RESUMEN
The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP-inhibited acetylcholinesterase (AChE) which can penetrate the blood-brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24-h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP-inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%-102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2-PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Reactivadores de la Colinesterasa , Músculo Esquelético , Organofosfatos , Oximas , Animales , Oximas/farmacología , Oximas/química , Ratas , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/sangre , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/toxicidad , Organofosfatos/toxicidad , Masculino , Reactivadores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/química , Compuestos de Piridinio/farmacología , Ratas Sprague-DawleyRESUMEN
Pyrogallol, a botanical hydrolysable tannin, has diverse medical and industrial applications. Its impact on aquatic ecosystems and fish health has been previously studied, revealing histopathological, immunological, biochemical, and haematological alterations in African catfish (Clarias gariepinus). In this study, the neurotoxic potential of pyrogallol was assessed through a 15-day exposure of catfish to concentrations of 1, 5, or 10â¯mg/L. Enzyme activities such as acetylcholinesterase (AchE), monoamine oxidase (MAO), aldehyde oxidase (AO), and nitric oxide (NO) were measured in serum and brain, along with histopathological examinations in the brain and heart. Pyrogallol exposure led to decreased AchE activity in the brain and serum, increased serum MAO activity, elevated AO in both brain and serum, and suppressed NO levels. Morphological abnormalities and dose-dependent pathological alterations were observed in the brain and heart, including neuropile deformities, shrunken Purkinje cells, cardiomyocyte degeneration, and increased collagen fibers. This suggests that pyrogallol induces adverse effects in fish.
Asunto(s)
Encéfalo , Bagres , Óxido Nítrico , Pirogalol , Contaminantes Químicos del Agua , Animales , Óxido Nítrico/metabolismo , Óxido Nítrico/sangre , Encéfalo/efectos de los fármacos , Encéfalo/patología , Pirogalol/toxicidad , Contaminantes Químicos del Agua/toxicidad , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/sangre , Corazón/efectos de los fármacos , Miocardio/patología , Miocardio/metabolismo , Monoaminooxidasa/metabolismo , CardiotoxicidadRESUMEN
Over the past fifty years, swine models have been used for organophosphorus intoxication studies. Among these studies and others on the swine model in general, some physiological data, especially cholinesterase activity highly impacted by organophosphorus compounds like nerve agent VX, still need to be completed. To support and compare our model to others, we have published the experimental protocol, the physiological values of 31 juvenile anesthetized pigs, and the 6â¯h-follow-up of six supplementary anesthetized control animals and 7 VX-intoxicated pigs. We reported hemodynamics and respiratory parameters, blood levels in several biochemical parameters, blood gas, and complete blood count and compared them to the literature. We also focused on tissue and blood cholinesterase activities and detailed them for acetylcholinesterase and butyrylcholinesterase. After establishing a broad physiological data set consistent with the literature, we reported several cardio-respiratory parameters that seem more affected by an organophosphate intoxication, like heart rate, arterial blood pressure, cardiac output, and respiratory rate. Within the blood, oxygen saturation (SpO2), lactatemia, base excess, and glycemia can also be measured and associated with the other parameters to evaluate the life-threatening status. This swine model is currently used to develop and evaluate medical countermeasures against organophosphate nerve agent intoxications.
