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acetylcholine chloride [keywords]
- Acetylcholinesterase Protein Level Is Preserved in the Alzheimer's Brain. [JOURNAL ARTICLE]
- J Mol Neurosci 2013 Dec 7.
Acetylcholinesterase (AChE) is a key enzyme in the cholinergic nervous system and is one of the most studied proteins in the field of Alzheimer's disease (AD). Moreover, alternative functions of AChE unrelated with the hydrolysis of acetylcholine are suspected. Until now, the majority of investigations on AChE in AD pathology have been focused on the determination of its enzymatic activity level, which is depleted in the AD brain. Despite this overall decrease, AChE activity increases at the vicinity of the two hallmarks of AD, the amyloid plaques and the neurofibrillary tangles (NFT). In fact, AChE may directly interact with Aβ in a manner that increases the deposition of Aβ to form plaques. In the context of protein-protein interactions, we have recently reported that AChE can interact with presenilin-1, the catalytic component of γ-secretase, influencing its expression level and also its activity. However, the alteration of AChE protein in the AD brain has not been determined. Here, we demonstrated by Western blotting and immunohistochemistry that a prominent pool of enzymatically inactive AChE protein existed in the AD brain. The potential significance of these unexpected levels of inactive AChE protein in the AD brain was discussed, especially in the context of protein-protein interactions with β-amyloid and presenilin-1.
- β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice. [JOURNAL ARTICLE]
- Diabetologia 2013 Dec 7.
Beta cell failure due to progressive secretory dysfunction and limited expansion of beta cell mass is a key feature of type 2 diabetes. Beta cell function and mass are controlled by glucose and hormones/neurotransmitters that activate G protein-coupled receptors or receptor tyrosine kinases. We have investigated the role of β-arrestin (ARRB)2, a scaffold protein known to modulate such receptor signalling, in the modulation of beta cell function and mass, with a specific interest in glucagon-like peptide-1 (GLP-1), muscarinic and insulin receptors.β-arrestin2-knockout mice and their wild-type littermates were fed a normal or a high-fat diet (HFD). Glucose tolerance, insulin sensitivity and insulin secretion were assessed in vivo. Beta cell mass was evaluated in pancreatic sections. Free cytosolic [Ca(2+)] and insulin secretion were determined using perifused islets. The insulin signalling pathway was evaluated by western blotting.Arrb2-knockout mice exhibited impaired glucose tolerance and insulin secretion in vivo, but normal insulin sensitivity compared with wild type. Surprisingly, the absence of ARRB2 did not affect glucose-stimulated insulin secretion or GLP-1- and acetylcholine-mediated amplifications from perifused islets, but it decreased the islet insulin content and beta cell mass. Additionally, there was no compensatory beta cell mass expansion through proliferation in response to the HFD. Furthermore, Arrb2 deletion altered the islet insulin signalling pathway.ARRB2 is unlikely to be involved in the regulation of insulin secretion, but it is required for beta cell mass plasticity. Additionally, we provide new insights into the mechanisms involved in insulin signalling in beta cells.
- The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2013 Dec 7.
Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.R3487/MEM3454, at doses of 0.1-10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose-response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.
- Evidence of presynaptic and postsynaptic action of local anesthetics in rats. [Journal Article]
- Acta Cir Bras 2013 Nov; 28(11):774-7.
To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro.Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL.-1The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine.LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine.In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.
- The effect of the augmentation of cholinergic neurotransmission by nicotine on EEG indices of visuospatial attention. [JOURNAL ARTICLE]
- Behav Brain Res 2013 Dec 4.
