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acetylcholine chloride [keywords]
- Chalcones as positive allosteric modulators of α7 nicotinic acetylcholine receptors: A new target for a privileged structure. [JOURNAL ARTICLE]
- Eur J Med Chem 2014 Sep 15.:724-739.
The α7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advantageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chalcones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of α7 nicotinic function. The most potent compound (2,4,2',5'-tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.
- Alpha rhythm oscillations and MMSE scores are differently modified by transdermal or oral rivastigmine in patients with Alzheimer's disease. [Journal Article]
- Am J Neurodegener Dis 2014; 3(2):72-83.
Alzheimer's disease (AD) is the most common cause of dementia in older patients. Rivastigmine, a reversible cholinesterase inhibitor, has been shown to improve the clinical manifestations of AD by delaying the breakdown of acetylcholine (ACh) released into synaptic clefts. Moreover, there is evidence that ACh modulates EEG alpha frequency.the objectives of this pilot study in patients with AD were to determine the effects of two formulations of RV (transdermal and oral) on Mini-Mental State Examination (MMSE) scores and on alpha frequency in particular the posterior dominant rhythm.twenty subjects with AD were randomly assigned to receive either RV transdermal patch (RV-TDP, n=10) or RV capsules (RV-CP, n=10) according to the standard recommended dosage regimen. All patients were driven to the maximum drug dosage. Diagnosis of AD was made according to NINCDS-ADRDA criteria and the Diagnostic and Statistical Manual of Mental Disorders IV. All patients underwent EEG recordings at the beginning and at the end of the 18-month study period using P3, P4, O1 and O2 electrodes each at high (10.5-13.0 Hz) and low (8.0-10.5 Hz) frequency. MMSE scores were determined at the start of the study and at three successive 6-month intervals (T0, T1, T2, and T3).administration of RV-DP increases the spectral power of alpha waves in the posterior region and is associated with improved cognitive function as evidenced by significant changes in MMSE scores.RV-DP provides an effective and long-term management option in patients with AD.
- Anticancer properties of novel aminoacetonitrile derivative monepantel (ADD 1566) in pre-clinical models of human ovarian cancer. [Journal Article]
- Am J Cancer Res 2014; 4(5):545-57.
Monepantel (MPL) is a new anthelmintic agent approved for the treatment of nematode infections in farm animals. As a nematicide, it acts through a nematode-specific nicotinic receptor subtype which explains its exceptional safety in rodents and mammals. In the present study, we evaluated its potential as an anticancer agent. In vitro treatment of epithelial ovarian cancer cells with MPL resulted in reduced cell viability, inhibition of cell proliferation and suppression of colony formation. Proliferation of human ovarian surface epithelial cells and other non-malignant cells were however minimally affected. MPL-induced inhibition was found to be independent of the acetylcholine nicotinic receptor (nAChR) indicating that, its target in cancer cells is probably different from that in nematodes. Analysis of MPL treated cells by flow cytometry revealed G1 phase cell cycle arrest. Accordingly, MPL treated cells expressed reduced levels of cyclins D1 and A whereas cyclin E2 expression was enhanced. Consistent with a G1 phase arrest, cellular levels of cyclin dependent kinases (CDKs) 2 and 4 were lower, whereas expression of CDK inhibitor p27(kip) was increased. In cells expressing the wild-type p53, MPL treatment led to increased p53 expression. In line with these results, MPL suppressed cellular thymidine incorporation thus impairing DNA synthesis and inducing cleavage of poly (ADP-ribose) polymerase (PARP-1). Combined these pre-clinical findings reveal for the first time the anticancer potential of monepantel.
- Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation and the level of CLIP-associating protein 2 (CLASP2) mediating the capture of microtubule plus-ends. [JOURNAL ARTICLE]
- J Biol Chem 2014 Sep 17.
