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1.
Pestic Biochem Physiol ; 170: 104701, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980054

RESUMO

Fifteen flavonoids isolated from the Eupatorium adenophorum showed inhibitory activities against acetylcholinesterase (AChE) isolated from Caenorhabditis elegans and Spodoptera litura. Their IC50 values ranged from 12.54 to 89.06µg/mL and 12.08 to 86.01µg/mL, respectively against the AChE isolated from the nematode and insect species. AChE was inhibited in a dose-dependent manner by all tested flavonoids, The isolated compound quercetagetin-7-O-(6-O-caffeoyl-ß-D-glucopyranoside) displayed the highest inhibitory effect against AChE from C. elegans and S. litura, with IC50 values of 12.54 µg/mL and 12.58 µg/mL, respectively. The structure-activity relationship of flavonoids on the inhibitory activities indicated that additional phenolic hydroxyl groups in the glucose were favorable for their inhibitory effects and the degree of increase in inhibitory activity also depended on the number of phenolic hydroxyl groups. The Lineweaver-Burk and Dixon plots indicated that quercetagetin-7-O-(6-O-caffeoyl-ß-d-glucopyranoside) is a reversible inhibitor against AChE. Quercetagetin-7-O-(6-O-caffeoyl-ß-d-glucopyranoside), 5,4'-Dihydroxytlavone and quercetin-3-O-ß-d-glucopyranoside inhibited AChE in a mixed-type competitive manner and these compounds might be the dual binding site AChE inhibitors. Further, nine compounds showed poisonous effects against C. elegans and inhibitory effects on the growth and development of S. litura.


Assuntos
Acetilcolinesterase , Ageratina , Animais , Caenorhabditis elegans , Inibidores da Colinesterase/farmacologia , Flavonoides/farmacologia
2.
Chem Biol Interact ; 330: 109225, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795450

RESUMO

Two types of cholinesterases (ChEs) are present in mammalian blood and tissues: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). While AChE regulates neurotransmission by hydrolyzing acetylcholine at the postsynaptic membranes and neuromuscular junctions, BChE in plasma has been suggested to be involved in detoxifying toxic compounds. This study was undertaken to establish the identity of circulating ChE activity in plasmas from domestic animals (bovine, ovine, caprine, porcine and equine) by assessing sensitivity to AChE-specific inhibitors (BW284c51 and edrophonium) and BChE-specific inhibitors (dibucaine, ethopropazine and Iso-OMPA) as well as binding to anti-FBS AChE monoclonal antibodies (MAbs). Based on the inhibition of ChE activity by ChE-specific inhibitors, it was determined that bovine, ovine and caprine plasma predominantly contain AChE, while porcine and equine plasma contain BChE. Three of the anti-FBS AChE MAbs, 4E5, 5E8 and 6H9, inhibited 85-98% of enzyme activity in bovine, ovine and caprine plasma, confirming that the esterase in these plasmas was AChE. These MAbs did not bind to purified recombinant human or mouse AChE, demonstrating that these MAbs were specific for AChEs from ruminant species. These MAbs did not inhibit the activity of purified human BChE, or ChE activity in porcine and equine plasma, confirming that the ChE in these plasmas was BChE. Taken together, these results demonstrate that anti-FBS AChE MAbs can serve as useful tools for distinguishing between AChEs from ruminant and non-ruminant species and BChEs.


Assuntos
Acetilcolinesterase/imunologia , Anticorpos Monoclonais/sangue , Butirilcolinesterase/imunologia , Acetilcolinesterase/sangue , Animais , Animais Domésticos/imunologia , Butirilcolinesterase/sangue , Bovinos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Sangue Fetal/imunologia , Humanos , Camundongos , Ruminantes/imunologia
3.
Planta Med ; 86(15): 1118-1124, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32668479

