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1.
Braz J Biol ; 83: e248842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495166

RESUMO

Acetylcholinesterase (AChE) activity levels can be used as an indicator for AChE inhibition due to pesticide poisoning in bird species. We assessed the comparative brain cholinesterase (AChE) activity level of five bird species inhabiting pesticide exposed croplands and Protected Area i.e. Deva Vatala National Park (DVNP), Bhimber by using a spectrophotometric method. AChE activity levels ranged from 56.3 to 85.9 µmol/min/g of brain tissue of birds representing DVNP. However, AChE activity levels ranged from 27.6 to 79.9 µmol/min/g of brain tissue of birds representing croplands. AChE activity levels observed in Jungle babbler, Common babbler, and Red-vented bulbul showed significant differences (P < 0.05) at two sites. However, White wagtail and Black drongo demonstrated non-significant differences (P > 0.05). Maximum inhibition was recorded in Jungle babbler (53%) followed by Common babbler (35%), Red-vented bulbul (18%), White wagtail (15%), and Black drongo (7%). The brain cholinesterase inhibition levels under-protected ecosystems (DVNP, Bhimber) and agricultural landscape suggest insecticidal contamination and its impact on avifauna diversity. The study also emphasizes on the importance of pesticide-free zones to protect the biodiversity of birds.


Assuntos
Praguicidas , Acetilcolinesterase , Animais , Aves , Inibidores da Colinesterase/toxicidade , Produtos Agrícolas , Ecossistema , Paquistão , Praguicidas/toxicidade
2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361024

RESUMO

The use of chemicals to boost food production increases as human consumption also increases. The insectidal, nematicidal and acaricidal chemical carbofuran (CAF), is among the highly toxic carbamate pesticide used today. Alongside, copper oxide nanoparticles (CuO) are also used as pesticides due to their broad-spectrum antimicrobial activity. The overuse of these pesticides may lead to leaching into the aquatic environments and could potentially cause adverse effects to aquatic animals. The aim of this study is to assess the effects of carbofuran and copper oxide nanoparticles into the cardiovascular system of zebrafish and unveil the mechanism behind them. We found that a combination of copper oxide nanoparticle and carbofuran increases cardiac edema in zebrafish larvae and disturbs cardiac rhythm of zebrafish. Furthermore, molecular docking data show that carbofuran inhibits acetylcholinesterase (AChE) activity in silico, thus leading to impair cardiac rhythms. Overall, our data suggest that copper oxide nanoparticle and carbofuran combinations work synergistically to enhance toxicity on the cardiovascular performance of zebrafish larvae.


Assuntos
Carbofurano/toxicidade , Inibidores da Colinesterase/toxicidade , Cobre/toxicidade , Coração/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Praguicidas/toxicidade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Sítios de Ligação , Carbofurano/farmacologia , Cardiotoxicidade , Sinergismo Farmacológico , Praguicidas/farmacologia , Ligação Proteica , Peixe-Zebra
3.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443482

RESUMO

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood-brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Acetilcolinesterase/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Simulação por Computador , Desenho de Fármacos , Humanos , Quinoxalinas/síntese química , Quinoxalinas/toxicidade , Relação Estrutura-Atividade
4.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206601

RESUMO

To identify biomarkers of ethyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A234)- or methyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A232)-inhibited butyrylcholinesterase (BChE), we investigated nonapeptide adducts containing the active site serine, which plays a key role in enzyme activity, using LC-MS/HRMS. Biomarkers were acquired as expected, and they exhibited a significant amount of fragment ions from the inhibiting agent itself, in contrast to the MS2 spectra of conventional nerve agents. These biomarkers had a higher abundance of [M+2H]2+ ions than [M+H]+ ions, making doubly charged ions more suitable for trace analysis.


