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acetylcholine chloride [keywords]
- Role of aqueous extract of Azadirachta indica leaves in an experimental model of Alzheimer's disease in rats. [Journal Article]
- Int J Appl Basic Med Res 2013 Jan; 3(1):37-47.
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by multiple cognitive deficits, is often accompanied by behavioral disorders and mood changes. Because of the non-availability of proper curative/preventive therapy for AD, the present study was designed to evaluate the possible role of Azadirachta indica in experimental AD in rats.Experimental AD in rats was produced by nucleus basalis magnacellularis lesion with ibotenic acid (IB) and intacerebroventricular administration of colchicine (Col). Different behavioral tests and biochemical analysis were performed to explore the role to A. indica in AD.A. indica exhibited anxiolytic activity in the open field test in Col lesion animals, which was comparable to that of diazepam. In the Elevated plus maze test, A. indica significantly alleviated IB and Col-induced anxiety. IB and Col-induced depression was mitigated by A. indica, and the results were comparable to that of imipramine. In Morris' water maze test, A. indica pre-treatment improved reference memory, working memory and spatial learning, which are at par with the effects of donepezil. Both IB and Col-induced deficits in active avoidance learning and retention of learned behavior were significantly reversed by A. indica. IB and Col-induced increased lipid peroxidase activity was significantly reversed by A. indica (reductions in malondialdehyde level). A. indica stabilized rise in superoxide dismutase and a decreasing trend in acetylcholine-esterase (AChE) activity was seen with IB and Col lesions. A. indica had no effect over the AChE activity.A. indica might be effective in clinical AD by virtue of its cognition enhancement, antidepressant and antianxiety properties.
- A literature review on the efficacy and safety of botulinum toxin: an injection in post-stroke spasticity. [Journal Article]
- Int J Prev Med 2013 May; 4(Suppl 2):S147-58.
A variety of techniques for the management of spasticity have been suggested, including positioning, cryotherapy, splinting and casting, biofeedback, electrical stimulation, and medical management by pharmacological agents, Botulinum toxin A (BTA) is now the pharmacological treatment of choice in focal spasticity. BTA by blocking acetylcholine release at neuromuscular junctions accounts for its therapeutic action to relieve spasticity.A computerized search of Pub Med was carried out to find the latest result about efficacy of BTA in management of post stroke spasticity.Among 84 articles were found, frothy of them included in this review and divided to lower and upper extremity.BTA is a treatment choice in reducing tone and managing post stroke spasticity .
- Glutamine supplementation alleviates vasculopathy and corrects metabolic profile in an in vivo model of endothelial cell dysfunction. [Journal Article]
- PLoS One 2013; 8(6):e65458.
Endothelial Cell Dysfunction (ECD) is a recognized harbinger of a host of chronic cardiovascular diseases. Using a mouse model of ECD triggered by treatment with L-Nω-methylarginine (L-NMMA), we previously demonstrated that renal microvasculature displays a perturbed protein profile, including diminished expression of two key enzymes of the Krebs cycle associated with a Warburg-type suppression of mitochondrial metabolism. We hypothesized that supplementation with L-glutamine (GLN), that can enter the Krebs cycle downstream this enzymatic bottleneck, would normalize vascular function and alleviate mitochondrial dysfunction. To test this hypothesis, mice with chronic L-NMMA-induced ECD were co-treated with GLN at different concentrations for 2 months. Results confirmed that L-NMMA led to a defect in acetylcholine-induced relaxation of aortic rings that was dose-dependently prevented by GLN. In caveolin-1 transgenic mice characterized by eNOS inactivation, L-NMMA further impaired vasorelaxation which was partially rescued by GLN co-treatment. Pro-inflammatory profile induced by L-NMMA was blunted in mice co-treated with GLN. Using an LC/MS platform for metabolite profiling, we sought to identify metabolic perturbations associated with ECD and offset by GLN supplementation. 3453 plasma molecules could be detected with 100% frequency in mice from at least one treatment group. Among these, 37 were found to be differentially expressed in a 4-way comparison of control vs. LNMMA both with and without GLN. One of such molecules, hippuric acid, an "uremic toxin" was found to be elevated in our non-uremic mice receiving L-NMMA, but normalized by treatment with GLN. Ex vivo analysis of hippuric acid effects on vasomotion demonstrated that it significantly reduced acetylcholine-induced vasorelaxation of vascular rings. In conclusion, functional and metabolic profiling of animals with early ECD revealed macrovasculopathy and that supplementation GLN is capable of improving vascular function. Metabolomic analyses reveal elevation of hippuric acid, which may further exacerbate vasculopathy even before the development of uremia.
- Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2013 Jun 17.
Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.
- Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2013 Jun 17.
Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-β-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m-mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum-which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei-suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD.
- Targets for botulinum toxin in the lower urinary tract. [JOURNAL ARTICLE]
- Neurourol Urodyn 2013 Jun 17.
BACKGROUND:Botulinum toxin type A (BoNT/A), one of the seven subtypes of Botulinum toxin, is commercially available naked or complexed to other proteins. Onabotulinum toxin type A is the most extensively studied BoNT/A brand. Dose equivalence studies between the different brands have never been carried out. BoNT/A is internalized by nerve fibers after binding synaptic vesicle proteins, and the final target of action is synaptosome-associated protein 25 kDa (SNAP-25), a membrane protein essential for synaptic vesicle fusion with the neuronal membrane.
METHODS:The current literature about botulinum toxin mechanisms was reviewed to provide an up to date knowledge about the topic.