RESUMO

Restoration of cholinergic function is considered a rational approach to enhance cognitive performance. Acetylcholinesterase inhibitors are still the best therapeutic option for Alzheimer's disease. The fruits of Piper longum have been used in traditional medicines for the treatment of memory loss. It was demonstrated that the dichloromethane extract of these fruits is able to inhibit acetylcholinesterase. Thus, the aim of this study was to identify the contained acetylcholinesterase inhibitors. The active zones were presented via TLC-bioautography, and five compounds were isolated in the process of a bioassay-guided phytochemical investigation. Their structures were characterized as piperine, methyl piperate, guineenisine, pipercide, and pellitorine using spectroscopy and spectrometry methods (UV, IR, MS, 1H-, and 13C-NMR). In vitro acetylcholinesterase inhibitory activities of the isolates and their IC50 values were determined via a colorimetric assay. Three of them exhibited enzyme inhibitory activities, with piperine being the most potent compound (IC50 of 0.3 mM). In order to investigate the binding mode of the tested compounds, docking studies were performed using the X-ray crystal structure of acetylcholinesterase from Tetronarce californica with the Protein Data Bank code 1EVE. The content of the active compounds in the extract was determined by a developed HPLC method. Piperine was present in the maximum quantity in the fruits (0.57%), whereas methyl piperate contained the minimum content (0.10%).


Assuntos
Piper , Acetilcolinesterase , Inibidores da Colinesterase/farmacologia , Frutas , Extratos Vegetais/farmacologia
4.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
5.
Chemosphere ; 258: 127344, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554011

RESUMO

Contamination by micro and nano plastics is actually considered as a global environmental preoccupation. The quantification of microplastics in natural habitats and the characterization of their potential effects in marine wild organisms is currently of high importance. The main objective of this work was to investigate the fate and the effects of a microplastic mixture (ratio of 1: polyethylene (PE), 1: polypropylene (PP)) in the wedge clam Donax trunculus. The assimilation kinetics of microplastics particles was assessed in different organs (gills, digestive gland and flesh) using three different protocols (direct observation, H2O2, and HNO3/HCl digestion) in order to compare method's efficacity. The main biological endpoints studied were Aceylcholinesterase (AChE) inhibition as a neurotoxicity biomarker, the Catalase (CAT) enzymatic activity and the Gluthation-S-Transfereases (GSTs) activities as oxidative stress and phase II detoxification phase markers, respectively. Results showed that the H2O2 digestion method was more efficient to assess particles assimilation than the direct observation and acid digestion. In all cases no particles were detected in clam's flesh and gills were the first target organ for micro-plastics accumulation. The exposure of Donax truculus to PP/PE mixture (0.06 g/Kg of sand) induce a significant inhibition of AChE activity in both gills and digestive gland and oxidative stress in all organs studied. This study brings new results on the potential accumulation of PP and PE associated to neurotoxicity and oxidative stress of the wedge clam Donax trunculus.


Assuntos
Bivalves/efeitos dos fármacos , Microplásticos/toxicidade , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Catalase/metabolismo , Inibidores da Colinesterase/farmacologia , Sinergismo Farmacológico , Glutationa Transferase/metabolismo , Polietileno/toxicidade , Polipropilenos/toxicidade
6.
Food Chem ; 327: 127045, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464460

RESUMO

In this study, the inhibitory potentials of food originated 34 phenolic acids, and flavonoid compounds were screened against acetylcholinesterase, butyrylcholinesterase, urease, and tyrosinase enzymes. All compounds included in this study exhibited high antioxidant activity with an ignorable cytotoxic activity. In general, they also showed poor anti-urease and anti-tyrosinase activities. Compounds in aglycone form (quercetin, myricetin, chrysin, and luteolin) showed strong anticholinesterase activities. No relation was observed between the tested bioactivities except from the case that aglycone compounds exhibited a strong positive relationship between antioxidant activities and anticholinesterase activity. Interestingly, there was a relation between the molecular weights of aglycone compounds and their anticholinesterase activities. The study showed that flavonoids with molecular mass of 250-320 g/mol have high potential of anticholinesterase activities and are valuable for future experiments on animals and humans. Potential inhibitory effects of these molecules on target proteins were investigated using docking and molecular dynamics calculations.