Asunto(s)
Compuestos Organotiofosforados , Animales , Compuestos Organotiofosforados/toxicidad , Porcinos , Modelos Animales de Enfermedad , Butirilcolinesterasa/sangre , Butirilcolinesterasa/metabolismo , Hemodinámica/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/sangre , Sustancias para la Guerra Química/toxicidad , AnestesiaRESUMEN
BACKGROUND: Organophosphate, pyrethroid, and neonicotinoid insecticides have resulted in adrenal and gonadal hormone disruption in animal and in vitro studies; limited epidemiologic evidence exists in humans. We assessed relationships of urinary insecticide metabolite concentrations with adrenal and gonadal hormones in adolescents living in Ecuadorean agricultural communities. METHODS: In 2016, we examined 522 Ecuadorian adolescents (11-17y, 50.7% female, 22% Indigenous; ESPINA study). We measured urinary insecticide metabolites, blood acetylcholinesterase activity (AChE), and salivary testosterone, dehydroepiandrosterone (DHEA), 17ß-estradiol, and cortisol. We used general linear models to assess linear (ß = % hormone difference per 50% increase of metabolite concentration) and curvilinear relationships (ß2 = hormone difference per unit increase in squared ln-metabolite) between ln-metabolite or AChE and ln-hormone concentrations, stratified by sex, adjusting for anthropometric, demographic, and awakening response variables. Bayesian Kernel Machine Regression was used to assess non-linear associations and interactions. RESULTS: The organophosphate metabolite malathion dicarboxylic acid (MDA) had positive associations with testosterone (ßboys = 5.88% [1.21%, 10.78%], ßgirls = 4.10% [-0.02%, 8.39%]), and cortisol (ßboys = 6.06 [-0.23%, 12.75%]. Para-nitrophenol (organophosphate) had negatively-trending curvilinear associations, with testosterone (ß2boys = -0.17 (-0.33, -0.003), p = 0.04) and DHEA (ß2boys = -0.49 (-0.80, -0.19), p = 0.001) in boys. The neonicotinoid summary score (ßboys = 5.60% [0.14%, 11.36%]) and the neonicotinoid acetamiprid-N-desmethyl (ßboys = 3.90% [1.28%, 6.58%]) were positively associated with 17ß-estradiol, measured in boys only. No associations between the pyrethroid 3-phenoxybenzoic acid and hormones were observed. In girls, bivariate response associations identified interactions of MDA, Para-nitrophenol, and 3,5,6-trichloro-2-pyridinol (organophosphates) with testosterone and DHEA concentrations. In boys, we observed an interaction of MDA and Para-nitrophenol with DHEA. No associations were identified for AChE. CONCLUSIONS: We observed evidence of endocrine disruption for specific organophosphate and neonicotinoid metabolite exposures in adolescents. Urinary organophosphate metabolites were associated with testosterone and DHEA concentrations, with stronger associations in boys than girls. Urinary neonicotinoids were positively associated with 17ß-estradiol. Longitudinal repeat-measures analyses would be beneficial for causal inference.
Asunto(s)
Biomarcadores , Insecticidas , Humanos , Adolescente , Femenino , Masculino , Ecuador , Insecticidas/orina , Insecticidas/sangre , Biomarcadores/orina , Biomarcadores/sangre , Niño , Hidrocortisona/orina , Deshidroepiandrosterona/orina , Deshidroepiandrosterona/sangre , Estradiol/sangre , Estradiol/orina , Agricultura , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Testosterona/sangre , Testosterona/orina , Saliva/química , Malatión/orinaRESUMEN
Pesticides safeguard crop health but may diminish cholinesterase activity in farmers, potentially leading to psychiatric disorders like depression and suicide attempts. This study, with 453 participants (225 pesticide-exposed farmers, 228 non-farmers) in Almería, Spain, aimed to investigate the presence of depressive symptoms and suicide attempts, the decrease acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity, and their relationship with pesticide exposure in farmers. Depressive symptoms were evaluated using the Spanish adaptation of the Beck Depression Inventory, and blood samples were analyzed for AChE and BChE activity. Farmers showed significantly increased risk of moderate/severe depression and suicide attempts compared to non-farmers (OR = 2.18; p = 0.001), with highest risks observed among mancozeb users (OR = 2.76; p = 0.001 for depression) and malathion users (OR = 3.50; p = 0.001 for suicide attempts). Findings emphasize elevated depression and suicide risks among pesticide-exposed farmers, particularly associated with chlorpyrifos, mancozeb, and malathion exposure.
