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1.
Vet Clin North Am Food Anim Pract ; 36(3): 673-688, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33032698

RESUMO

In the western United States, poisonous plants most often affect grazing livestock, and the related livestock losses are estimated to cost the grazing livestock industry more than $200 million annually. Many of these toxic plants contain neurotoxins that damage or alter the function of neurologic cells in the central and peripheral nervous systems. The objectives of this article are to present common North American neurotoxic plants, including conditions of poisoning, clinical disease, pathologic changes, and available diagnostics, to identify poisoned animals and the potential prognosis for poisoned animals.


Assuntos
Gado , Síndromes Neurotóxicas/veterinária , Neurotoxinas/envenenamento , Intoxicação por Plantas/veterinária , Plantas Tóxicas/envenenamento , Animais , Síndromes Neurotóxicas/etiologia , Estados Unidos
2.
Chem Biol Interact ; 330: 109232, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860822

RESUMO

Currently, whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation contributes to neuropathy induced by 2,5-Hexanedione (HD), the toxic metabolite of n-hexane, remains unknown. In this study, we found that HD intoxication elevated NLRP3 expression, caspase-1 activation and interleukin-1ß production in sciatic nerve of rats, indicating activation of NLRP3 inflammasome. The increased cleavage of gasdermin D (GSDMD) protein, an important mediator of pyroptosis, and axon degeneration were also observed in sciatic nerves of HD-intoxicated rats. Interestingly, glybenclamide, a widely used inhibitor of NLRP3 inflammasome, significantly reduced NLRP3 inflammasome activation, which was associated with decreased GSDMD cleavage and axon degeneration as well as improved motor performance of HD-intoxicated rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glybenclamide attenuated macrophage infiltration, activation and M1 polarization in sciatic nerves of HD-intoxicated rats. Furthermore, decreased malondialdehyde (MDA) contents and increased glutathione (GSH) level and total anti-oxidative capacity were also observed in sciatic nerves of rats treated with combined glybenclamide and HD compared with HD alone group. Altogether, our findings suggest that NLRP3 inflammasome activation contributes to HD-induced neurotoxicity by enhancing macrophage infiltration and activation as well as oxidative stress, providing a novel mechanism of neuropathy induced by this neurotoxicant.


Assuntos
Hexanonas/toxicidade , Macrófagos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/farmacologia , Síndromes Neurotóxicas/etiologia , Animais , Antioxidantes/metabolismo , Movimento Celular/efeitos dos fármacos , Glutationa/metabolismo , Glibureto/farmacologia , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Ratos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
3.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
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.
Ecotoxicol Environ Saf ; 201: 110725, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32474209

RESUMO

Lincomycin hydrochloride is one of the commonly used drugs in clinic. However, it has many side effects on patients, and its mechanism is still poorly understood. In this study, 6 h post-fertilization (6 hpf) zebrafish embryos were exposed to several concentrations of lincomycin hydrochloride (15, 30, 60 µg/mL) for up to 24 or 96 hpf to detect their developmental toxicity and neurotoxicity, and to 6 days post-fertilization (6 dpf) to detect their behavioral toxicity. Our results showed that lincomycin hydrochloride could lead to embryonic head deformities (unclear ventricles, smaller ventricles, fewer new neurons). The studies showed that the frequency of spontaneous tail flick of zebrafish embryo increased at 24 hpf, and the lincomycin hydrochloride exposed zebrafish embryos showed increased heart rate, shorter body length, and yolk sac edema with severe pericardial edema at 96 hpf. The studies also showed that lincomycin hydrochloride increased oxidative stress level, Acetylcholinesterase (AChE) activity, ATPase activity and apoptosis in zebrafish larvae. In addition, the swimming behavior of zebrafish larvae decreased with the increase of lincomycin hydrochloride concentration, but the angular velocity and meandering degree increased, which might be due to the decreased activity of AChE and ATPase, as well as the decreased expression of genes related to neurodevelopment and neurotransmitter system, leading to the change of their motor behaviors. In summary, we found that lincomycin hydrochloride induced developmental toxicity and neurotoxicity in zebrafish larvae, contributing to a more comprehensive evaluation of the safety of the drug.