Assuntos
Inibidores da Colinesterase/química , Flavonoides/química , Hidroxibenzoatos/química , Plantas Comestíveis/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Hidroxibenzoatos/metabolismo , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Plantas Comestíveis/metabolismo
7.
Chem Biol Interact ; 326: 109139, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32454005

RESUMO

Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich phenols can reactivate the inhibited enzyme very effectively, and may therefore represent an attractive complementary class of reactivators. In this paper we further probe the effect of structural variation on the in vitro efficacy of Mannich phenol based reactivators. Thus, we present the synthesis of 14 compounds that are close variants of the previously reported 4-amino-2-(1-pyrrolidinylmethyl)-phenol, a very effective non-oxime reactivator, and 3 dimeric Mannich phenols. All compounds were assessed for their ability to reactivate human acetylcholinesterase inhibited by the nerve agents VX, tabun, sarin, cyclosarin and paraoxon in vitro. It was confirmed that the potency of the compounds is highly sensitive to small structural changes, leading to diminished reactivation potency in many cases. However, the presence of 4-substituted alkylamine substituents (as exemplified with the 4-benzylamine-variant) was tolerated. More surprisingly, the dimeric compounds demonstrated non-typical behavior and displayed some reactivation potency as well. Both findings may open up new avenues for designing more effective non-oxime reactivators.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacologia , Oximas/química , Oximas/farmacologia , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Reativadores da Colinesterase/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Relação Estrutura-Atividade
8.
BMC Complement Med Ther ; 20(1): 129, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345272

RESUMO

BACKGROUND: Evolvulus alsinoides (Linn.) Linn. (Convolvulaceae) is a therapeutic herb alleviating brain patterns associated with three categories of regulatory principles of the body, mind, and behaviour. In the current research, enzyme inhibition and cytotoxic potentials of E. alsinoides (L.) L. leaf extract has been studied validating its potential application. METHODS: The plant phenolics in the leaf extracts obtained via cold-maceration with solvents viz.: n-hexane, chloroform, ethyl acetate, methanol, and water were quantitatively analyzed. The antioxidant potency was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Ability of Plasma (FRAP) assays at five concentrations (100-500 µg). The enzyme inhibition potential was performed with α-amylase, α-glucosidase, and acetylcholinesterase at seven concentrations (25-500 µg). The experiments were done in triplicates and statistically validated using Minitab-17 and SPSS 22. RESULTS: Water extract contain 45.08 ± 0.02 mg GAE/g, 49.30 ± 0.07 mg GAE/g, 211.21 ± 0.02 mg QE/g tannins, phenolics, flavonoids respectively. Its antioxidant activity was supported by IC50 52.43 ± 0.2 µg/mL (DPPH assay) and 41.58 ± 0.03 (FRAP assay). Methanolic extract inhibits α-amylase with IC50 1.33 ± 0.05 µg/mL. Water extract inhibits α-glucosidase and acetylcholinesterase with IC50 3.58 ± 0.02 µg/mL and 4.46 ± 0.03 µg/mL. Cytotoxicity studies with SH-SY5Y cell-line substantiate the inhibition potential of water extract with IC50 103.0035 µg/mL. DISCUSSION AND CONCLUSIONS: The extracts with potent antioxidant and enzyme-inhibiting activity were determined. The findings of the research are the first report about the inhibition effects of Evolvulus alsinoides (Linn.) Linn extracts against α-amylase, α-glucosidase and acetylcholinesterase. The extracts shall be examined in future studies to evaluate its pharmaceutical potential.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Diabetes Mellitus/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , Acetilcolinesterase , Doença de Alzheimer/enzimologia , Linhagem Celular Tumoral , Convolvulaceae/química , Diabetes Mellitus/enzimologia , Humanos , Índia , Medicina Ayurvédica , Extratos Vegetais/química , Folhas de Planta/química , alfa-Glucosidases
9.
Chem Biol Interact ; 324: 109092, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278739