Asunto(s)
Butirilcolinesterasa , Depresión , Agricultores , Exposición Profesional , Plaguicidas , Intento de Suicidio , Humanos , Masculino , Plaguicidas/toxicidad , Persona de Mediana Edad , Agricultores/psicología , Intento de Suicidio/estadística & datos numéricos , Intento de Suicidio/psicología , Depresión/inducido químicamente , Depresión/epidemiología , Femenino , Exposición Profesional/efectos adversos , Adulto , Butirilcolinesterasa/sangre , Acetilcolinesterasa/sangre , España/epidemiología , AncianoRESUMEN
Biomonitoring of pesticide exposure has become a public concern because of its potential health effects. The present study investigated the acetylcholinesterase (AChE) inhibitory levels and their associated health effects in agricultural areas in Telangana, India. This cross-sectional included 341 exposed participants and 152 control participants from agricultural areas. A structured questionnaire was completed and blood and urine samples were collected to measure pesticides, dialkyle phosphate (DAP) metabolites, and AChE activity using liquid chromatography-tandem mass spectrometry and reversed-phase high-performance liquid chromatography. twenty-eight pesticides were detected in blood samples at concentrations ranging 0.42-45.77 ng/mL. Six DAP metabolites were also measured in urine, and all DAP metabolites were significantly higher in the exposed group. AChE activity is significantly reduced in individuals exposed for >10 years, raising concerns regarding possible neurological disorders. These results emphasise the urgent need to investigate the health effects of pesticides exposure, especially in agriculture.
Asunto(s)
Inhibidores de la Colinesterasa , Exposición Profesional , Plaguicidas , Humanos , Exposición Profesional/análisis , India , Plaguicidas/orina , Adulto , Masculino , Estudios Transversales , Femenino , Persona de Mediana Edad , Agricultores , Adulto Joven , Agricultura , Acetilcolinesterasa/sangreRESUMEN
The objectives of the study were to evaluate the impact of pesticide exposure on farmer health during non-active rice farming and active rice farming periods and present the change in the individual cholinesterase activities (%reduction) on the geographic information system (GIS) mapping in Nakhon Ratchasima Province, Thailand. Acetyl- and butyryl-cholinesterase (AChE and BuChE) activities were monitored during both study periods using Test-mate ChE (Model 400). The location of paddy fields was specified using Garmin geographic positioning system MAP 62s. Fifty-eight farmers who participated in this study had an average age of 49.2 ± 6.9 years. Higher prevalence of all health symptoms was observed among farmer participants during the active rice farming period comparing to the non-active rice farming period (p < 0.01). Furthermore, farmers had significantly lower activities of AChE and BuChE during the active rice farming period comparing to the non-active rice farming period (p < 0.01). Our findings indicate that the GIS mapping indicate that the cases with a significant enzyme inhibition have dispersed across the agricultural and the nearby residential areas. This, investigation can be used to promote safer use of pesticides among farmers and mitigate pesticide exposure among residents living in close proximity to a rice field.
Asunto(s)
Sistemas de Información Geográfica , Exposición Profesional/efectos adversos , Oryza/crecimiento & desarrollo , Plaguicidas/toxicidad , Acetilcolinesterasa/sangre , Adulto , Enfermedades de los Trabajadores Agrícolas/sangre , Enfermedades de los Trabajadores Agrícolas/enzimología , Agricultura , Butirilcolinesterasa/sangre , Agricultores/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , TailandiaRESUMEN
The contact poison VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate) is a chemical warfare agent that is one of the most toxic organophosphorus compounds known. Its primary mechanism of toxic action is through the inhibition of acetylcholinesterase and resultant respiratory paralysis. The majority of work on VX has thus concentrated on its potent anticholinesterase activity and acute toxicity, with few studies investigating potential long-term effects. In this report we describe the effects of VX in aggregating rat brain cell cultures out to 28 days post-exposure. Cholinesterase activity was rapidly inhibited (60 min IC50 = 0.73 +/- 0.27 nM), but recovered towards baseline values over the next four weeks. Apoptotic cell death, as measured using caspase-3 activity was evident only at 100 µM concentrations. Cell type specific enzymatic markers (glutamine synthase, choline acetyltransferase and 2',3'-cyclic nucleotide 3'-phosphodiesterase) showed no significant changes. Total Akt levels were unchanged, while an increased phosphorylation of this protein was noted only at the highest VX concentration on the first day post-exposure. In contrast, significant and delayed (28 days post-exposure) decreases were noted in vascular endothelial growth factor (VEGF) levels, a protein whose reduced levels are known to contribute to neurodegenerative disorders. These observations may indicate that the long-term effects noted in some survivors of nerve agent intoxication may be due to VX-induced declines in brain VEGF levels.