RESULTS:Immunoreactivity to cleaved SNAP-25, the end product of BoNT/A activity, has been identified in parasympathetic (pre- and postganglionic), sympathetic, and afferent fibers. A consistent decrease in the release of acetylcholine from parasympathetic, norepinephrine from sympathetic, and glutamate and neuropeptides from sensory neurons follows BoNT/A administration. Immunoreactivity to cleaved SNAP-25 was not identified in the urothelium or in myofibroblasts. Nevertheless, a decreased release of ATP and neurotrophins from the urothelial cells has been consistently observed after BoNT/A. The toxin does not cause apoptosis in the bladder. However, injection in rat and dog prostates was shown to induce apoptosis in acinar and stromal cells.
CONCLUSION:There is now robust information to support that the mechanism of action of BoNT/A in the bladder involves neurotransmitter release from nerve fibers and urothelial cells. Which neurotransmitter is more relevant is, however, unclear. Likewise, the long duration of effect, the importance of the volume of vehicle injected and the selection of specific injection sites, like the trigone, needs further evaluation. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc.
- High Expression of CHRNA1 is Associated with Reduced Survival in Early Stage Lung Adenocarcinoma after Complete Resection. [JOURNAL ARTICLE]
- Ann Surg Oncol 2013 Jun 18.
BACKGROUND:Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths around the world, and a high recurrence rate after complete resection is an important issue reducing the cure rate and survival of patients with early stage NSCLC. Several pathologic biomarkers are associated with recurrence in early stage lung cancer after complete resection.
METHODS:We evaluated the expression and prognostic value of the α1 subunit of the nicotinic acetylcholine receptor (CHRNA1) as well as other pathologic features of tumor tissues resected from patients with stage I adenocarcinoma of the lung.
RESULTS:A high ratio (173/185) of CHRNA1 expression (93.5 %) was found in stage I lung adenocarcinoma. In the multivariate survival analysis, tumor necrosis, angiolymphatic invasion, perineural invasion, and CHRNA1 expression were independent poor prognostic factors for both recurrence-free and overall survival (OS). Patients expressing CHRNA1 had worse median recurrence-free survival (60.6 vs. 77.9 months, P = 0.03) and OS (65.1 vs. 77.9 months, P = 0.04) compared with CHRNA1-negative patients.
CONCLUSIONS:CHRNA1 expression could be directly tested from the tumor after complete resection. In early stage NSCLC, it could be a useful prognostic factor for recurrence and survival.
- Rivastigmine reverses cognitive deficit and acetylcholinesterase activity induced by ketamine in an animal model of schizophrenia. [JOURNAL ARTICLE]
- Metab Brain Dis 2013 Jun 19.
Schizophrenia is one of the most disabling mental disorders that affects up to 1 % of the population worldwide. Although the causes of this disorder remain unknown, it has been extensively characterized by a broad range of emotional, ideational and cognitive impairments. Studies indicate that schizophrenia affects neurotransmitters such as dopamine, glutamate and acetylcholine. Recent studies suggest that rivastigmine (an acetylcholinesterase inhibitor) is important to improve the cognitive symptoms of schizophrenia. Therefore, the present study evaluated the protective effect of rivastigmine against the ketamine-induced behavioral (hyperlocomotion and cognitive deficit) and biochemical (increase of acetylcholinesterase activity) changes which characterize an animal model of schizophrenia in rats. Our results indicated that rivastigmine was effective to improve the cognitive deficit in different task (immediate memory, long term memory and short term memory) induced by ketamine in rats. Moreover, we observed that rivastigmina reversed the increase of acetylcholinesterase activity induced by ketamine in the cerebral cortex, hippocampus and striatum. However, rivastigmine was not able to prevent the ketamine-induced hyperlocomotion. In conslusion, ours results indicate that cholinergic system might be an important therapeutic target in the physiopathology of schizophrenia, mainly in the cognition, but additional studies should be carried.
- ATRA alters humoral responses associated with amelioration of EAMG symptoms by balancing Tfh/Tfr helper cell profiles. [JOURNAL ARTICLE]
- Clin Immunol 2013 May 24; 148(2):162-176.
All-trans retinoic acid (ATRA) is a vitamin A metabolite with diverse immunomodulatory actions used therapeutically in the treatment of some autoimmune diseases. However, the effects that ATRA may have on diminishing myasthenia gravis (MG) symptoms remain undefined. This study investigated the effect of ATRA on experimental autoimmune myasthenia gravis (EAMG) in vivo and in vitro. Data presented in this study demonstrated that intraperitoneal injection of ATRA ameliorated EAMG pathology in rats associated with reduced total anti-acetylcholine receptor (AChR) serum IgG levels. We observed that EAMG development was accompanied by an increase in follicular helper T cells (Tfh, defined as CD4(+)CXCR5(+)ICOS(high)) and a decrease of follicular regulatory T cells (Tfr, defined as CD4(+)Foxp3(+)CXCR5(+)ICOS(median)) and that the Tfh:Tfr ratio was altered following ATRA administration. In addition, ATRA treatment restored the Th1/Th2/Th17/Treg balance. In vitro, ATRA inhibited AChR-specific cell proliferation and eliciting apoptosis in these cells without affecting the cell cycle. ATRA also altered the Th distribution in animals presenting with EAMG resulting in a reduction in Th1/Th17/Tfh cells and increasing the number of Th2/Treg/Tfr cell types. These results suggested that ATRA reduced EAMG severity by regulating Th cell profiles thereby providing new insights into the development of novel MG (or related) therapies.
- Changes in the Cholinergic System between Bipolar Depression and Euthymia as Measured with [(123)I]5IA Single Photon Emission Computed Tomography. [JOURNAL ARTICLE]
- Biol Psychiatry 2013 Jun 14.