Depletion Of ACh Research Articles

Acetylcholine Conformational Flexibility and Its Neutral Hydrolysis in Aqueous Solution

AbstractEnzymatic hydrolysis is the main target to deal with ACh depletion. However, a recent study indicates that the non‐enzymatic one may contribute to the depletion. This study highlights the necessity of considering possible conformers, discrete‐continuum models, and dispersive effects for investigating the neutral (non‐enzymatic) hydrolysis of flexible molecules in aqueous solution. We systematically built the possible conformers within the first‐principles framework. The results confirm the reactivity of high‐energy ACh conformer towards neutral hydrolysis. We proposed that conformational changes occur before the hydrolysis. The calculated activation and reaction energy shows that the discrete‐continuum solvation model gives the closest result to experimental observations. This study also shows that neglecting dispersive effects brings unreliable structures in the initial state, which leads to unreliable activation energy.

Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.

So far, there is no effective disease-modifying therapies for Alzheimer’s Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510-1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477-485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of α7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110-1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia.

Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice

SUMMARYA subset of patients with Parkinson’s disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson’s disease dementia; PDD). Brains from PDD patients show extensive cholinergic loss as well as dopamine (DA) depletion. We used a mutant mouse model to directly test whether combined cholinergic and DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3-sensitive choline transporter (CHTHET) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA depletion in CHTHET and wild-type (WT) littermates via intra-striatal infusion of 6-hydroxydopamine (6-OHDA), or used vehicle as control. Executive function and memory were evaluated using rodent versions of cognitive tasks commonly used with human subjects: the set-shifting task and spatial and novel-object recognition paradigms. Our studies revealed impaired acquisition of attentional set in the set-shifting paradigm in WT-6OHDA and CHTHET-vehicle mice that was exacerbated in the CHTHET-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHTHET-6OHDA mice compared with all other groups. Treatment with acetylcholinesterase (AChE) inhibitors physostigmine (0.05 or 0.1 mg/kg) and donepezil (0.1 and 0.3 mg/kg) reversed the impaired object recognition of the CHTHET-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh and DA depletion as compared with either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD.

Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: a case report

BackgroundVisual hallucinations are commonly seen in various neurological and psychiatric disorders including schizophrenia. Current models of visual processing and studies in diseases including Parkinsons Disease and Lewy Body Dementia propose that Acetylcholine (Ach) plays a pivotal role in our ability to accurately interpret visual stimuli. Depletion of Ach is thought to be associated with visual hallucination generation. AchEI's have been used in the targeted treatment of visual hallucinations in dementia and Parkinson's Disease patients. In Schizophrenia, it is thought that a similar Ach depletion leads to visual hallucinations and may provide a target for drug treatmentCase PresentationWe present a case of a patient with Schizophrenia presenting with treatment resistant and significantly distressing visual hallucinations. After optimising treatment for schizophrenia we used Rivastigmine, an AchEI, as an adjunct to treat her symptoms successfully.ConclusionsThis case is the first to illustrate this novel use of an AchEI in the targeted treatment of visual hallucinations in a patient with Schizophrenia. Targeted therapy of this kind can be considered in challenging cases although more evidence is required in this field.

Depression of neuromuscular transmission in methylmercury-poisoned rats: a glass microelectrode and single fiber electromyography study.

Changes in neuromuscular transmission were examined in methylmercury (MeHg)-poisoned rats, given a total oral dose of 60 mg CH3HgCl at 5 mg/kg/day. A microelectrode study was done on the 21st day. The mean quantal content and mean values of the immediately available pool of ACh in the MeHg-poisoned rats were reduced as compared to those in the control rats, but the mean values for the release probability of ACh did not differ significantly. Stimulation single fiber electromyography (SFEMG) was done on the biceps femoris muscle at 1, 5, 10 and 20 Hz on the 28th day. Both a significant and consistent increase in jitter were found at increasing stimulation rates in the MeHg-poisoned rats. The SFEMG findings suggest presynaptic involvement due to accelerated depletion of ACh. We confirmed that neuromuscular transmission is depressed in MeHg-poisoned rats in vivo and in vitro.

シンポジウム２‐４ 神経変性疾患研究の焦点‐新たな病的因子の登場と臨床への展望‐ 神経変性と炎症：ＦＴＤＰ−１７モデルマウスをもちいて

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.

P-648 - Improving effect of acute and chronic MKC-231, a choline uptake enhancer on working memory deficits and hippocampal ACh depletion induced by ethylcholine aziridinium ion (AF64A) in mice.

P-648 - Improving effect of acute and chronic MKC-231, a choline uptake enhancer on working memory deficits and hippocampal ACh depletion induced by ethylcholine aziridinium ion (AF64A) in mice.