Assuntos
Butirilcolinesterase/sangue , Agentes Neurotóxicos , Organofosfatos , Plasma , Biomarcadores/sangue , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Humanos , Agentes Neurotóxicos/farmacocinética , Agentes Neurotóxicos/toxicidade , Organofosfatos/farmacocinética , Organofosfatos/toxicidade
5.
Chemistry ; 27(53): 13280-13305, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34185362

RESUMO

Nerve agents are tetrahedral organophosphorus compounds (OPs) that were developed in the last century to irreversibly inhibit acetylcholinesterase (AChE) and therefore impede neurological signaling in living organisms. Exposure to OPs leads to a rapid development of symptoms from excessive salivation, nasal congestion and chest pain to convulsion and asphyxiation which if left untreated may lead to death. These potent toxins are prepared on a large scale from inexpensive staring materials, making it feasible for terrorist groups or states to use them against military and civilians. The existing antidotes provide limited protection and are difficult to apply to a large number of affected individuals. While new prophylactics are currently being developed, there is still need for therapeutics capable of both preventing and reversing the effects of OP poisoning. In this review, we describe how the science of molecular recognition can expand the pallet of tools for rapid and safe sequestration of nerve agents.


Assuntos
Agentes Neurotóxicos , Acetilcolinesterase , Antídotos , Inibidores da Colinesterase/toxicidade , Humanos , Agentes Neurotóxicos/toxicidade , Compostos Organofosforados
6.
Artigo em Inglês | MEDLINE | ID: mdl-33794375

RESUMO

Harmine is a beta-carboline and harmala alkaloid with extensive bioactivities. However, its toxicity, especially in neural system, is not systematically assessed and the toxic mechanism is not yet clear. Using Caenorhabditis elegans (C. elegans) as a model system, we found that harmine exhibited dosage dependent (0, 5, 10, 20, 40, 80, 160, and 320 µmol/L) toxic effect, such as growth inhibition, egg laying defects, shortened life span and increased mortality. Although harmine did not result in obvious structural alterations in neurite or death of neurons, it did show direct acetylcholinesterase inhibition activity. Further, we found that harmine treatment decreased worm pharyngeal pump rate and lowered the content of nitric oxide (NO) in worm body, implying foraging disorders, which is an indicator of acetylcholinergic neuron activity inhibition. Besides, network pharmacology and molecular docking reveals that acetylcholinesterase is one of the major neural toxicity targets as well. Above all, harmine can directly inhibit the activity of acetylcholinesterase, leading to excessive accumulation of acetylcholine, which may be one of the harmine neurotoxicity mechanisms.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Harmina/toxicidade , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais
7.
Environ Sci Pollut Res Int ; 28(35): 48595-48609, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33913109

RESUMO

Inhibition of cholinesterases has been frequently used as a biomarker for contamination of aquatic environments, because these enzymes are frequent targets for toxic effects of contaminants, such as insecticides derived from phosphoric and carbamic acids. However, this enzyme is also responsive to other contaminants, including metals. The use of cholinesterase inhibition as effect criterion in ecotoxicology studies requires the previous characterization of the specific enzymatic forms that can be present in the different tissues and/or organs of species. This work characterized the soluble ChEs present in the brain and dorsal muscle of three marine fish species, namely Scomber scombrus, Sardina pilchardus and Chelidonichthys lucerna. Pesticides (chlorpyrifos) and metals (copper sulphate) in vitro assays were conducted to quantify the effects of these contaminants on cholinesterases activity. The results of this study showed that acetylcholinesterase (AChE) was the predominant form present in the brain tissues of the three species and in the muscle tissue of one species (Sardina pilchardus). For Scomber scombrus and Chelidonichthys lucerna, the cholinesterase form present in the muscle tissue evidenced properties between the classic acetylcholinesterase and those of pseudocholinesterase forms. The results for the metal (copper) and pesticide (chlorpyrifos) showed that this species may be suitable for monitoring contaminations for these types of contaminants.