The cholinergic system has been implicated in visuospatial attention but the exact role remains unclear. In visuospatial attention, bias refers to neuronal signals that modulate the sensitivity of sensory cortex, while disengagement refers to the decoupling of attention making reorienting possible. In the current study we investigated the effect of facilitating cholinergic neurotransmission by nicotine (Nicorette Freshmint 2mg, polacrilex chewing gum) on behavioural and electrophysiological indices of bias and disengagement. Sixteen non-smoking participants performed in a Visual Spatial Cueing (VSC) task while EEG was recorded. A randomized, single-blind, crossover design was implemented. Based on the scarce literature, it was expected that nicotine would specifically augment disengagement related processing, especially manifest as an increase of the modulation of the Late Positive Deflection (LPD) by validity of cueing. No effect was expected on bias related components (cue-locked: EDAN, LDAP; target-locked: P1 and N1 modulations). Results show weak indications for a reduction of the reaction time validity effect by nicotine, but only for half of the sample in which the validity effect on the pretest was largest. Nicotine reduced the result of bias as indexed by a reduced P1 modulation by validity, especially in subjects with strong peripheral responses to nicotine. Nicotine did not affect ERP manifestations of the directing of bias (EDAN, LDAP) or disengagement (LPD).
- Age-related Hearing Loss: GABA, Nicotinic Acetylcholine and NMDA Receptor Expression Changes in Spiral Ganglion Neurons of the Mouse. [JOURNAL ARTICLE]
- Neuroscience 2013 Dec 5.
Age-related hearing loss - presbycusis - is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate gamma-amino butyric acid A (GABAA) receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit β2, and N-methyl-D-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative RT-PCR techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40 dB from 3-48 kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40 dB from 6-49 kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. Spiral ganglion neuron (SGN) density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1 amplitude. mRNA and protein expression of GABAAR α1 and AChR β2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss.
- Pyrrolidine dithiocarbamate protects against scopolamine-induced cognitive impairment in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 3.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that leads to disturbances of cognitive functions. Although the primary cause of AD remains unclear, brain acetylcholine deficiency, oxidative stress and neuroinflammation may be considered the principal pathogenic factors. The present study was constructed to investigate the anti-amnestic effect of pyrrolidine dithiocarbamate (PDTC) on scopolamine-induced behavioral, neurochemical and biochemical changes in rats. PDTC (50 and 100mg/kg) and donepezil (2.5mg/kg) were orally administered for 14 successive days. Dementia was induced at the end of the treatment period by a single injection of scopolamine (20mg/kg; i.p.), and Y-maze test was conducted 30min thereafter. Rats were then sacrificed and homogenates of cortical and hippocampal tissues were used for the estimation of noradrenaline, dopamine, serotonin and heat shock protein 70 contents along with acetylcholinesterase activity. In addition, certain oxidative stress markers, pro-inflammatory and anti-inflammatory cytokines were assessed. Histological examination of cortical and hippocampal tissues was also performed. Scopolamine resulted in memory impairment that was coupled by alterations in the estimated neurotransmitters, heat shock protein 70, acetylcholinesterase activity, oxidative stress as well as inflammatory biomarkers. Histological analysis revealed serious damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Pretreatment of rats with PDTC in both doses mitigated scopolamine-induced behavioral, biochemical, neurochemical and histological changes in a manner comparable to donepezil. The observed anti-amnestic effect of PDTC makes it a promising candidate for clinical trials in patients with cognitive impairment.
- Early Stress Prevents the Potentiation of Muscarinic Excitation by Calcium Release in Adult Prefrontal Cortex. [JOURNAL ARTICLE]
- Biol Psychiatry 2013 Oct 28.
