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- Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase. [JOURNAL ARTICLE]
- Bioorg Med Chem 2014 Jun 26.
A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
- Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand (18) F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys. [JOURNAL ARTICLE]
- Synapse 2014 Jul 17.
Objective: (18) F-(-)-NCFHEB (also known as (18) F-(-)-Flubatine) is a new radioligand to image α4β2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as (18) F-2-F-A85380. The goal of this study was to assess the sensitivity of (18) F-(-)-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors. Methods: Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. (18) F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP . Results: (18) F-(-)-NCFHEB fP was 0.89±0.04. At baseline, (18) F-(-)-NCFHEB VT /fP ranged from 7.9±1.3 mL plasma/cm(3) tissue in the cerebellum to 34.3±8.4 mL plasma/cm(3) tissue in the thalamus. Physostigmine induced a dose-dependent reduction of (18) F-(-)-NCFHEB VT /fP of 34±9% in the putamen, 32±8% in the thalamus, 25±8% in the cortex, and 23±10% in the hippocampus. With donepezil, (18) F-(-)-NCFHEB VT /fP was reduced by 24±2%, 14+3% and 14±5%, 10±6% in the same regions. Conclusion: (18) F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
- Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum. [JOURNAL ARTICLE]
- J Radiat Res 2014 Jun 8.
It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.
- Surgery-induced changes in rat IL1ß and acetylcholine metabolism: role of physostigmine. [JOURNAL ARTICLE]
- Clin Exp Pharmacol Physiol 2014 May 29.
Pharmacological enhancement of cholinergic activities by administering physostigmine is known to induce protective effects. It is unclear, however, whether the impact of physostigmine on inflammation and acetylcholine metabolism is related to different types of surgical intervention or to anesthesia alone. To determine this, rats were subjected to partial liver resection (PLR) or sham surgery. A control group only received anesthesia. Half of each treatment group received a single intraoperative dose of physostigmine; the others received placebo. Acetylcholine esterase (ACHE) activity and IL1ß and acetylcholine (ACH) concentrations were determined. Both PLR and sham operation induced a time-dependent increase in plasma concentration of IL1ß (3.9 and 4.8-fold) as compared to rats that received anesthesia alone. In rat brain, IL1ß had increased by about twofold after surgery as compared to controls. Blood ACHE was transiently decreased after surgery. Brain ACHE activity increased 1.3-fold (p=0.014) only after PLR; consequently, the cerebral ACH concentration was significantly reduced. Physostigmine administration significantly reduced IL1ß and ACHE levels. Cerebral ACH concentration was markedly increased from 543.9±121.5 (placebo) to 653.5±93.3 ng mg(-1) protein (p<0.001) after administering physostigmine. We conclude that a single dose of physostigmine intraoperatively had a sustained anti-inflammatory effect up to 120 min after injection that was especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts neuroprotective action by increasing levels of the neurotransmitter ACH. This article is protected by copyright. All rights reserved.
- Microcirculatory Effects of Physostigmine on Experimental Burn Edema. [JOURNAL ARTICLE]
- J Burn Care Res 2014 May 12.
In order to further understand the role of the cholinergic anti-inflammatory pathway, the authors determined the effects of burn plasma from donor rats (DRs) on the microvascular circulation of healthy recipient rats and whether these could be altered by pretreatment with physostigmine (PT).DRs underwent thermal injury (100°C water, 12 seconds, 30% BSA) for positive controls. For negative controls DRs underwent sham burn (same procedure but water at 37°C). DR-plasma (harvested 4 hours posttrauma) was transferred to healthy rats. Bolus injection of PT (70 μg/kg body weight) was performed 15 minutes before starting the infusion of DR-plasma in the study group. Intravital microscopy was performed in mesenteric venules (0/60/120 minutes). Edema was assessed by FITC-albumin extravasation. Additionally, leukocyte rolling and sticking (cells/mm) as well as hemodynamic parameters were assessed.Burn plasma transfer significantly increases albumin extravasation in healthy individuals when compared with sham-burn treatment. Additional bolus administration of PT (70 μg/kg body weight) to burn plasma treatment reduces plasma extravasation to sham-burn levels. PT also attenuates leukocyte-endothelial interactions. After 120 minutes no significant changes in the systemic circulation (mean arterial pressure, heart rate, wall shear rate) were found between the groups.Burn plasma transfer results in significant increases in plasma extravasation and leukocyte-endothelial wall adherence, which are reversed by pretreatment with PT. These results suggest that the cholinergic anti-inflammatory pathway may play a role in the microcirculatory response to thermal injury.
- Use of a Physostigmine Continuous Infusion for the Treatment of Severe and Recurrent Antimuscarinic Toxicity in a Mixed Drug Overdose. [JOURNAL ARTICLE]
- J Med Toxicol 2014 May 6.