Assuntos
Clorpirifos , Praguicidas , Acetilcolinesterase , Animais , Inibidores da Colinesterase/toxicidade , Colinesterases
8.
Toxicology ; 456: 152787, 2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-33887375

RESUMO

Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD50). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD50) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD50) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD50 of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-α, NF-κB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.


Assuntos
Ondas Encefálicas/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Disfunção Cognitiva/induzido quimicamente , Sarina/toxicidade , Animais , Ondas Encefálicas/fisiologia , Inibidores da Colinesterase/administração & dosagem , Colinesterases/metabolismo , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/fisiopatologia , Eletrocorticografia/efeitos dos fármacos , Eletrocorticografia/métodos , Masculino , Camundongos , Sarina/administração & dosagem
9.
Biomed Pharmacother ; 138: 111443, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33667786

RESUMO

Dichlorvos is a known risk factor for organ toxicity. The liver and kidney are essential metabolic tissues but it is unclear whether or not there is associated redox dyshomeostasis in both organs in physiological and pathological states. Uric acid accumulation and glutathione dysregulation have been implicated in the aetiopathogenesis of organ damage. The antioxidant potentials of L-arginine have been shown in various conditions. The present study was thus designed to investigate the synchrony in hepatic and renal uric acid and glutathione status in dichlorvos-induced hepatorenal damage and to probe the possible therapeutic role of L-arginine. Twenty-one male Wistar rats were treated with standard rat diet and water, dichlorvos, or dichlorvos and L-arginine. Our findings revealed that dichlorvos significantly impaired hepatic and renal functions, increased hepatic and renal malondialdehyde, but reduced glutathione and activities of superoxide dismutase, catalase, and glutathione peroxidase. These events were accompanied by increased accumulation of plasma, hepatic, and renal uric acid as well as reduced body weight gain, and hepatic and renal weights. Histopathological examinations revealed hepatic and renal architectural derangement and cellular necrosis and degeneration in dichlorvos-exposed rats. Interestingly, L-arginine reversed dichlorvos-induced systemic, hepatic and renal synchronous redox dyshomeostasis. L-arginine administration also improved hepatic and renal cytoarchitecture. It is thus concluded that dichlorvos triggered synchronous uric acid generation and glutathione alterations in the liver and kidney. L-arginine confers protection against dichlorvos-induced hepatorenal damage via suppression of uric acid generation and blockade of glutathione dysregulation.


Assuntos
Injúria Renal Aguda/prevenção & controle , Arginina/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Diclorvós/toxicidade , Glutationa/antagonistas & inibidores , Ácido Úrico/antagonistas & inibidores , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Arginina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Inibidores da Colinesterase/toxicidade , Glutationa/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Ácido Úrico/metabolismo
10.
Bioorg Med Chem ; 37: 116109, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33780813

RESUMO

A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment.


Assuntos
Fármacos do Sistema Nervoso Central/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Demência Vascular/tratamento farmacológico , Diosgenina/análogos & derivados , Diosgenina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/metabolismo , Fármacos do Sistema Nervoso Central/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Diosgenina/metabolismo , Diosgenina/toxicidade , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção/efeitos dos fármacos , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/toxicidade , Ligação Proteica , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
11.
Toxicol Appl Pharmacol ; 419: 115512, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33785355