RESUMO

Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger that protects from the toxicity of nerve agents. Non-human primates are suitable models for toxicity studies that cannot be performed in humans. We evaluated the biochemical properties of native macaque (MaBChE) tetramers, compared to recombinant MaBChE monomers, PEGylated recombinant MaBChE tetramers and monomers, and native HuBChE tetramers. Km and kcat values for butyrylthiocholine were independent of subunit assembly status. The Km for all forms of MaBChE was about 70 µM, compared to 13 µM for HuBChE. The kcat was about 100,000 min-1 for MaBChE and 30,000 min-1 for HuBChE. The reversible inhibitor ethopropazine had similar Ki values of 0.05 µM for all MaBChE forms and HuBChE. The bimolecular rate constant, ki, for inhibition by diisopropylfluorophosphate (DFP), an analog of sarin, was 2.2 to 2.5 × 107 M-1 min-1 for all MaBChE forms and for HuBChE. A major difference between MaBChE and HuBChE was the rate of reactivation by 2-PAM. The second order rate constant for reactivation of DFP-inhibited MaBChE by 2-PAM was 1.4 M-1 min-1, but was 380 fold faster for DFP-inhibited HuBChE (kr 531 M-1 min-1). The acyl pocket of MaBChE has Leu285 in place of Pro285 in HuBChE. The reactivation rate of DFP-inhibited HuBChE mutant P285L by 2-PAM was reduced 5.8-fold (kr 92 M-1 min-1) indicating that P285 determines whether 2-PAM binds in an orientation that favors release of diisopropylphosphate. DFP-inhibited MaBChE treated with 0.2 M 2-PAM recovered 10% of its original activity, whereas DFP-inhibited HuBChE recovered 80% activity. It was concluded that the biochemical properties of MaBChE are similar to those of HuBChE except for the reactivation of DFP-inhibited BChE.


Assuntos
Butirilcolinesterase/química , Reativadores da Colinesterase/química , Compostos de Pralidoxima/química , Prolina/química , Sequência de Aminoácidos , Animais , Inibidores da Colinesterase/farmacologia , Humanos , Cinética , Macaca , Macaca mulatta , Fenotiazinas/farmacologia , Alinhamento de Sequência
10.
Br J Anaesth ; 124(5): 553-561, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139135

RESUMO

BACKGROUND: Residual neuromuscular block has been associated with postoperative pulmonary complications. We hypothesised that sugammadex reduces postoperative pulmonary complications in patients aged ≥70 yr having surgery ≥3 h, compared with neostigmine. METHODS: Patients were enrolled in an open-label, assessor-blinded, randomised, controlled trial. At surgical closure, subjects were equally randomised to receive sugammadex 2 mg kg-1 or neostigmine 0.07 mg kg-1 (maximum 5 mg) for rocuronium reversal. The primary endpoint was incidence of postoperative pulmonary complications. Secondary endpoints included residual paralysis (train-of-four ratio <0.9 in the PACU) and Phase 1 recovery (time to attain pain control and stable respiratory, haemodynamic, and neurological status). The analysis was by intention-to-treat. RESULTS: Of the 200 subjects randomised, 98 received sugammadex and 99 received neostigmine. There was no significant difference in the primary endpoint of postoperative pulmonary complications despite a signal towards reduced incidence for sugammadex (33% vs 40%; odds ratio [OR]=0.74; 95% confidence interval [CI]=[0.40, 1.37]; P=0.30) compared with neostigmine. Sugammadex decreased residual neuromuscular block (10% vs 49%; OR=0.11, 95% CI=[0.04, 0.25]; P<0.001). Phase 1 recovery time was comparable between sugammadex (97.3 min [standard deviation, sd=54.3]) and neostigmine (110.0 min [sd=62.0]), difference -12.7 min (95% CI, [-29.2, 3.9], P=0.13). In an exploratory analysis, there were fewer 30 day hospital readmissions in the sugammadex group compared with the neostigmine group (5% vs 15%; OR=0.30, 95% CI=[0.08, 0.91]; P=0.03). CONCLUSIONS: In older adults undergoing prolonged surgery, sugammadex was associated with a 40% reduction in residual neuromuscular block, a 10% reduction in 30 day hospital readmission rate, but no difference in the occurrence of postoperative pulmonary complications. Based on this exploratory study, larger studies should determine whether sugammadex may reduce postoperative pulmonary complications and 30 day hospital readmissions. CLINICAL TRIAL REGISTRATION: NCT02861131.