Asunto(s)
Encéfalo/efectos de los fármacos , Sustancias para la Guerra Química/toxicidad , Compuestos Organotiofosforados/toxicidad , Acetilcolinesterasa/sangre , Acetilcolinesterasa/efectos de los fármacos , Animales , Apoptosis , Encéfalo/enzimología , Agregación Celular , Células Cultivadas , Inhibidores de la Colinesterasa/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Pruebas de Toxicidad Aguda , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A novel ratiometric fluorescence strategy for detection of acetylcholestinerase (AChE) is proposed based on carbon nitride quantum dots (g-CNQD) and the complex (PA) formed between phenylboronic acid (PBA) and alizarin red S (ARS). PA showed fluorescence at 598 nm and quenched the fluorescence of g-CNQD at 438 nm. Through UV-visible absorption, fluorescence, and fluorescence lifetime measurements, the quenching effect was demonstrated as inner filter effect (IFE). When Cu2+ was added, the coordination of ARS and Cu2+ decreased the fluorescence of PA at 598 nm and recovered that of g-CNQD at 438 nm. In the presence of AChE it catalyzed the hydrolysis of acetylthiocholine (ATCh) to produce thiocholine (TCh) which competed with ARS for binding to Cu2+; thus, the fluorescence at 598 nm increased and that at 438 nm decreased again. Under the mediation of Cu2+, the fluorescence ratio F598/F438 of PA-CNQD probe had good linear relationship with AChE concentration in the range 0.5-15 mU/mL with a detection limit of 0.36 mU/mL. The method was successfully applied to the determination of AChE in human serum and the screening of inhibitors.
Asunto(s)
Acetilcolinesterasa/sangre , Técnicas Biosensibles/métodos , Cobre/química , Fluorescencia , HumanosRESUMEN
Pesticides use in Southeast Asia has increased steadily, driven by the growth of large-scale commercial farming, as well as a desire to maximise food production in rural subsistence economies. Given that use of chemical pesticides, such as organophosphates and carbamates, has known potential health impacts, there are concerns about the safety of agricultural workers, and a need for a better evidence base to underpin regulation and worker education. This study, undertaken in 9 districts in Lao PDR, Thailand and Vietnam, will interview agricultural workers to investigate how they use pesticides, their knowledge of risks and self-protective practices, and their self-reported illness symptoms. In each district researchers will recruit and interview 120 participants engaged in vegetable farming, who have recently used pesticides, making a total of 1080 subjects divided equally between the three study countries. Workers' degree of pesticides exposure will be determined from acetyl cholinesterase concentrations in capillary blood samples collected using field test kits, and these data will be analysed together with the interview findings. Country findings will be compared and contrasted, and general patterns noted. Knowledge gained about risky behaviours, self-protective practices and degree of association with serious pesticides exposure will assist policy makers and inform health improvement programmes.
Asunto(s)
Acetilcolinesterasa/sangre , Enfermedades de los Trabajadores Agrícolas/sangre , Agricultores , Conocimientos, Actitudes y Práctica en Salud , Exposición Profesional/análisis , Plaguicidas/análisis , Proyectos de Investigación , Estado de Salud , Humanos , Laos , Tailandia , VietnamRESUMEN
Alzheimer's disease (AD) is classified pathologically as a progressive neurological disorder associated with memory decline. The study was designed to assess the underlying molecular signaling involved in the neuroprotective effect of the 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone (2NCP) as a novel therapeutic agent for AD. In this connection, in vitro cholinesterases inhibitory and antioxidant activities were investigated. In vivo studies were carried out on a well-known 5xFAD mice model in different behavioural models such as light/dark box,balance beam, rotarod, elevated plus maze (EPM),novel object recognition (NOR), paddling Y-maze, and Morris water maze (MWM) tests. Hippocampus (HC) and frontal cortex (FC) homogenates were examined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, glutathione S-transferase (GST), glutathione (GSH), and catalase. Further, we examined the expression of inflammatory cytokines and Nrf2 in the HC and FC through RT-PCR. Computational studies were conducted to predict the binding mode of the 2NCP with target sites of nuclear factor-κB (NF-κB) and cholinesterases. The findings of in vitro assays revealed that the IC50 values of the 2NCP against AChE and BChE were 17 and 23 µg/ml respectively. DPPH antioxidant assay displayed an IC50 value for the 2NCP was 62 µg/ml. Whereas, theex vivo study depicted that the activities of AChE and BChEwere significantly reduced. Moreover, free radicals load, GSH level, catalase and GST activities were significantly declined. Furthermore, in vivostudies showed that the 2NCP treated animals exhibited gradual