Assuntos
Lincomicina/toxicidade , Síndromes Neurotóxicas/etiologia , Acetilcolinesterase/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Síndromes Neurotóxicas/congênito , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra
7.
Lancet Haematol ; 7(5): e408-e417, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359452

RESUMO

In children who receive neurotoxic chemotherapy, peripheral neurotoxicity occurs frequently, necessitates dose reduction or treatment cessation, and affects function and long-term quality of life. No treatments exist for peripheral neurotoxicity and few assessment measures are specific to children. We did a systematic review to analyse the published literature concerning the evaluation of assessment measures for paediatric chemotherapy-induced peripheral neurotoxicity. We searched PubMed, CINAHL, PsycINFO, and Embase on Nov 7-8, 2018; of 1409 articles, seven met the inclusion criteria. A total of 335 children (excluding ten healthy controls) were enrolled in the seven studies and the sample sizes ranged from 17 to 86 individuals. 276 (82%) of the 335 children were actively undergoing chemotherapy treatment. Most studies did not comprehensively evaluate the psychometric properties of assessment measures for chemotherapy-induced peripheral neurotoxicity. By use of a narrative analysis that combined approaches from the Joanna Briggs Institute (Adelaide, SA, Australia) and the quality of diagnostic accuracy studies assessment method (known as QUADAS), only one study was deemed high quality. We identified two variants of the Total Neuropathy Score, two grading scales, two semi-objective tests, one patient-reported outcome, and several mobility measures. The National Cancer Institute Common Terminology Criteria for Adverse Events and the Balis grading scales showed lower sensitivity and specificity than the items of the Total Neuropathy Score. Although there is insufficient evidence to support the use of most approaches to assess chemotherapy-induced peripheral neurotoxicity in children, two variants of the Total Neuropathy Score, the pediatric-modified Total Neuropathy Score and the Total Neuropathy Score-pediatric vincristine, are promising but require further testing. Other approaches are less sensitive or less feasible. A patient-reported outcome measure for chemotherapy-induced peripheral neurotoxicity in children is needed.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Criança , Humanos , Síndromes Neurotóxicas/diagnóstico , Pediatria , Doenças do Sistema Nervoso Periférico/diagnóstico
8.
Chemosphere ; 255: 127007, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32416396

RESUMO

Chiral organophosphorus pollutants are existed ubiquitously in the ecological environment, but the enantioselective toxicities of these nerve agents to humans and their molecular bases have not been fully elucidated. Using experimental and computational approaches, this story was to explore the neurotoxic response process of the target acetylcholinesterase (AChE) to chiral phenthoate and further decipher the microscopic mechanism of such toxicological effect at the enantiomeric level. The results showed that the toxic reaction of AChE with chiral phenthoate exhibited significant enantioselectivity, and (R)-phenthoate (K=1.486 × 105 M-1) has a bioaffinity for the nerve enzyme nearly three times that of (S)-phenthoate (K=4.503 × 104 M-1). Dynamic research outcomes interpreted the wet experiments, and the inherent conformational flexibility of the target enzyme has a great influence on the enantioselective neurotoxicological action processes, especially reflected in the conformational changes of the three key loop regions (i.e. residues His-447, Gly-448, and Tyr-449; residues Gly-122, Phe-123, and Tyr-124; and residues Thr-75, Leu-76, and Tyr-77) around the reaction patch. This was supported by the quantitative results of conformational studies derived from circular dichroism spectroscopy (α-helix: 34.7%→30.2%/31.6%; ß-sheet: 23.6%→19.5%/20.7%; turn: 19.2%→22.4%/21.9%; and random coil: 22.5%→27.9%/25.8%). Meanwhile, via analyzing the modes of toxic action and free energies, we can find that (R)-phenthoate has a strong inhibitory effect on the enzymatic activity of AChE, as compared with (S)-phenthoate, and electrostatic energy (-23.79/-17.77 kJ mol-1) played a critical role in toxicological reactions. These points were the underlying causes of chiral phenthoate displaying different degrees of enantioselective neurotoxicity.