Assuntos
Recuperação Demorada da Anestesia/prevenção & controle , Pneumopatias/prevenção & controle , Neostigmina/farmacologia , Complicações Pós-Operatórias/prevenção & controle , Sugammadex/farmacologia , Idoso , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/farmacologia , Método Duplo-Cego , Feminino , Humanos , Período Intraoperatório , Pneumopatias/etiologia , Masculino , Bloqueio Neuromuscular , Junção Neuromuscular/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Readmissão do Paciente/estatística & dados numéricos , Rocurônio/antagonistas & inibidores
11.
Chem Biol Interact ; 319: 109019, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092302

RESUMO

The inhibition of the enzyme acetylcholinesterase (AChE) is a frequently used therapeutic option to treat Alzheimer's disease (AD). By decreasing the levels of acetylcholine degradation in the synaptic space, some cognitive functions of patients suffering from this disease are significantly improved. Rivastigmine is one of the most widely used AChE inhibitors. The objective of this work was to determine the effects of this drug on human erythrocytes, which have a type of AChE in the cell membrane. To that end, human erythrocytes and molecular models of its membrane constituted by dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. They correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. The experimental results obtained by X-ray diffraction and differential scanning calorimetry (DSC) indicated that rivastigmine molecules were able to interact with both phospholipids. Fluorescence spectroscopy results showed that rivastigmine produce a slight change in the acyl chain packing order and a weak displacement of the water molecules of the hydrophobic-hydrophilic membrane interface. On the other hand, observations by scanning electron microscopy (SEM) showed that the drug changed the normal biconcave shape of erythrocytes in stomatocytes (cup-shaped cells) and echinocytes (speculated shaped).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Eritrócitos/efeitos dos fármacos , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Varredura Diferencial de Calorimetria/métodos , Forma Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/metabolismo , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Humanos , Microscopia Eletrônica de Varredura/métodos , Modelos Moleculares , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Espectrometria de Fluorescência/métodos , Difração de Raios X/métodos
12.
Nat Chem Biol ; 16(3): 240-249, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080630

RESUMO

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.


Assuntos
Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Colinérgicos/farmacologia , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação
13.
PLoS One ; 15(2): e0227820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032361

RESUMO

Cognitive impairment is a common complication observed after a stroke. Currently there are no definitively proven pharmacologic therapies for recovery from post-stroke cognitive impairment and vascular dementia. In this meta-analysis, we evaluated the efficacy and safety of cholinesterase inhibitors in their improvement of cognition in patients with post-stroke cognitive impairment and vascular dementia. We conducted a meta-analysis using seven eligible studies from 305 published articles. We investigated the differences in Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, before and after cholinergic augmentation in patients with post-stroke cognitive impairment and vascular dementia. MMSE and ADAS-cog scores were also compared during the subsequent follow-up periods. MMSE score of patients with post-stroke cognitive impairment was increased after cholinergic augmentation throughout the 24 weeks with mean differences [MD] of 3.000, 1.732, 1.578 1.516, and 1.222, at 4, 4-8, 8-12, 12-18, and 18-24 weeks, respectively. In addition, ADAS-cog scores decreased at 6, 12, 18, and 24 weeks by pharmaceutical augmentation, but not with placebo with mean differences [MD] of -2.333, -2.913, -2.767, -2.416, and -1.859, respectively. This meta-analysis shows that acetylcholinesterase inhibitors maintain a stable pattern of improved cognitive function in patients with post stroke cognitive impairment and vascular dementia without the increased risk of side effects.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
14.
Medicine (Baltimore) ; 99(7): e19130, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049831