The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs, and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters is not yet understood. To examine this we used myotubes cultured on agrin patches that induce AChR clustering in a two-dimensional manner. We show that expression of a CLASP2 mutant, in which the nine GSK3 target serines are mutated to alanine (CLASP2-9XS/A) and which is resistant to GSK3β-dependent phosphorylation, promotes MT capture at clusters and increases AChR cluster size, compared to myotubes that express similar levels of wild type CLASP2, or that are non-infected. Conversely, myotubes expressing a phosphomimetic form of CLASP2 (CLASP2-8XS/D) show enrichment of immobile mutant CLASP2 in clusters, but MT capture and AChR cluster size are reduced. Taken together our data suggest that both GSK3β-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus-ends.
- Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha 7 nicotinic acetylcholine receptor. [JOURNAL ARTICLE]
- J Neurophysiol 2014 Sep 17.
The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs, and by increasing glutamate and noradrenaline release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic inhibitory postsynaptic spontaneous currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc identified 5-HT DRN neurons using the whole-cell voltage patch clamp technique. Administration of nicotine (1 μM) increased sIPSCs frequency in 72% identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSCs frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.
- Acupuncture stimulation improves scopolamine-induced cognitive impairment via activation of cholinergic system and regulation of BDNF and CREB expressions in rats. [JOURNAL ARTICLE]
- BMC Complement Altern Med 2014 Sep 17; 14(1):338.
Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseases and effectively improve cognitive and memory impairment. The aim of this study was to examine whether acupuncture stimulation at the Baihui (GV20) acupoint improves memory defects caused by scopolamine (SCO) administration in rats. We also investigated the effects of acupuncture stimulation at GV20 on the cholinergic system as well as the expression of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) in the hippocampus.SCO (2 mg/kg, i.p.) was administered to male rats once daily for 14 days. Acupuncture stimulation at GV20 was performed for 5 min before SCO injection. After inducing cognitive impairment via SCO administration, we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test to assess behavior.Acupuncture stimulation at GV20 improved memory impairment as measured by the PAT and reduced the escape latency for finding the platform in the MWM test. Acupuncture stimulation at GV20 significantly alleviated memory-associated decreases in the levels of choline acetyltransferase (ChAT), BDNF and CREB proteins in the hippocampus. Additionally, acupuncture stimulation at GV20 significantly restored the expression of choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), BDNF and CREB mRNA in the hippocampus. These results demonstrate that acupuncture stimulation at GV20 exerts significant neuroprotective effects against SCO-induced neuronal impairment and memory dysfunction in rats.These findings suggest that acupuncture stimulation at GV20 might be useful in various neurodegenerative diseases to improve cognitive functioning via stimulating cholinergic enzyme activities and regulating BDNF and CREB expression in the brain.
- Cholinergic System Dysfunction and Neurodegenerative Diseases: Cause or Effect? [JOURNAL ARTICLE]
- CNS Neurol Disord Drug Targets 2014 Sep 17.
Acetylcholine (ACh) has been the first molecule to be identified as neurotransmitter. The cholinergic and cholinoceptive areas, both in central and peripheral nervous system, have been well documented. Acetylcholine has been described to control, during embryogenesis, cell proliferation as well as neuron and glial cell survival and differentiation. In the adult, ACh and its receptors are distributed in the nervous system and in the other tissues. More recently, new physiological roles in neuronal and non-neuronal tissues have been proposed for ACh as well as its possible involvement in different pathologies. Altered levels of ACh or modified receptors expression and function, in selected areas of the nervous system, have been described in several neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington as well as in psychiatric disorders such as schizophrenia. Frequently own cognitive, behavioral and motor disabilities that characterize these pathologies are correlated to cholinergic circuit dysfunction. Moreover the involvement of ACh as modulator of the inflammation, in and out of the nervous system, has suggested that its altered functions might represent an additional pathogenetic mechanism negatively influencing the disease outcome as recently suggested in multiple sclerosis. The present review will focus on identifying the cause/effect relationship that may explain the cholinergic dysfunction in several nervous system disorders. Moreover the possible therapeutic novelties including cholinesterase inhibitors, muscarinic agonists and antagonists, and genetic therapy will be discussed.