RESUMO

Nerve agents are highly toxic organophosphorus compounds that inhibit acetylcholinesterase resulting in rapid accumulation of the neurotransmitter acetylcholine (ACh) causing a cholinergic syndrome including respiratory failure. In the present study, respiratory responses and antimuscarinic treatment efficacy was evaluated ex vivo using rat precision-cut lung slices (PCLS) exposed to the nerve agent VX. The respiratory effects were evaluated either by adding exogenous ACh directly to the culture medium or by applying electric-field stimulation (EFS) to the PCLS to achieve a release of endogenous ACh from neurons in the lung tissue. The airway contraction induced by both methods was enhanced by VX and resulted in lingering airway recovery, in particular when airways were exposed to a high VX-dose. Both contractions induced by EFS and exogenously added ACh were significantly reduced by administration of the antimuscarinic drugs atropine or scopolamine. Two additions of atropine or scopolamine after maximal ACh-induced airway response was demonstrated effective to reverse the contraction. By adding consecutive doubled doses of antimuscarinics, high efficiency to reduce the cholinergic airway response was observed. However, the airways were not completely recovered by atropine or scopolamine, indicating that non-muscarinic mechanisms were involved in the smooth muscle contractions. In conclusion, it was demonstrated that antimuscarinic treatment reversed airway contraction induced by VX but supplemental pharmacological interventions are needed to fully recover the airways. Further studies should therefore clarify the mechanisms of physiological responses in lung tissue following nerve agent exposures to improve the medical management of poisoned individuals.


Assuntos
Atropina/farmacologia , Fibras Colinérgicas/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Pulmão/inervação , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/inervação , Compostos Organotiofosforados/toxicidade , Escopolamina/farmacologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Fibras Colinérgicas/enzimologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Ratos Sprague-Dawley
12.
Toxicology ; 452: 152719, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33592259

RESUMO

Organophosphorus compounds (OPs) include nerve agents and insecticides that potently inhibit acetylcholinesterase (AChE), an essential enzyme found throughout the nervous system. High exposure levels to OPs lead to seizures, cardiac arrest, and death if left untreated. Oximes are a critical piece to the therapeutic regimen which remove the OP from the inhibited AChE and restore normal cholinergic function. The current oximes 2-PAM, MMB-4, TMB-4, HI-6, and obidoxime (OBD) have two drawbacks: lack of broad spectrum protection against multiple OP structures and poor brain penetration to protect against OP central neurotoxicity. An alternative strategy to enhance therapy is reactivation of serum butyrylcholinesterase (BChE). BChE is stoichiometrically inhibited by OPs with no apparent toxic result. Inhibition of BChE in the serum followed by reactivation could create a pseudo-catalytic scavenger allowing numerous regenerations of BChE to detoxify circulating OP molecules before they can reach target AChE. BChE in serum from rats, guinea pigs or humans was screened for the reactivation potential of our novel substituted phenoxyalkyl pyridinium oximes, plus 2-PAM, MMB-4, TMB-4, HI-6, and OBD (100µM) in vitro after inhibition by highly relevant surrogates of sarin, VX, and cyclosarin, and also DFP, and the insecticidal active metabolites paraoxon, phorate-oxon, and phorate-oxon sulfoxide. Novel oxime 15 demonstrated significant broad spectrum reactivation of OP-inhibited rat serum BChE while novel oxime 20 demonstrated significant broad spectrum reactivation of OP-inhibited human serum BChE. All tested oximes were poor reactivators of OP-inhibited guinea pig serum BChE. The bis-pyridinium oximes were poor BChE reactivators overall. BChE reactivation may be an additional mechanism to attenuate OP toxicity and contribute to therapeutic efficacy.


Assuntos
Butirilcolinesterase/sangue , Inibidores da Colinesterase/toxicidade , Agentes Neurotóxicos/toxicidade , Organofosfatos/toxicidade , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Animais , Cobaias , Humanos , Oximas/química , Compostos de Piridínio/química , Ratos
13.
Artigo em Inglês | MEDLINE | ID: mdl-33412300