Assuntos
Acetilcolinesterase/química , Poluentes Ambientais/química , Poluentes Ambientais/toxicidade , Síndromes Neurotóxicas/etiologia , Compostos Organotiofosforados/química , Compostos Organotiofosforados/toxicidade , Dicroísmo Circular , Humanos , Modelos Teóricos , Simulação de Dinâmica Molecular , Fenômenos Físicos , Estrutura Secundária de Proteína , Estereoisomerismo
9.
Biosci Trends ; 14(2): 139-143, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: covidwho-100189

RESUMO

In late March and early April 2020, the antimalarial drug, chloroquine, has been approved as an emergency treatment for the coronavirus disease 2019 (COVID-19) in the United States and in Europe. Although infrequent, neuropsychiatric symptoms have been reported in patients who received chloroquine for the treatment of malaria or autoimmune diseases. In this study, aiming to investigate these adverse events (AEs) using a large self-reporting database, we conducted a disproportionality analysis for the detection of neuropsychiatric AE signals associated with the use of chloroquine (or hydroxychloroquine), reported to FDA Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 and the fourth quarter of 2019. We included 2,389,474 AE cases, among which 520 cases developed neuropsychiatric AE following the use of chloroquine. Adjusted reporting odds ratio (ROR) for the development of each of the neuropsychiatric AEs following the use of chloroquine was calculated using a multilevel model: exposure to chloroquine was associated with a statistically significant high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness, (lower 95% confidence interval of the adjusted ROR > 1), although the degree of increase in their ROR was limited. There was no statistically significant high reporting of any other neuropsychiatric AE, including suicide, psychosis, confusion, and agitation. Current pharmacovigilance study results did not suggest any potential link between the use of chloroquine and an increased risk of suicide, psychosis, confusion, and agitation, which would be informative during the emergency use of chloroquine for the treatment of COVID-19.


Assuntos
Cloroquina/efeitos adversos , Transtornos Mentais/induzido quimicamente , Síndromes Neurotóxicas/etiologia , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Betacoronavirus/isolamento & purificação , Cloroquina/administração & dosagem , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration
10.
Biosci Trends ; 14(2): 139-143, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32321905

RESUMO

In late March and early April 2020, the antimalarial drug, chloroquine, has been approved as an emergency treatment for the coronavirus disease 2019 (COVID-19) in the United States and in Europe. Although infrequent, neuropsychiatric symptoms have been reported in patients who received chloroquine for the treatment of malaria or autoimmune diseases. In this study, aiming to investigate these adverse events (AEs) using a large self-reporting database, we conducted a disproportionality analysis for the detection of neuropsychiatric AE signals associated with the use of chloroquine (or hydroxychloroquine), reported to FDA Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 and the fourth quarter of 2019. We included 2,389,474 AE cases, among which 520 cases developed neuropsychiatric AE following the use of chloroquine. Adjusted reporting odds ratio (ROR) for the development of each of the neuropsychiatric AEs following the use of chloroquine was calculated using a multilevel model: exposure to chloroquine was associated with a statistically significant high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness, (lower 95% confidence interval of the adjusted ROR > 1), although the degree of increase in their ROR was limited. There was no statistically significant high reporting of any other neuropsychiatric AE, including suicide, psychosis, confusion, and agitation. Current pharmacovigilance study results did not suggest any potential link between the use of chloroquine and an increased risk of suicide, psychosis, confusion, and agitation, which would be informative during the emergency use of chloroquine for the treatment of COVID-19.


Assuntos
Cloroquina/efeitos adversos , Transtornos Mentais/induzido quimicamente , Síndromes Neurotóxicas/etiologia , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Betacoronavirus/isolamento & purificação , Cloroquina/administração & dosagem , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration
11.
Zhonghua Zhong Liu Za Zhi ; 42(3): 170-179, 2020 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-32252195

