongoing effort to bolster the basalis-neocortical and septo-hippocampal cholinergic systems that are severely altered in AD, using precursor loading (choline, lecithin), pre-synaptic releasing drugs (linopirdine, ondansetron), CI (physostigmine, HP-029, valnacrine, heptylphysostigmine, SDZ ENA 7 13), non-selective (arecoline, oxotremorine, bethanechol) and selective musarinic receptor agonists (LY 246708). To date, five major controlled clinical trials using THA have been published and are commented upon in terms of design, outcome variables, and toxicity. THA as a long-acting C1 has generated a lot of knowledge about drug testing in AD. Although the benefivrisk ratio is inadequate for marketing, future studies will have benefited from the THA experience. New regroupment of clinical investigators, such as the Consortium of Canadian Centres for Clinical Cognitive Research and the US Clinical Trials Consortium for AD is made possible to a great extent by the THA studies. Other CI is tested as symptomatic treatment for AD, but one must not forget that the ultimate goal is to understand the cause of AD, prevent it or at least delay its progression.

Comparison of tetrahydroaminoacridine and physostigmine on scopolamine-induced free swim behavior in the rat

The effect of acetylcholinesterase inhibitors on free swim behavior in rats pretreated with scopolamine (0.32 mg/kg, IP) was examined. Long-Evans rats received a single 5-min testing trial in a 1.5 m black swimming pool, and swim distance in three concentric annulus corridors (peripheral, middle, and inner) and the number of body-turn transitions (greater than 45 degrees) were measured. Physostigmine (1.0 mg/kg, IP) increased swim distance in the middle and inner annulus corridors, compared to tetrahydroaminoacridine (2.0 mg/kg and 10 mg/kg, IP) and scopolamine alone (control) (Ps less than 0.01), and increased body-turn transitions, compared to all the other groups (Ps less than 0.05), but had no significant effect on peripheral annulus corridor swim distance, total swim distance, or swim speed. The results suggest that physostigmine produces uniquely different free swim patterns from tetrahydroaminoacridine following cholinergic blockade. These findings have implications for investigations attempting to restore spatial learning and navigation (e.g., Morris water maze) using acetylcholinesterase inhibitors following experimentally-induced cholinergic losses.

The effect of acetylcholinesterase inhibition on the release of acetylcholine from the striatum in vivo: Interaction with autoreceptor responses

The release of acetylcholine from the rat striatum is under inhibitory control of muscarinic autoreceptors. Since in vivo release studies are generally performed in the presence of an acetylcholinesterase inhibitor, modifications of responses to muscarinic receptor agonists and antagonists may be expected. In this study we show that the addition of 0.1 μM neostigmine bromide to the perfusion Ringer in a dialysis experiment attenuates the responses obtained by infusion of 100 μM oxotremorine and potentiates the effect of infusion of 1 μM atropine. Furthermore it is shown that under physiological conditions the muscarinic autoreceptors are not fully occupied, since infusion of 1 μM atropine did not affect the release of acetylcholine when no acetylcholinesterase inhibitor was added to the perfusion Ringer.

The effect of acetylcholinesterase-inhibition on the tonus of guinea-pig bronchial smooth muscle

The irreversible acetylcholinesterase inhibitor soman (O-[1,2,2-trimethylpropyl]-methyl-phosphonofluoridate) induced contraction of guinea-pig primary bronchial smooth muscle. The apparent affinity ( ed 50) of acetylcholine (ACh) was altered from control value of 12 μM to 0.3 μM following exposure of the bronchial smooth muscle to 14 μM soman for 15 min in vitro. The ed 50 of the cholinergic agonist carbachol was not changed even when the acetylcholinesterase (AChE) activity was inhibited completely. The intrinsic activity (α) of ACh and carbachol was not significantly changed after exposure to soman for 15 min. The results demonstrate that the effect of soman is only due to its anticholinesterase activity. Furthermore, the contraction induced by histamine was not altered by concentrations of soman which increase the cholinergic stimulation. This indicates that histamine does not induce contraction of bronchial smooth muscle in guinea pig through the release of ACh or by modulation of muscarinic receptors. Furthermore, soman also inhibited the carboxylesterase activity in the primary bronchi. In respiratory tissue this group of enzymes may have a major protective function, due to their ability to bind several organophosphorus compounds. Compared to studies performed on other species, this study shows that guinea-pig bronchi are very sensitive to the AChE-inhibitor soman. Therefore, exposure to very low concentrations of AChE-inhibitors may induce contraction of bronchial smooth muscle.