Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain. [Journal Article]
- 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.
- Effects of acetylcholinesterase inhibition on quality of recovery from isoflurane-induced anesthesia in horses. [Journal Article]
- Am J Vet Res 2014 Mar; 75(3):223-30.
Objective-To compare effects of 2 acetylcholinesterase inhibitors on recovery quality of horses anesthetized with isoflurane. Animals-6 horses in phase 1, 7 horses in phase 2A, and 14 horses in phase 2B. Procedures-The study comprised 3 phases (2 randomized, blinded crossover phases in horses undergoing orthopedic procedures and 1 prospective dose-determining phase). In phase 1, horses were anesthetized with isoflurane and received neostigmine or saline (0.9% NaCl) solution prior to anesthetic recovery. Phase 2A was a physostigmine dose-determining phase. In phase 2B, horses were anesthetized with isoflurane and received neostigmine or physostigmine prior to recovery. Objective recovery events were recorded and subjective visual analogue scale scores of recovery quality were assigned from video recordings. Results-Recovery measures in phase 1 were not different between horses receiving neostigmine or saline solution. In phase 2A, 0.04 mg of physostigmine/kg was the highest cumulative dose that did not cause clinically relevant adverse behavioral or gastrointestinal effects. Horses receiving physostigmine had higher mean ± SD visual analogue scale recovery scores (70.8 ± 13.3 mm) than did horses receiving neostigmine (62.4 ± 12.8 mm) in phase 2B, with fewer attempts until sternal and standing recovery. Incidence of colic behavior did not differ among groups. Conclusions and Clinical Relevance-Inhibition with physostigmine improved anesthetic recovery quality in horses anesthetized with isoflurane, compared with recovery quality for horses receiving neostigmine. Inhibition of central muscarinic receptors by inhalation anesthetics may underlie emergence delirium in horses recovering from anesthesia.
- Copper(I)-catalyzed aryl or vinyl addition to electron-deficient alkenes cascaded by cationic cyclization. [Journal Article]
- Org Lett 2014 Mar 7; 16(5):1322-5.
An exoselective copper-catalyzed arylation- and vinylation-carbocyclization of electron-deficient alkenes was developed to provide rapid and efficient access to a variety of functionalized 3,3-disubstituted oxindoles. With this method, a highly efficient and concise formal synthesis of (±)-physostigmine and (±)-physovenine has been completed.
- [Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex]. [English Abstract, Journal Article]
- Sheng Li Xue Bao 2013 Dec 25; 65(6):607-15.
The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects.
- In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat. [Journal Article]
- Clin Exp Pharmacol Physiol 2014 Feb; 41(2):139-46.
Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
- Functional study on the mutations in the silkworm (Bombyx mori) acetylcholinesterase type 1 gene (ace1) and its recombinant proteins. [Journal Article, Research Support, Non-U.S. Gov't]
- Mol Biol Rep 2014 Jan; 41(1):429-37.
The acetylcholinesterase of Lepidoptera insects is encoded by two genes, ace1 and ace2. The expression of the ace1 gene is significantly higher than that of the ace2 gene, and mutations in ace1 are one of the major reasons for pesticide resistance in insects. In order to investigate the effects of the mutations in ace1's characteristic sites on pesticide resistance, we generated mutations for three amino acids using site-directed mutagenesis, which were Ala(GCG)303Ser(TCG), Gly(GGA)329Ala(GCA) and Leu (TCT)554Ser(TTC). The Baculovirus expression system was used for the eukaryotic expression of the wild type ace1 (wace1) and the mutant ace1 (mace1). SDS-PAGE and Western blotting were used to detect the targeting proteins with expected sizeof about 76 kDa. The expression products were purified for the determination of AChE activity and the inhibitory effects of physostigmine and phoxim. We observed no significant differences in the overall activity of the wild type and mutant AChEs. However, with 10 min of physostigmine (10 μM) inhibition, the remaining activity of the wild type AChE was significantly lower than that of the mutant AChE. Ten min inhibition with 33.4 μM phoxim also resulted in significantly lower remaining activity of the wild type AChE than that of the mutant AChE. These results indicated that mutations for the three amino acids reduced the sensitivity of AChE to physostigmine and phoxim, which laid the foundation for future in vivo studies on AChE's roles in pesticide resistance.