RESUMO

Taxanes are cornerstones of cancer chemotherapy and can be used for the treatment of various tumors, including breast cancer. Taxane-associated peripheral neuropathy is a common adverse effect of taxanes, leading to discontinuation of drug therapy, affecting drug treatment outcomes, and severely affecting patients' quality of life. This consensus addresses and recommends the pathogenesis, clinical features, associated risk factors, diagnostic evaluation, prevention, and treatment of taxane-related peripheral neuropathy. It is hoped that this consensus will standardize the current management of taxane-related peripheral neuropathy in China and improve clinicians' understanding of taxane-related peripheral neuropathy, thereby improving patient outcomes and improving patient quality of life.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Síndromes Neurotóxicas/diagnóstico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Hidrocarbonetos Aromáticos com Pontes , China , Consenso , Humanos , Síndromes Neurotóxicas/etiologia , Guias de Prática Clínica como Assunto , Qualidade de Vida
12.
Toxicology ; 438: 152442, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32278051

RESUMO

Bisphenol A (BPA) is a well-known endocrine disruptor used to manufacture polycarbonate plastics and epoxy resins. BPA exposure especially occupational perinatal exposure to has been linked to numerous adverse effects for the offspring. Available data have shown that perinatal exposure to BPA contributes to neurodegenerative pathological changes; however, the potential mechanisms remain unclear. This study attempted to investigate the long-term consequences of perinatal exposure to BPA on the offspring mouse brain. The pregnant mice were given either a vehicle control or BPA (2, 10, 100 µg/kg/d) from day 6 of gestation until weaning (P6-PND21, foetal and neonatal exposure). At 3, 6 and 9 months of age, the neurotoxic effects in the offspring in each group were investigated. We found that the spine density but not the dendritic branches in the hippocampus were noticeably reduced at 6 and 9 months of age. Meanwhile, p-Tau, the characteristic protein for tauopathy, was dramatically increased in both the hippocampus and cortex at 3-9 months of age. Mechanically, the balance of kinase and protein phosphatase, which plays critical roles in p-Tau regulation, was disturbed. It indicated that GSK3ß and CDK5, two critical kinases, were activated in most of the BPA perinatal exposure group, while protein phosphatase 2A (PP2A), one of the important phosphatases, regulated p-Tau expression through its demethylation, methylation and phosphorylation. Taken together, the present study may be translatable to the human occupational BPA exposure due to a similar exposure level. BPA perinatal exposure causes long-term adverse effects on the mouse brain and may be a risk factor for tauopathies, and the CDK5/GSK3ß/PP2A axis might be a promising therapeutic target for BPA-induced neurodegenerative pathological changes.


Assuntos
Compostos Benzidrílicos/toxicidade , Córtex Cerebral/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Disruptores Endócrinos/toxicidade , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Proteína Fosfatase 2/metabolismo , Proteínas tau/metabolismo , Animais , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/enzimologia , Espinhas Dendríticas/patologia , Feminino , Idade Gestacional , Hipocampo/enzimologia , Hipocampo/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/enzimologia , Síndromes Neurotóxicas/patologia , Fosforilação , Gravidez
14.
Brain Behav Immun ; 87: 18-22, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32240762

RESUMO

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.


Assuntos
Infecções por Coronavirus/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Pneumonia Viral/fisiopatologia , Betacoronavirus , Transtornos da Consciência/etiologia , Transtornos da Consciência/fisiopatologia , Coronavirus Humano 229E , Infecções por Coronavirus/complicações , Coronavirus Humano NL63 , Coronavirus Humano OC43 , Disgeusia/etiologia , Disgeusia/fisiopatologia , Encefalite/etiologia , Encefalite/fisiopatologia , Encefalite Viral/etiologia , Encefalite Viral/fisiopatologia , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio , Doenças do Sistema Nervoso/etiologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Síndromes Neurotóxicas/virologia , Transtornos do Olfato/etiologia , Transtornos do Olfato/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Polineuropatias/etiologia , Polineuropatias/fisiopatologia , Vírus da SARS , Convulsões/etiologia , Convulsões/fisiopatologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/fisiopatologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia
15.
Br J Anaesth ; 124(5): 603-613, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151384

RESUMO

BACKGROUND: The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABAA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABAA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABAA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development. METHODS: The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups. RESULTS: CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABAA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents. CONCLUSIONS: The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.