RESUMO

Flavonoids are rich in seeds, citrus fruits, olive oil, tea and red wine. Citrus flavonoids constitute an important type of flavonoids. Naringin and naringenin belong to flavonoids with known antioxidant and were found to display antioxidant activities. Malathion is an organophosphorus pesticide that has been broadly used throughout the world to control weeds and pests. It has also been used in public health for mosquito control and fruit fly eradication programs. Malathion, naringin, and naringenin were added to be in 40, 80, and 160 mg doses in Saccharomyces cerevisiae cultures mainly used to determine the antioxidant capacity, it is known that they have shown similar results to man. At the end of the experiment, total protein, malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), vitamin K, vitamin E, vitamin D, ergosterol, stigmasterol, ß-Sitosterol, and fatty acids were analyzed by HPLC (high performance liquid chromatography) and GC (gas chromatography) devices in the tested S. cerevisiae samples. The contents of the yeast cell of octanoic acid (C8:0), lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1n-7), heptadecanoic acid (C17:0), stearic acid (C18:0), oleic acid (C18:1n-9), and linoleic acid (C18:2n-6) were identified. There were statistically significant changes in total protein, MDA, GSH, GSSG, vitamin K, vitamin E, vitamin D, phytosterol and fatty acid levels. It was determined that naringin and naringenin showed statistically significant decreases against malathion toxicity on these parameters. From this study it is found that, the mitigating effect of naringin against DPPH stable free radical was higher than that of naringenin. Citrus flavonoid, naringin showed promising antioxidant activity which can be used as effective protecting agents against oxidative stress.


Assuntos
Antioxidantes/farmacologia , Flavanonas/farmacologia , Malation/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos , Compostos de Bifenilo , Inibidores da Colinesterase/toxicidade , Picratos
14.
Chemosphere ; 268: 129488, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33485672

RESUMO

Organophosphorus pesticides (OPs) interfere with the activity of acetylcholinesterase (AChE), a vital enzyme that regulates the functioning of the nervous system, resulting in acetylcholine (Ach) accumulation at the synapses and myoneural junctions. It remains unknown whether the commonly used OPs in South India also interfere with the AChE activity and their toxicokinetics in humans remains poorly understood. We collected peripheral blood samples from OP-associated suicide cases (hospitalised) and analysed the pesticide concentration and AChE activity, and the toxicokinetics of six commonly used pesticides. LC-MS/MS was used for the estimation of pesticide concentration. Based on a comparison of six pesticide kinetic profiles and toxicokinetic parameters, we concluded that chlorpyrifos ingestion resulted in the highest concentration of chlopyrifos among the identified pesticides, followed by acephate, triazophos, propanil, while dimethoate exhibited the lowest concentration. Based on a time-course analysis, we observed a faster elimination phase for monocrotophos and dimethoate. We observed that there was a significant decrease in the mean concentration of monocrotophos (64 ng/mL) (P = 0.015), while the mean value of AChE (1.08 unit/mL) increased over time. While monocrotophos and dimethoate elimination phases were remarkable in human subjects, the other pesticides did notdemonstrate similar elimination phases owing to their low rate of metabolism and high stability.


Assuntos
Praguicidas , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Cromatografia Líquida , Humanos , Índia , Compostos Organofosforados , Praguicidas/toxicidade , Espectrometria de Massas em Tandem , Toxicocinética
15.
Toxicology ; 450: 152679, 2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33460720

RESUMO

Urinary dialkylphosphates (DAPs) are measured to assess exposure to organophosphorus pesticides (OPs), but they are common metabolites of OPs and not specific indices for individual agents. Biomonitoring (BM) of urinary DAPs has been widely adopted as an assessment of individual exposure in general environments, however, guidance values for DAPs based on health effects have yet to be established. The present study aimed to clarify the relationship between the amount of urinary dimethylphosphate (DMP), a metabolite of dichlorvos (DDVP), and the inhibition of cholinesterase (ChE) activity in rats exposed to DDVP. The relationship was analyzed using a nonlinear model analysis, and the excretion level of urinary DMP equivalent to ChE 20 % inhibition (EL20) and the lower limit of the 95 % confidence interval of EL20 (ELL20) were estimated. EL20 and ELL20 (mg/24 h urine) of brain, erythrocyte, and plasma ChE activities after 10-day administration of DDVP were 0.21 and 0.15, 0.11 and 0.06, and 0.23 and 0.09, respectively. Extrapolating ELL20 of the brain ChE to humans, the range of 24 h urinary DMP concentration according to the 20 % inhibition of cholinesterase activity was estimated to be 20.5-30.8 mg/l. In conclusion, the amount of urinary DMP as ELL20 for DDVP exposure was identified and could probably be used as a novel index for the assessment of risk from OP exposure. Further studies are needed to clarify the ELL20 s derived from OPs other than DDVP, for informing efforts to establish guidance values of urinary OP metabolites that should prevent neurotoxicity.