The experience of early stress contributes to the etiology of several psychiatric disorders and can lead to lasting deficits in working memory and attention. These executive functions require activation of the prefrontal cortex (PFC) by muscarinic M1 acetylcholine (ACh) receptors. Such Gαq-protein coupled receptors trigger the release of calcium (Ca(2+)) from internal stores and elicit prolonged neuronal excitation.In brain slices of rat PFC, we employed multiphoton imaging simultaneously with whole-cell electrophysiological recordings to examine potential interactions between ACh-induced Ca(2+) release and excitatory currents in adulthood, across postnatal development, and following the early stress of repeated maternal separation, a rodent model for depression. We also investigated developmental changes in related genes in these groups.Acetylcholine-induced Ca(2+) release potentiates ACh-elicited excitatory currents. In the healthy PFC, this potentiation of muscarinic excitation emerges in young adulthood, when executive function typically reaches maturity. However, the developmental consolidation of muscarinic ACh signaling is abolished in adults with a history of early stress, where ACh responses retain an adolescent phenotype. In prefrontal cortex, these rats show a disruption in the expression of multiple developmentally regulated genes associated with Gαq and Ca(2+) signaling. Pharmacologic and ionic manipulations reveal that the enhancement of muscarinic excitation in the healthy adult PFC arises via the electrogenic process of sodium/Ca(2+) exchange.This work illustrates a long-lasting disruption in ACh-mediated cortical excitation following early stress and raises the possibility that such cellular mechanisms may disrupt the maturation of executive function.
- Regulatory effect of nicotine on collagen-induced arthritis and on the induction and function of in vitro-cultured Th17 cells. [JOURNAL ARTICLE]
- Mod Rheumatol 2013 Dec 9.
Objectives. To determine the effect of nicotine stimulation on collagen-induced arthritis (CIA), especially on Th17 cells, and the influence of activated acetylcholine receptor signaling on the induction and function of in vitro-cultured Th17 cells. Methods. Mice were divided into control and experimental (nicotine) group, and PBS or nicotine-PBS was orally administered from Day 21 to Day 28. Phenotypic changes in spleen CD4(+) cells were measured by flow cytometry. α7nAChR expression in Th17 cells was detected using flow cytometry, western blotting and real-time PCR. Purified Th17 cells were further stimulated with nicotine. The cytometric bead array (CBA) assay was employed to measure TNF-α levels in mice serum and IL-17A levels in the supernatants of nicotine-treated cell cultures. Results. Compared with their counterparts, mice receiving oral nicotine showed a delayed progress of arthritis and more attenuated signs of histological changes. Moreover, serum TNFα levels were lower in the nicotine-treated group. Spleen IL-17 level of nicotine-treated mice was lower than that of the control group, and the mRNA expression of pro-inflammatory cytokines (IL-17A and IL-6) in splenocytes were also lower than that of the control group. α7nAChR expression was detected on in vitro-cultured IL-17A(+) cells. Cells treated with 10 (- 6) M nicotine expressed lower IL-17A levels. Similarly, supernatants from nicotine-treated cell cultures also showed lower IL-17A levels. Conclusions. Nicotine stimulation attenuated signs and severity of arthritis in mice. Activation of nicotine acetylcholine receptors on in vitro-cultured Th17 cells decreased their pro-inflammatory function, which may play a potential role in alleviating arthritis in mice.
- The vagus nerve attenuates fulminant hepatitis by activating the Src kinase in Kuppfer cells. [JOURNAL ARTICLE]
- Scand J Immunol 2013 Dec 9.
The parasympathetic nervous system has been known to modify innate immune responses. In animal models, acetylcholine (Ach) released from the distal ends of nerves has been shown to inhibit inflammatory responses such as endotoxic shock, pancreatitis, intestinal inflammation, etc. However, its role in LPS-induced fulminant hepatitis remains to be elucidated. Here, we demonstrate that the vagus nerve acts as a suppressor in the liver after challenge with LPS plus D-gal. The vagus nerve acts through the α7 AchR expressed on the surface of Kupffer cells, inhibiting the production of the proinflammatory cytokines TNF and IL-6. A mechanism study revealed that the suppressive effect of Ach may occur through the activation of Src kinase and subsequent inhibition of the Myd88 signal pathway. Our study has suggested a suppressive role of vagus nerve in the modulation of liver inflammatory responses, which should be noticed during clinical massive hepatectomy and liver transplantation. The nicotinic anti-inflammatory pathway may also be a potential target for sepsis after liver transplantation. This article is protected by copyright. All rights reserved.