Therapeutic effect of THA on hemicholinium-3-induced learning impairment is independent of serotonergic and noradrenergic systems

Tetrahydroaminoacridine (THA: Tacrine) has previously been shown to reverse deficits in spatial discrimination learning induced by hemicholinium-3 (HC-3). In the present experiments the effects of prior depletion of serotonin (5-HT) or noradrenaline (NA) on this reversal were examined. In the first experiment 5-HT lesions were made by injecting 5,7-DHT (2 x 50 micrograms/5 microliters) into the lateral ventricles of rats pretreated with desmethylimipramine (DMI 25 mg/kg IP). A permanently indwelling guide tube was then implanted over the right lateral ventricle. Subsequent testing under drug-free conditions, revealed no effect of the lesion on the number of trials needed to attain criterion (nine consecutive correct choices) in two-platform spatial discrimination learning in a watermaze. Using a latin square design rats were then tested for the effects of HC-3 and THA. HC-3 (5 micrograms/5 microliters ICV) or placebo (CSF) were injected 60 min before the start of a 30-trial training session. THA (4.6, 10 mg/kg SC) or placebo were then injected 15 min before training. Choice accuracy but not choice latency was significantly impaired by HC-3 and the effect was reversed by THA in both sham operated and 5-HT lesioned rats. In the second experiment two injections of DSP-4 (50 mg/kg IP) were given, following cannulation, to deplete forebrain NA. The lesion had no effect on spatial learning under drug-free conditions and failed to block the THA-induced reversal of spatial discrimination learning deficits following HC-3. These results confirm that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and that the deficit is reversed by THA.(ABSTRACT TRUNCATED AT 250 WORDS)

Influences of cholecystokinin and analogues on memory processes

AbstractEvidence is reviewed to assign the role of cholecystokinins in the cognitive and memory processes. Rat brain contains about 550 ng of CCK‐8. When injected, icv or sc, in doses of less than 100 ng of CCK or caerulein, these peptides prevent experimental amnesia and prolong extinction of the already‐learned tasks. Caerulein is nearly 10 times as potent as CCK‐8, and the effects of both peptides are long‐lasting. Pretreatment with these peptides also prevents scopolamine‐induced amnesia, and reverses the ACh depletion in the frontal and temporal cortices as well as in the hippocampus. CCK‐8 antagonists in small doses produce complete amnesia, further supporting the hypothesis that endogenous CCK‐8 modulates the memory processes in the brain. Neurochemical data suggest participation of the NMDA receptors, protein kinase C, and protein synthesis in the action of CCK‐8 and caerulein. Sub‐diaphragmatical vagotomy abolishes the memory‐enhancing effects of these peptides when administered peripherally. Thus, CCK‐8 and caerulein are likely to affect not only the receptors localized in the CNS, but also to stimulate peripheral receptors associated with the vagus. Alternatively, the vagus may be the major pathway for CCK transport from the visceral organs to the brain.

Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics

The effects of hemicholinium-3 (HC-3) on spatial discrimination learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical "float" (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 micrograms/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 micrograms/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46-460 micrograms/kg/SC) and tetrahydroaminoacridine (THA) (2.2-10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046-1 mg/kg/SC), aceclidine (1-10 mg/kg/SC), oxotremorine (30-100 micrograms/kg/SC) and RS-86 (0.46, 1.0 microgram/kg/SC) were also effective. Pilocarpine (0.22-2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6-10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The alpha 2 agonist, clonidine (46, 100 micrograms/kg SC) and the antagonist idazoxan (32, 100 micrograms/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 micrograms/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 micrograms/kg) or by the benzodiazapine antagonist ZK-93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.

Changes in acetylcholine concentration, miniature end-plate potentials and synaptic vesicles in frog neuromuscular preparations during lanthanum treatment

1. ACh content and synaptic ultrastructure were compared in neuromuscular preparations (sartorius muscle of Rana esculenta) incubated in control saline and in saline containing 1 mM LaCl 3. ACh concentrations remained constant for 6 hr in control preparations. 2. La 3+ caused a 38% depletion of ACh within the first 30 min with subsequent recovery to 120% of control values within 3–4 hr. Recovery was prevented by hemicholinium-3. 3. At 23°C La 3+ caused complete loss of synaptic vesicles; no depletion was seen at 4°C. 4. Initially MEPP frequency increased 300- to 700-fold (23°C), then declined. Mean vesicle diameter did not change, but SD increased. As the frequency of MEPPs declined, the percentage of s-MEPPs greatly increased. 5. La 3+ had a postsynaptic effect which increased the amplitudes of both s-MEPPs and bell-MEPPs within a few seconds. 6. The s-MEPP mean did not change during the course of La 3+ treatment although the bell-MEPP mean usually decreased. 7. How the decrease in synaptic vesicles, decrease in MEPP frequencies, and changes in ACh levels relate to changes in the percentage of different classes of quanta is discussed.

Effects of electrical stimulation on acetylcholine levels in central cholinergic nerve terminals

These studies explored some of the characteristics of the cholinergic septal-hippocampal neurons. Acetylcholine (Ach) levels were measured after various conditions of electrical stimulation of the medial septal area. Stimulation (40 Hz) for varying periods of duration up to 60 min did not alter hippocampal Ach levels. However, when 10 μg of hemicholinium-3 bromide (HC-3) were injected into the lateral ventricles immediately prior to stimulation, there was a maximal 50% depletion of Ach levels after 7.5 min of stimulation. There was no significant depletion of Ach when 1 or 5 μg of HC-3 was utilized, and there was no further depletion (beyond that observed with 10 μg) when 15 or 20 μg were injected. In experiments where the stimulation frequencies were varied, it was observed that 0.4 and 1 Hz did not lower Ach levels, whereas frequencies between 10 and 100 Hz resulted in a similar 50% depletion at 7.5 min. Three days after cessation of stimulation (40 Hz, 10 μg HC-3), Ach levels had returned to that of untreated controls. Stimulation of the corpus striatum did not have any effect on hippocampal Ach levels.

Cerebral acetylcholine in thiamine deficiency.

SummaryThis study assesses the hypothesis that severe thiamine deficiency may lead to a depletion of cerebral ACh, which, in turn, may be responsible for the cerebral dysfunction seen in this condi...