Assuntos
Inibidores da Colinesterase/toxicidade , Colinesterases/metabolismo , Diclorvós/toxicidade , Dinâmica não Linear , Compostos Organofosforados/urina , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar
16.
Curr Med Chem ; 28(7): 1422-1442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32334495

RESUMO

BACKGROUND: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the Organophosphates (OPs) capable of restricting the enzyme Acetylcholinesterase (AChE), which in turn, controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today, it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relatively long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the Blood-Brain Barrier (BBB). This fact compromises their capacity to reactivating AChE inside the nervous system. METHODS: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. RESULTS: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents' development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. CONCLUSION: To develop these new agents, the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics), organic synthesis, spectroscopic methodologies, biology, biochemical and biophysical information, medicinal chemistry, pharmacology and toxicology, is necessary.


Assuntos
Acetilcolinesterase , Reativadores da Colinesterase , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Simulação por Computador , Humanos , Compostos Organofosforados/toxicidade , Oximas/farmacologia
17.
Int J Biol Macromol ; 166: 1352-1364, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161083

RESUMO

In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513-4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC50 > 10 µM, eqBChE IC50 = 3.73 ± 1.90 µM). Molecular dynamic (MD) simulation validated the binding pattern of 2513-4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513-4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513-4169 against toxic Aß1-42. In vivo behavioral study further confirmed the great efficacy of 2513-4169 on reversing Aß1-42-induced cognitive impairment of mice and clearing the toxic Aß1-42 in brains. Moreover, 2513-4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513-4169 is a promising lead compound for future optimization to discover anti-AD treating agents.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Cognição/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular/métodos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/toxicidade , Relação Quantitativa Estrutura-Atividade
18.
Toxicol Lett ; 338: 32-39, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33253782

RESUMO

Repeated low-level exposure to sarin results to hippocampus dysfunction. Metabonomics involves a holistic analysis of a set of metabolites in an organism in the search for a relationship between these metabolites and physiological or pathological changes. The objective of the present study was to evaluate the effects of repeated exposure to low-level sarin on the metabonomics in hippocampus of a guinea pig model. Guinea pigs were divided randomly into control and sarin treated groups (n = 14). Guinea pigs in the control group received saline; while the sarin-treated group received 0.4×LD50 (16.8 µg/kg) sarin. Daily injections (a total of 14 days) were administered sc between the shoulder blades in a volume of 1.0 ml/kg body weight. At the end of the final injection, 6 animals in each group were chosen for Morris water maze test. The rest guinea pigs (n = 8 for each group) were sacrificed by decapitation, and hippocampus were dissected for analysis. Compared with the control-group, the escape latency in sarin-group was significantly (p < 0.05) longer while the crossing times were significantly decreased in the Morris water task (p < 0.05). Sarin inhibited activities of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in hippocampus. The AChE activity of hippocampus from sarin-treated groups is equivalent to 59.9 ± 6.4 %, and the NTE activity of hippocampus from sarin-groups is equivalent to 78.1 ± 8.3 % of that from control-group. Metabolites were identified and validated. A total of 14 variables were selected as potential biomarkers. Phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylinositol (PI), Lysophosphatidylethanolamine (LysoPE or LPE)] and sphingolipids (SPs) [sphinganine (SA), phytosphingosine (PSO) and sphinganine-1-phosphate (SA1P)] were clearly modified. In conclusion, repeated low-dose exposures to sarin disrupted the homeostasis of phospholipid and sphingolipid metabolism in guinea pig hippocampus and may lead to a neuronal-specific function disorders. Identified metabolites such as SA1P need to be studied more deeply on their biological function that against sarin lesions. In future research, we should pay more attention to characterize the physiological roles of lipid metabolism enzymes as well as their involvement in pathologies induced by repeated low-level sarin exposure.