- The effects of a sublethal dose of botulinum serotype e on the swimming performance of channel catfish fingerlings. [Journal Article]
- J Aquat Anim Health 2014 Sep; 26(3):149-53.
Abstract Visceral toxicosis of catfish (VTC) is a disease of cultured Channel Catfish Ictalurus punctatus in the Mississippi Delta region and surrounding states. The etiology of VTC is associated with botulinum serotype E (BoNT/E), which causes blockage of acetylcholine release at the neuromuscular junction, leading to weakness and paralysis of skeletal muscles (including those involved in swimming). This study attempted to determine if sublethal exposure to purified BoNT/E caused reductions in swimming performance and metabolism of Channel Catfish. Catfish swimming performance was assessed on stocker-sized Channel Catfish (mean weight ± SD, 62.35 ± 2.5 g) with 10 sham-injected fish and 10 fish injected with a sublethal dose of BoNT/E. A modified Blazka-type swim chamber was used to assess swimming performance. We injected Channel Catfish with either 0.015% trypsin or 400 pg purified BoNT/E digested with 0.015% trypsin intracoelomically, then acclimated an individual catfish in the swim chamber for 17 h prior to the swimming trial. Water temperature was maintained at ∼28°C, and dissolved oxygen (DO) was between 4 and 7 mg/L. A critical swimming speed (Ucrit) protocol was followed, and DO and temperature were monitored every 2 min throughout the swim trial. Cost of transport was calculated from the oxygen consumption at each test speed (10-70 cm/s). There was a statistical difference between the Ucrits (P = 0.0034), but no differences were found between the cost of transports (P = 0.67) of the sham-injected and BoNT/E groups. There was a difference in the cost of transport as it relates to the speeds tested (P < 0.0001), cost of transports being highest at low speeds and decreasing as speed increased. These results indicate that botulinum E interferes with the swimming speed of the catfish, which could contribute to the mortality from the disease of VTC and potentially make the fish more susceptible to predation. Received September 20, 2013; accepted February 14, 2014.
- GABAB modulation of dopamine release in the nucleus accumbens core. [JOURNAL ARTICLE]
- Eur J Neurosci 2014 Sep 17.
Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ-Aminobutyric acid type B (GABAB ) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug-seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast-scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration-dependently decreased single pulse-evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen-mediated suppression of DA release persisted after a locomotor-sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen-mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.
- New Insights into the Relationship between mIGF-1-Induced Hypertrophy and Ca2+ Handling in Differentiated Satellite Cells. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e107753.
Muscle regeneration involves the activation of satellite cells, is regulated at the genetic and epigenetic levels, and is strongly influenced by gene activation and environmental conditions. The aim of this study was to determine whether the overexpression of mIGF-1 can modify functional features of satellite cells during the differentiation process, particularly in relation to modifications of intracellular Ca2+ handling. Satellite cells were isolated from wild-type and MLC/mIGF-1 transgenic mice. The cells were differentiated in vitro, and morphological analyses, intracellular Ca2+ measurements, and ionic current recordings were performed. mIGF-1 overexpression accelerates satellite cell differentiation and promotes myotube hypertrophy. In addition, mIGF-1 overexpression-induced potentiation of myogenesis triggers both quantitative and qualitative changes to the control of intracellular Ca2+ handling. In particular, the differentiated MLC/mIGF-1 transgenic myotubes have reduced velocity and amplitude of intracellular Ca2+ increases after stimulation with caffeine, KCl and acetylcholine. This appears to be due, at least in part, to changes in the physico-chemical state of the sarcolemma (increased membrane lipid oxidation, increased output currents) and to increased expression of dihydropyridine voltage-operated Ca2+ channels. Interestingly, extracellular ATP and GTP evoke intracellular Ca2+ mobilization to greater extents in the MLC/mIGF-1 transgenic satellite cells, compared to the wild-type cells. These data suggest that these MLC/mIGF-1 transgenic satellite cells are more sensitive to trophic stimuli, which can potentiate the effects of mIGF-1 on the myogenic programme.