memory improvement and improved motor functions. RT-PCR study revealed that mRNA levels of the inflammatory mediators (IL-1ß, IL-6, TNF-α) were significantly reduced, while the expression of antioxidant Nrf2 was significantly increased.The molecular docking studies further confirmed that the 2NCP showed excellent binding affinities for NF-κB and cholinesterases. Taken together, the 2NCP improves spatial memory and learning, short- and long-term memory,markedly inhibits cholinesterases, reduced neuroinflammation, and mitigated oxidative stress in the 5xFAD mice; hence the 2NCP may be a potential candidate for the management of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Memoria Espacial/efectos de los fármacos , Acetilcolinesterasa/sangre , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/enzimología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/sangre , Mediadores de Inflamación/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Transgénicos , Simulación del Acoplamiento Molecular , Enfermedades Neuroinflamatorias/enzimología , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Transducción de SeñalRESUMEN
BACKGROUND: Acute and chronic besnoitiosis in extensive natural-service herds can have relevant effects in the health of bulls and negative consequences in their productive performance. Recent progress has been made in order to elucidate the pathogenesis of this disease. In this context, the study of biomarkers of inflammation in serum would contribute to gaining knowledge about the physiopathology of bovine besnoitiosis. Serological biomarkers could help in early diagnosis and prognosis, as seropositive bulls may have mild or severe testicular lesions. METHODS: Herein, we have investigated the diagnostic and/or prognostic value of a panel of serum (serological) biomarkers related to inflammation, including total protein, globulin and albumin, haptoglobin (Hp), adenosine deaminase (ADA) paraoxonase-1 (PON-1) and acetylcholinesterase (AChE) in naturally and experimentally B. besnoiti-infected males classified according to different clinical phases of the disease (acute, chronic and subclinical besnoitiosis). RESULTS: Results showed a similar response pattern in these biomarkers for naturally and experimentally infected cattle, with a few relevant variations. Most significant changes occurred during the acute phase of infection, although significant changes in a few biomarkers were also observed during the chronic infection. Haptoglobin, albumin, PON-1 and ADA were identified as the biomarkers that showed changes of higher magnitude in the acute phase of the infection, whereas high total protein and globulin values were found in chronically infected cattle. We have described the changes of a panel of inflammatory biomarkers of acute and chronic bovine besnoitiosis. CONCLUSIONS: In summary, several biomarkers with promising diagnostic value have been identified. The biomarkers associated with acute infection are related to previously reported molecular biomarkers in testicular parenchyma of infected bulls and could help in the diagnosis of early infections and complement results from specific immunoglobulin M (IgM) detection.
Asunto(s)
Biomarcadores/sangre , Enfermedades de los Bovinos/sangre , Coccidiosis/veterinaria , Acetilcolinesterasa/sangre , Adenosina Desaminasa/sangre , Animales , Arildialquilfosfatasa/sangre , Bovinos , Enfermedades de los Bovinos/diagnóstico , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/parasitología , Coccidios/genética , Coccidios/fisiología , Coccidiosis/sangre , Coccidiosis/inmunología , Coccidiosis/parasitología , Globulinas/análisis , Haptoglobinas/análisisRESUMEN
Allium hookeri (AH) is a medicinal food that has been used in Southeast Asia for various physiological activities. The objective of this study was to investigate the activation of the cholinergic system and the anti-neuroinflammation effects of AH on scopolamine-induced memory impairment in mice. Scopolamine (1 mg/kg body weight, i.p.) impaired the performance of the mice on the Y-maze test, passive avoidance test, and water maze test. However, the number of error actions was reduced in the AH groups supplemented with leaf and root extracts from AH. AH treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. AH significantly improved the cholinergic system by decreasing acetylcholinesterase activity, and increasing acetylcholine concentration. The serum inflammatory cytokines (IL-1ß, IL-6, and IFN-γ) increased by scopolamine treatment were regulated by the administration of AH extracts. Overexpression of NF-κB signaling and cytokines in liver tissue due to scopolamine were controlled by administration of AH extracts. AH also significantly decreased Aß and caspase-3 expression but increased NeuN and ChAT. The results suggest that AH extracts improve cognitive effects, and the root extracts are more effective in relieving the scopolamine-induced memory impairment. They have neuroprotective effects and reduce the development of neuroinflammation.