RESUMO

BACKGROUND: Sugammadex reverses rocuronium-induced neuromuscular blockade quickly and effectively. This study compared efficacy of sugammadex and pyridostigmine for reversal of rocuronium-induced light block or minimal block in children scheduled for elective entropion surgery. METHODS: A prospective randomized study was conducted on 60 pediatric patients aged 1 to 11 years and scheduled for entropion surgery under sevoflurane anesthesia. Neuromuscular blockade was achieved by administration of 0.6 mg/kg rocuronium and assessed using train-of-four (TOF) ulnar nerve stimulation. Patients were randomly assigned to 2 groups receiving sugammadex 2 mg/kg or pyridostigmine 0.2 mg/kg plus glycopyrrolate 0.01 mg/kg. Primary outcomes were time from reversal agents administration to TOF ratio 0.9 and time from reversal agent administration to TOF ratio 1.0. Time from TOF ratio 0.9 to extubation, time from TOF ratio 1.0 to extubation, and postoperative adverse events were also recorded. RESULTS: There were no substantial differences in demographic variables. Time from reversal agents administration to TOF ratio 0.9 and time from reversal agents to TOF ratio 1.0 were significantly faster in sugammadex group: 1.30 ±â€Š0.84 versus 3.53 ±â€Š2.73 minutes (P < .001) and 2.75 ±â€Š1.00 versus 5.73 ±â€Š2.83 minutes (P < .001). Extubation time was shorter in sugammadex group. Incidence of skin rash, nausea, vomiting, and postoperative residual neuromuscular blockade (airway obstruction) was not statistically different between groups. Incidence of patients agitation in recovery room was lower in sugammadex group. CONCLUSION: Sugammadex provided more rapid reversal of rocuronium-induced neuromuscular blockade in pediatric patients undergoing surgery lasting 30 to 60 minutes than did pyridostigmine plus glycopyrrolate, with no differences in incidence of adverse events between groups.


Assuntos
Inibidores da Colinesterase/administração & dosagem , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Brometo de Piridostigmina/administração & dosagem , Rocurônio/antagonistas & inibidores , Sugammadex/administração & dosagem , Criança , Pré-Escolar , Inibidores da Colinesterase/farmacologia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Brometo de Piridostigmina/farmacologia , Distribuição Aleatória , Método Simples-Cego , Sugammadex/farmacologia , Fatores de Tempo
15.
J Pharmacol Exp Ther ; 373(1): 10-23, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31907304

RESUMO

Although there has been an increasing appreciation for functional differences between the dorsal (dH) and ventral (vH) hippocampal sectors, there is a lack of information characterizing the cholinergic and noncholinergic mechanisms of acetylcholinesterase inhibitors on synaptic transmission along the hippocampal dorsoventral axis. Diisopropylfluorophosphate (DFP) is an organophosphate (OP) that is commonly employed as a nerve agent surrogate in vitro as well as in rodent models of disease states, such as Gulf War Illness. The present study investigated the cholinergic and noncholinergic mechanisms responsible for the effects of acute DFP exposure on dH and vH synaptic transmission in a hippocampal slice preparation. A paired-pulse extracellular recording protocol was used to monitor the population spike (PS) amplitude as well as the PS paired-pulse ratio (PS-PPR) in the CA1 subfield of the dH and the vH. We observed that DFP-induced PS1 inhibition was produced by a cholinergic mechanism in the dH, whereas a noncholinergic mechanism was indispensable in mediating the inhibitory effect of DFP on the PS1 in the vH. PS-PPR in both dH and vH sectors was increased by acute DFP exposure, an effect that was blocked by an N-methyl-D-aspartate receptor antagonist but not by cholinergic antagonists. Clinical reports have indicated dorsoventral-specific hippocampal abnormalities in cases of OP intoxications. Therefore, the observed dorsoventral-specific noncholinergic mechanisms underlying the effects of DFP on hippocampal synaptic transmission may have important implications for the treatment of OP overexposures. SIGNIFICANCE STATEMENT: It is unknown if acetylcholinesterase inhibitors differentially impact dorsal and ventral hippocampal synaptic transmission. The data in the present study show that an organophosphate, diisopropylfluorophosphate, impacts glutamatergic transmission along the dorsoventral axis in a hippocampal slice preparation via distinct cholinergic and noncholinergic mechanisms. These findings may provide insight into investigations of therapeutic agents that target noncholinergic mechanisms in cases of organophosphate overexposures.