Assuntos
Inibidores da Colinesterase/toxicidade , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Fosfolipídeos/metabolismo , Sarina/toxicidade , Esfingolipídeos/metabolismo , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/metabolismo , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cobaias , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Homeostase , Lipidômica , Masculino , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Aprendizagem Espacial/efeitos dos fármacos
19.
Int J Biol Macromol ; 167: 1361-1370, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33217462

RESUMO

Essential oils (EOs) are bioactive compounds with therapeutic potential for use as alternatives or as support to conventional treatments. However, EOs present limitations, such as sensibility to environmental factors, which can be overcome through microencapsulation. The objective of this study was to produce, by spray drying, chitosan microparticles (CMs) loaded with EO of Lemongrass (Cymbopogon flexuosus), Geranium (Pelargonium x ssp) and Copaiba (Copaifera officinalis). Physicochemical and biological characterization of these microparticles showed that CMs presented spherical morphology, had an average size range of 2-3 µm with positive zeta potential (ZP) values, and enhanced thermal stability, compared to free EO. The encapsulation efficiency (EE) ranged from 4.8-58.6%, depending on the oil's properties. In vitro EO release from CMs was determined at different pHs, with 94% release observed in acid media. All microparticles were non-hemolytic at concentrations of up to 0.1 mg·mL-1. EOs and CMs presented acetylcholinesterase (AChE) inhibition activity (IC 50 ranged from 11.92 to 28.18 µg·mL-1). Geranium and Copaiba EOs presented higher toxicity against Artemia salina, and greater inhibition of acetylcholinesterase, indicating potential bioactivity for Alzheimer's disease (AD). Our findings demonstrate that CM systems may show promise for the controlled release of these EOs.


Assuntos
Artemia/efeitos dos fármacos , Cápsulas/química , Quitosana/química , Inibidores da Colinesterase/farmacologia , Cymbopogon/química , Fabaceae/química , Óleos Voláteis/análise , Pelargonium/química , Animais , Sangue/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Cymbopogon/toxicidade , Fabaceae/toxicidade , Hemólise , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Microscopia Eletrônica de Varredura , Óleos Voláteis/química , Tamanho da Partícula , Pelargonium/toxicidade , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Environ Toxicol Pharmacol ; 82: 103547, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33188889

RESUMO

DDVP is a commonly used pesticide in Nigeria and those involved with DDVP manufacturing, packaging or utilizing facilities seldom use PPE to limit pesticide exposure. The study aim was to determine the impact of chronic exposure to DDVP by monitoring hematological and biochemical changes in Wistar rats. Male rats (n = 60; 150-180 g) were exposed to graded DDVP concentrations (0%, 20 %, 40 %, 60 %, 80 % and 100 %) via inhalation route for 60 days. Body weights were initially measured and then at 20-day intervals. Blood samples were collected for hematology and serum biochemistry on day 61. Results showed significant (p < 0.05) polycythemia, neutrophilia, thrombocytosis, hepatic and renal derangement in rats exposed to DDVP. Also, albumin, AST, ALP, creatinine, blood urea nitrogen, bilirubin levels and dyslipidemia significantly increased. Cholinergic signs and stunted growth were observed in higher concentrations. Study emphasized hazards of DDVP mishandling and risks of non-compliance with PPE use by workers in-contact with DDVP, as well as misuse/abuse in animals.


Assuntos
Inibidores da Colinesterase/toxicidade , Diclorvós/toxicidade , Inseticidas/toxicidade , Administração por Inalação , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Colesterol/sangue , Creatinina/sangue , Eritrócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Masculino , Ratos Wistar
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