Asunto(s)
Allium , Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Neuronas Colinérgicas/efectos de los fármacos , Cognición/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Citocinas/sangre , Mediadores de Inflamación/sangre , Trastornos de la Memoria/tratamiento farmacológico , Memoria/efectos de los fármacos , Nootrópicos/farmacología , Extractos Vegetales/farmacología , Acetilcolina/sangre , Acetilcolinesterasa/sangre , Allium/química , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI/sangre , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/psicología , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Raíces de Plantas , EscopolaminaRESUMEN
Maintaining hemodynamic stability during the induction and maintenance of anesthesia is one of the challenges of the anesthesiologist. Patients with vascular disease are at increased risk of instability due to imbalance between the sympathetic and parasympathetic parts of the autonomic nervous system, a balance accessible by serum cholinesterase activity. We aim to characterize the dynamics of cholinesterase activity in patients undergoing general anesthesia (GA) and surgery. This was a prospective study of 57 patients undergoing ambulatory or vascular surgery under GA. Cholinesterase activity was measured before the induction of anesthesia, after 15 min and at the end of surgery by calculating the capacity of serum acetylcholinesterase (AChE) and butyrylcholinesterase to hydrolyze AcetylThioCholine. Data on atherosclerotic disease, anesthesia management were analyzed. Both AChE and total cholinergic status (CS) decreased significantly after GA induction at 15 min and even more so by the end of surgery. Vascular surgery patients had lower baseline cholinesterase activity compared to ambulatory surgery patients. Patients requiring intraoperative administration of phenylephrine for hemodynamic support (21.1%) had a significantly lower level of AChE and CS compared to untreated patients. Our findings serve as a mirror to the sympathetic/parasympathetic imbalance during GA, with a marked decrease in the parasympathetic tone. The data of a subgroup analysis show a correlation between low cholinesterase activity and an increase in the need for hemodynamic support.
Asunto(s)
Acetilcolinesterasa/sangre , Anestesia General , Butirilcolinesterasa/sangre , Enfermedades Vasculares/cirugía , Adulto , Anciano , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Vasculares/sangreRESUMEN
A convenient and sensitive colorimetric assay for acetylcholinesterase (AChE) and its inhibitor has been designed based on the oxidase-like activity of {100}-faceted Pd square nanoplates which are grown in situ on reduced graphene oxide (PdSP@rGO). PdSP@rGO can effectively catalyze the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) without the assistance of H2O2 to generate blue oxidized TMB (oxTMB) with a characteristic absorption peak at 652 nm. In the presence of AChE, acetylthiocholine (ATCh), a typical AChE substrate, is hydrolyzed to thiocholine (TCh). The generated TCh can effectively inhibit the PdSP@rGO-triggered chromogenic reaction of TMB via cheating with Pd, resulting in color fading and decrease in absorbance. Thus, a sensitive probe for AChE activity is constructed with a working range of 0.25-5 mU mL-1 and a limit of detection (LOD) of 0.0625 mU mL-1. Furthermore, because of the inhibition effect of tacrine on AChE, tacrine is also detected through the colorimetric AChE assay system within the concentrations range 0.025-0.4 µM with a LOD of 0.00229 µM. Hence, a rapid and facile colorimetric procedure to sensitively detect AChE and its inhibitor can be anticipated through modulating the oxidase-like activity of PdSP@rGO. Colorimetric method for detection of AChE and its inhibitor is established by modulating the oxidase mimetic activity of {100}-faceted Pd square nanoplates on reduced graphene oxide (PdSP@rGO).