Physostigmine was once a widely used antidote for the treatment of antimuscarinic toxicity. However, reports describing the association of physostigmine with asystole and seizures in severe tricyclic antidepressant poisoning resulted in a decrease in use. Recent literature has demonstrated that physostigmine is a safe and effective antidote for the treatment of antimuscarinic toxicity. There are only two previously published articles regarding the use of physostigmine administered as a continuous intravenous infusion for persistent antimuscarinic toxicity. We present a case of physostigmine continuous infusion for the treatment of antimuscarinic symptoms in a polydrug overdose due to the ingestion of diphenhydramine along with bupropion, citalopram, acetaminophen, and naproxen.A 13-year-old female presented with hyperthermia, myoclonus and rigidity, hallucinations, severe agitation, and antimuscarinic toxicity including inability to sweat after a polydrug overdose. Several doses of lorazepam were administered followed by physostigmine which produced resolution of hallucinations and attenuation of the antimuscarinic symptoms including perspiration, temperature improvement, and decreased agitation. After periods of improvement and recurrence of antimuscarinic effects, a continuous infusion of physostigmine was administered at 2 mg/h and continued for almost 8 h to maintain attenuation of symptoms. GABAergic agents including lorazepam and phenobarbital were used later in the hospital course for presumed symptoms of serotonergic and adrenergic toxicity after resolution of antimuscarinic effects. The patient did not experience any adverse effects of physostigmine administration.Physostigmine administered as a continuous infusion may be a reasonable treatment option for severe and recurrent symptoms related to antimuscarinic toxicity.
- [Psychopharmalogical treatment of delirium in the elderly]. [English Abstract, Journal Article]
- Med Monatsschr Pharm 2014 Apr; 37(4):124-31; quiz 133-4.
Delirium is frequent in hospitalized elderly. Treatment of the medical problems causing delirium is paramount. Mostly antipsychotics are used for treatment of psychological and behavioral symptoms in delirium. Increased mortality of elderly and demented patients receiving antipsychotics suggests caution in prescribing antipsychotics for delirium. Standard treatment is low-dose haloperidol. If more sedation is needed, melperone or pipamperone can be used. In delirious Parkinsonian patients or if dementia with Lewy-bodies is suspected quetiapine is better tolerated. Other sedating antipsychotics like prothipendyl, promethazine or levomepromazin are considered inappropriate medication in the elderly due to their anticholinergic and orthostatic side effects. Cholinesterase inhibitors are not effective in delirium, except physostigmine for treatment of anticholinergic intoxication confined to intensive care. Benzodiazepines are effective in alcohol- und benzodiazepine-withdrawal, but may induce delirium (paradox reaction). Clomethiazole is contraindicated in frequent pulmonal conditions in the elderly like COPD. Chloral hydrate is considered inappropriate medication in the elderly due to QTc-prolongation. On intensive care units clonidine and recently dexmedetomidine are useful. At the moment there are no data indicating melatonin being effective for treatment of delirium.
- mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells. [Journal Article]
- BMC Pulm Med 2014; 14(1):53.
Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses.Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
- Acetylcholinesterase Inhibitory Activity and Molecular Docking Study of 1-Nitro-2-Phenylethane, the Main Constituent of Aniba canelilla Essential Oil. [JOURNAL ARTICLE]
- Chem Biol Drug Des 2014 Mar 24.
The odoriferous principle of Aniba canelilla (H.B.K.) Mez is due 1-nitro-2-phenylethane, the main constituent of its essential oil and also responsible for the plant's cinnamon scent. This nitroderivative was previously reported by their antioxidant, antinociception, cardiovascular, and vasorelaxant properties, and now it was tested as the inhibitor of acetylcholinesterase using bioautography on TLC plates. The oil and a purified fraction containing 1-nitro-2-phenylethane were analyzed by GC and GC-MS. The percentage content of 1-nitro-2-phenylethane in the oil and after fractionation was 70.2% and 98.0%, respectively. The results showed that the oil and 1-nitro-2-phenylethane are strong acetylcholinesterase inhibitors with the detection limit of 0.01 ng, equivalent to physostigmine used as the positive control. A molecular docking study was used to determine the position and conformation of the 1-nitro-2-phenylethane inhibitor in the receptor-binding pocket of the acetylcholinesterase enzyme. The nitrogroup of 1-nitro-2-phenylethane was positioned near of the catalytic serine residue of acetylcholinesterase, forming strong hydrogen bond with its hydroxyl group. Therefore, the electronegative character of 1-nitro-2-phenylethane may explain the interaction that occurs with the catalytic serine residue and its significant inhibitory activity of acetylcholinesterase.
- Inhibition of acetylcholinesterase modulates NMDA receptor antagonist mediated alterations in the developing brain. [Journal Article, Research Support, Non-U.S. Gov't]
- Int J Mol Sci 2014; 15(3):3784-98.
Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.