Assuntos
Inibidores da Colinesterase/farmacologia , Hipocampo/efeitos dos fármacos , Isoflurofato/farmacologia , Agentes Neurotóxicos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia
16.
J Enzyme Inhib Med Chem ; 35(1): 498-505, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914836

RESUMO

Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.


Assuntos
Amidas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Corantes Fluorescentes/farmacologia , Amidas/síntese química , Amidas/química , Animais , Butirilcolinesterase/isolamento & purificação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular
17.
Food Chem ; 314: 126181, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954938

RESUMO

The study analyzed the inhibitory effects (IC50) of crude and purified extracts from Maliniak, Cerise, Black Prince and Lima tomatoes on the formation of advanced glycation end products (AGEs), the activity of angiotensin-converting (ACE) and acetylcholinesterase (AChE) enzymes. Polyphenol composition (LC-MS) and antioxidant capacity (PCL, FRAP) were measured. The purified extracts of Black Prince tomatoes were the most potent inhibitors of AGEs in BSA-GLU (7.20mg/mL) and BSA-MGO (9.53mg/mL) models. The purified extracts of Cerise and Black Prince tomatoes had the highest ACE (0.50-0.44mg/mL) and AChE (7.93-5.83mg/mL) inhibitory activity. Cerise variety showed the highest polyphenol concentrations in crude (488.93µg/g DM) and purified (8394.99µg/g DM) extracts. The highest PCLACW and FRAP values were found for Cerise purified extracts (71.83 and 87.78µmol Trolox/g DM). Caffeic acid, caffeoyl-glucose, linocaffein, glucosyl-coumarate, vanillic acid, rutin and TPI values were significantly correlated with BSA-MGO, anti-ACE, anti-AChE and PCLACW parameters.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Colinesterase/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Lycopersicon esculentum/química , Extratos Vegetais/farmacologia , Polifenóis/análise , Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/análise , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Extratos Vegetais/isolamento & purificação , Especificidade da Espécie
18.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936622

RESUMO

Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar ß-amyloid 1-42 (Aß42), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA's) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Ácidos Cumáricos/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Acetilcolina/metabolismo , Acetilcolinesterase , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/química , Ácido Glutâmico/genética , Humanos , Ferro/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia
19.
J Enzyme Inhib Med Chem ; 35(1): 460-467, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899981

RESUMO

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.


Assuntos
Benzilaminas/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Oxazóis/química , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Técnicas Eletroquímicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Processos Fotoquímicos , Relação Estrutura-Atividade
20.
J Enzyme Inhib Med Chem ; 35(1): 424-431, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899985

RESUMO

A series of 16 novel benzenesulfonamides incorporating 1,3,5-triazine moieties substituted with aromatic amines, dimethylamine, morpholine and piperidine were investigated. These compounds were assayed for antioxidant properties by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, 2,2`-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical decolarisation assay and metal chelating methods. They were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase, which are associated with several diseases such as Alzheimer, Parkinson and pigmentation disorders. These benzenesulfonamides showed moderate DPPH radical scavenging and metal chelating activity, and low ABTS cation radical scavenging activity. Compounds 2 b, 3d and 3 h showed inhibitory potency against AChE with % inhibition values of >90. BChE was also effectively inhibited by most of the synthesised compounds with >90% inhibition potency. Tyrosinase was less inhibited by these compounds.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Antioxidantes/farmacologia , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazinas/química , Benzotiazóis/química , Compostos de Bifenilo/química , Picratos/química , Ácidos Sulfônicos/química
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