Assuntos
Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/toxicidade , Pregnanodionas/toxicidade , Esteroides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Agonistas de Receptores de GABA-A/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Hipocampo/patologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacologia , Propofol/administração & dosagem , Propofol/farmacologia , Propofol/toxicidade , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Esteroides/administração & dosagem , Esteroides/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
17.
Ecotoxicol Environ Saf ; 194: 110382, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146195

RESUMO

Deoxynivalenol(DON) has broad toxicity in livestock, but we know little about its neurotoxic mechanisms. We investigated DON neurotoxicity in the cerebral cortex, cerebellum, and hippocampus of "Duroc × Landrace × Yokshire" piglets. Control piglets were fed a basal diet, while those in low- and high-treatment groups were fed diets with 1.3 mg/kg and 2.2 mg/kg DON, respectively. After a 60 d trial, scanning electron microscopy revealed the destruction of hippocampal cell ultrastructure. As DON concentrations increased, oxidative damage also increased in the cerebral cortex, cerebellum, and hippocampus. Norepinephrine and 5-hydroxytryptamine concentrations tended to increase, whereas dopamine and γ-aminobutyric acid concentrations decreased. We also observed an increase in calcium concentration, relative mRNA expression of calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII phosphorylation. However, calmodulin (CaM) mRNA and protein content decreased. Overall, our results suggest that DON acts through the Ca2+/CaM/CaMKII signaling pathway to influence cerebral lipid peroxidation and neurotransmitter levels.


Assuntos
Encéfalo/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Neurotransmissores/metabolismo , Tricotecenos/toxicidade , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Dieta , Masculino , Síndromes Neurotóxicas/metabolismo , Oxirredução , Suínos , Desmame
18.
Br J Anaesth ; 124(5): 585-593, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32145876

RESUMO

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work.


Assuntos
Anestésicos/efeitos adversos , Pesquisa Biomédica/normas , Avaliação Pré-Clínica de Medicamentos/normas , Síndromes Neurotóxicas/etiologia , Relatório de Pesquisa/normas , Animais , Pesquisa Biomédica/métodos , Criança , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Parcerias Público-Privadas
19.
Environ Health ; 19(1): 31, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160895

RESUMO

BACKGROUND: The overwhelming number of potentially toxic chemicals in consumer products and in our daily environment makes it unrealistic to carry out in-depth analyses of each product with the objective of banning and eliminating toxic chemicals from our environment. OBJECTIVES: To present the challenges that environmental toxicology and epidemiology are currently facing in the context of ubiquitous chemical pollution. DISCUSSION: We propose a realistic and pragmatic approach to this Herculean problem.


Assuntos
Poluentes Ambientais/toxicidade , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Medição de Risco/métodos , Testes de Toxicidade/métodos , Substâncias Perigosas/toxicidade , Humanos
20.
Anticancer Res ; 40(2): 865-871, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014930

RESUMO

BACKGROUND/AIM: Oxaliplatin-induced neurotoxicity (OIN) can be severe and dose-limiting with clinically significant symptoms that persist for years. Few published reports have described postoperative exacerbation of OIN and more longitudinal data are needed to better characterize the phenomenon. PATIENTS AND METHODS: We identified 13 patients diagnosed with colon (n=7), rectal (n=4) or pancreatic (n=2) cancer who experienced postoperative OIN exacerbation at our medical center. Charts were reviewed for demographic and clinical data regarding OIN. RESULTS: OIN exacerbation was documented 0.5-7.0 months after the first surgery following oxaliplatin exposure, with a median duration of 10.6 months (range=1.4-86.1 months). OIN exacerbation persisted in 3/13 patients at last follow-up, and improved to pre-operative levels in 6/13 patients (with complete resolution in 4/13) within a median of 3.6 months from initial exacerbation. CONCLUSION: Given the widespread use of oxaliplatin in neoadjuvant and first-line treatment for gastrointestinal cancers, further study is warranted to prospectively and systematically define risks for postoperative OIN exacerbation.


Assuntos
Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Oxaliplatina/uso terapêutico , Adulto , Feminino , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Período Pós-Operatório
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