Asunto(s)
Acetilcolinesterasa/sangre , Colorimetría/métodos , Grafito/química , Nanopartículas del Metal/química , Acetilcolinesterasa/química , Acetiltiocolina/química , Bencidinas/química , Catálisis , Inhibidores de la Colinesterasa/análisis , Compuestos Cromogénicos/química , Humanos , Límite de Detección , Oxidación-Reducción , Paladio/química , Tacrina/análisisRESUMEN
BACKGROUND: Increased acetylcholinesterase (AChE) activity on frozen sections of rectal mucosal biopsies accurately diagnoses Hirschsprung disease (HD). But the quest for a biomarker in blood as a screening test prompts one to look for AChE in blood and study its role in HD diagnosis. AIM: To develop a low-cost reliable method to estimate the AChE activity in plasma and red blood cells (RBCs) in normal children (control) and study its role in HD (test). MATERIALS AND METHODS: Optimized method derived after modifying and standardizing known AChE assay protocols for blood were employed on 30 controls to define the AChE cut-off range, on 40 suspected HD cases to categorize them as HD/non-HD based on cut-off values and later compared with gold standard tissue AChE histochemistry of rectal mucosal biopsies. RESULTS: An optimal in-house modified methods of Ellman's was found best suited to analyze plasma AChE activity, method by Wilson and Henderson was optimal for extraction and AChE estimation in RBCs. AChE levels (controls) obtained were 1.03 ± 0.31 U/mL and 5.17 ± 1.52 U/mL in plasma and RBCs, respectively while the plasma AChE was 1.35 ± 0.84 U/mL (HD) and 1.62 ± 0.85 U/mL (non-HD) while RBC AChE was 4.29 ± 3.2 U/mL (HD) and 6.48 ± 4.31 U/mL (non-HD). Sensitivity was 66.67% and 55.56%, specificity was 22.73% and 45.45%, and an accuracy rate of 42.5% and 50% for plasma and RBC, respectively. CONCLUSIONS: Mutually exclusive AChE activity range identified for test blood samples overlapped with the normal and hence, not considered a diagnostic tool for HD.
Asunto(s)
Acetilcolinesterasa/análisis , Acetilcolinesterasa/sangre , Eritrocitos/enzimología , Enfermedad de Hirschsprung/sangre , Enfermedad de Hirschsprung/diagnóstico , Recto/enzimología , Acetilcolinesterasa/metabolismo , Biomarcadores/análisis , Biomarcadores/sangre , Biopsia , Niño , Preescolar , Método Doble Ciego , Tránsito Gastrointestinal/fisiología , Enfermedad de Hirschsprung/patología , Histocitoquímica/métodos , Humanos , India , Membrana Mucosa/enzimología , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
The mechanism of toxic action for organophosphates (OPs) is the persistent inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and subsequent hyperstimulation of the nervous system. Organophosphates display a wide range of acute toxicities. Differences in the OP's chemistries results in differences in the compound's metabolism and toxicity. Acute toxicities of OPs appear to be principally dependent on compound specific efficiencies of detoxication, and less dependent upon efficiencies of bioactivation and sensitivity of AChE. Serine esterases, such as carboxylesterase (CaE) and butyrylcholinesterase (BChE), play a prominent role in OP detoxication. Organophosphates can stoichiometrically inhibit these enzymes, removing OPs from circulation thus providing protection for the target enzyme, AChE. This in vitro study investigated age-related sensitivity of AChE, BChE and CaE to twelve structurally different OPs in rat tissues. Sensitivity of esterases to these OPs was assessed by inhibitory concentration 50s (IC50s). The OPs displayed a wide range of inhibitory potency toward AChE with IC50s in the low nM-µM range with no differences among ages; however, the CaE IC50s generally increased with age reflecting greater protection in adults. These results suggest age-related differences in acute toxicities of OPs in mammals are primarily a result of their detoxication capacities.