- Belladonna Alkaloid Intoxication: The 10-Year Experience of a Large Tertiary Care Pediatric Hospital. [JOURNAL ARTICLE]
- Am J Ther 2013 Nov 20.
The belladonna alkaloids can be isolated from a number of plants, which contain hallucinogens that represent a serious danger to infants, children, and adolescents. Roots, leaves, and fruits of the plant contain the alkaloids atropine, hyoscyamine, and scopolamine, which can lead to an anticholinergic toxidrome; however, not all characteristics of the toxidrome are necessarily present in each case of poisoning. A retrospective chart review of all children seen following anticholinergic ingestions, between April 2001 and November 2010, at the Hospital for Sick Children in Toronto. Ten children, with a mean age of 15.5 years (range, 15-18 years), were identified; 5 had used jimsonweed and the others had a variety of tablets containing atropine. All 10 presented with severe anticholinergic symptoms and 2 with suicide attempts. Treatments included charcoal, benzodiazepines, haloperidol, and physostigmine, and 2 patients were intubated. Ingestion and subsequent severe anticholinergic toxidrome occurred exclusively in adolescents. It is important to educate this age group regarding the toxicity and potential risks associated with the recreational use of these plants and substances. Physostigmine can help in both the diagnosis and management of patients intoxicated with these substances.
- Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease. [Journal Article]
- J Pharm Pharmacol 2013 Dec; 65(12):1701-25.
The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl- and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies.Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors.The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.
- Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment. [Journal Article, Research Support, Non-U.S. Gov't]
- J Pharm Pharmacol 2013 Dec; 65(12):1681-700.
Alzheimer's disease (AD) is the most common cause of dementia, being responsible for high healthcare costs and familial hardships. Despite the efforts of researchers, no treatment able to delay or stop AD progress exists. Currently, the available treatments are only symptomatic, cholinesterase inhibitors being the most widely used drugs. Here we describe several natural compounds with anticholinesterase (acetylcholinesterase and butyrylcholinesterase) activity and also some synthetic compounds whose structures are based on those of natural compounds.Galantamine and rivastigmine are two cholinesterase inhibitors used in therapeutics: galantamine is a natural alkaloid that was extracted for the first time from Galanthus nivalis L., while rivastigmine is a synthetic alkaloid, the structure of which is modelled on that of natural physostigmine. Alkaloids include a high number of compounds with anticholinesterases activity at the submicromolar range. Quinones and stilbenes are less well studied regarding cholinesterase inhibition, although some of them, such as sargaquinoic acid or (+)-α-viniferin, show promising activity. Among flavonoids, flavones and isoflavones are the most potent compounds. Xanthones and monoterpenes are generally weak cholinesterase inhibitors.Nature is an almost endless source of bioactive compounds. Several natural compounds have anticholinesterase activity and others can be used as leader compounds for the synthesis of new drugs.
- Unusual acetylation-dependent reaction cascade in the biosynthesis of the pyrroloindole drug physostigmine. [Journal Article, Research Support, Non-U.S. Gov't]
- Angew Chem Int Ed Engl 2014 Jan 3; 53(1):136-9.
Physostigmine is a parasympathomimetic drug used to treat a variety of neurological disorders, including Alzheimer's disease and glaucoma. Because of its potent biological activity and unique pyrroloindole skeleton, physostigmine has been the target of many organic syntheses. However, the biosynthesis of physostigmine has been relatively understudied. In this study, we identified a biosynthetic gene cluster for physostigmine by genome mining. The 8.5 kb gene cluster encodes eight proteins (PsmA-H), seven of which are required for the synthesis of physostigmine from 5-hydroxytryptophan, as shown by in vitro total reconstitution. Further genetic and enzymatic studies enabled us to delineate the biosynthetic pathway for physostigmine. The pathway features an unusual reaction cascade consisting of highly coordinated methylation and acetylation/deacetylation reactions.