Asunto(s)
Acetilcolinesterasa/metabolismo , Envejecimiento/metabolismo , Butirilcolinesterasa/metabolismo , Carboxilesterasa/metabolismo , Inhibidores de la Colinesterasa/toxicidad , Organofosfatos/toxicidad , Plaguicidas/toxicidad , Acetilcolinesterasa/sangre , Animales , Encéfalo/enzimología , Carboxilesterasa/sangre , Hígado/enzimología , Pulmón/enzimología , Masculino , Músculo Esquelético/enzimología , Miocardio/enzimología , Ratas Sprague-DawleyRESUMEN
Pesticides are globally used to eliminate pests from crops and plants. The increased use of pesticides has posed a serious threat to human health. This study evaluates the effects of pesticide exposure on pregnancy outcomes in tea garden workers (TGW). The acetylcholinesterase (AChE) activity was measured in the maternal blood, placenta, and cord blood of TGW and housewives (HWs). The placental structure and expression of hypoxia-inducible factor (HIF)-1α were also analyzed in TGW and HW groups delivering low birth weight (LBW) and normal birth weight (NBW) babies. A significantly decreased AChE activity was observed in maternal blood and cord blood in TGW as compared with HW in the LBW group. However, it did not change significantly in the NBW group (p < .05). The adjusted regression analysis of birth outcomes (birth weight, head circumference, infant's length, and ponderal index) revealed a significant and positive association with the levels of AChE activity in maternal blood, placenta, and cord blood in TGW (p < .05). The histological analysis showed significantly higher placental syncytial knots, chorangiosis, fibrinoid deposition, necrosis, and stromal fibrosis in the LBW group of TGW. Microinfarction, increased fibrinoid deposition, and atypical villi characteristics, such as mushroom-like structures, were observed during scanning electron microscopy along with increased HIF-1α expression in placental tissues of TGW exposed to pesticides. Results suggest that occupational pesticide exposure during pregnancy may decrease AChE activity and cause in utero pathological changes accompanied by an increased HIF-1α expression, which also contributes to placental insufficiency and fetal growth restriction.
Asunto(s)
Acetilcolinesterasa/sangre , Exposición Materna/efectos adversos , Exposición Profesional/efectos adversos , Plaguicidas/toxicidad , Placenta/metabolismo , Té , Adulto , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Masculino , Placenta/patología , EmbarazoRESUMEN
Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation.
Asunto(s)
Atropina , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa , Antagonistas Muscarínicos , Cloruro de Obidoxima , Compuestos Organotiofosforados/toxicidad , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Animales , Atropina/sangre , Atropina/farmacocinética , Atropina/uso terapéutico , Encéfalo/metabolismo , Reactivadores de la Colinesterasa/sangre , Reactivadores de la Colinesterasa/farmacocinética , Reactivadores de la Colinesterasa/uso terapéutico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Cobayas , Masculino , Antagonistas Muscarínicos/sangre , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/uso terapéutico , Cloruro de Obidoxima/sangre , Cloruro de Obidoxima/farmacocinética , Cloruro de Obidoxima/uso terapéutico , Resultado del TratamientoRESUMEN
Imidacloprid is a neonicotinoid insecticide that acts selectively as an agonist on insect nicotinic acetylcholine receptors. It is used for crop protection worldwide, as well as for non-agricultural uses. Imidacloprid systemic accumulation in food is an important source of imidacloprid exposure. Due to the undisputable need for investigations of imidacloprid toxicity in non-target species, we evaluated the effects of a 28-day oral exposure to low doses of imidacloprid (0.06â¯mg/kg b. w./day, 0.8â¯mg/kg b. w./day and 2.25â¯mg/kg b. w./day) on cholinesterase activity, oxidative stress responses and primary DNA damage in the blood and brain tissue of male Wistar rats. Exposure to imidacloprid did not cause significant changes in total cholinesterase, acetylcholinesterase and butyrylcholinesterase activities in plasma and brain tissue. Reactive oxygen species levels and lipid peroxidation increased significantly in the plasma of rats treated with the lowest dose of imidacloprid. Activities of glutathione-peroxidase in plasma and brain and superoxide dismutase in erythrocytes increased significantly at the highest applied dose. High performance liquid chromatography with UV diode array detector revealed the presence of imidacloprid in the plasma of all the treated animals and in the brain of the animals treated with the two higher doses. The alkaline comet assay results showed significant peripheral blood leukocyte damage at the lowest dose of imidacloprid and dose-dependent brain cell DNA damage. Oral 28-day exposure to low doses of imidacloprid in rats resulted in detectable levels of imidacloprid in plasma and brain tissue that directly induced DNA damage, particularly in brain tissue, with slight changes in plasma oxidative stress parameters.