RESUMEN
El metotrexato es un fármaco análogo del ácido fólico ampliamente utilizado en el tratamiento de enfermedades autoinmunes, leucemias y linfomas. Su uso puede ocasionar la aparición de múltiples efectos adversos entre los que se encuentran aquellos relacionados con la presencia de toxicidad neurológica, que puede presentarse de forma aguda, subaguda o crónica. La neurotoxicidad subaguda es aquella que ocurre típicamente entre los 2 y los 14 días posteriores a la administración y puede manifestarse con una amplia gama de síntomas neurológicos. En la mayoría de los casos, no recurre con futuras exposiciones al medicamento. Presentamos tres casos de neurotoxicidad subaguda por metotrexato con manifestaciones clínicas diferentes en pacientes oncohematológicos que se internaron entre los años 2018 y 2020. Dos de ellos presentaron recurrencia frente a la nueva administración del fármaco y todos evidenciaron lesiones en resonancia magnética nuclear.
Methotrexate is a folic acid analogue widely used in the treatment of autoimmune diseases, leukemias, and lymphomas. Methotrexate use may cause multiple adverse effects, including those related to the presence of neurological toxicity, which may be acute, subacute, or chronic. Subacute neurotoxicity typically occurs between 2 and 14 days after administration and may present as a wide range of neurological symptoms. In most cases, it does not recur with future exposures to the drug. Here we describe 3 cases of subacute methotrexate neurotoxicity with different clinical manifestations in patients with oncohematological disease who were hospitalized between 2018 and 2020. Two of them showed recurrence with a new drug administration. Lesions were observed in the magnetic resonance imaging tests of all of them.
Asunto(s)
Humanos , Masculino , Niño , Adolescente , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Linfoma , Imagen por Resonancia Magnética , Metotrexato/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversosRESUMEN
Methotrexate is a folic acid analogue widely used in the treatment of autoimmune diseases, leukemias, and lymphomas. Methotrexate use may cause multiple adverse effects, including those related to the presence of neurological toxicity, which may be acute, subacute, or chronic. Subacute neurotoxicity typically occursbetween 2 and 14 days after administration and may present as a wide range of neurological symptoms.In most cases, it does not recur with future exposures to the drug. Here we describe 3 cases of subacute methotrexate neurotoxicity with different clinical manifestations in patients with oncohematological disease who were hospitalized between 2018 and 2020. Two of them showed recurrence with a new drug administration. Lesions were observed in the magnetic resonance imaging tests of all of them.
El metotrexato es un fármaco análogo del ácido fólico ampliamente utilizado en el tratamiento de enfermedades autoinmunes, leucemias y linfomas. Su uso puede ocasionar la aparición de múltiples efectos adversos entre los que se encuentran aquellos relacionados con la presencia de toxicidad neurológica, que puede presentarse de forma aguda, subaguda o crónica. La neurotoxicidad subaguda es aquella que ocurre típicamente entre los 2 y los 14 días posteriores a la administración y puede manifestarse con una amplia gama de síntomas neurológicos. En la mayoría de los casos, no recurre con futuras exposiciones al medicamento. Presentamos tres casos de neurotoxicidad subaguda por metotrexato con manifestaciones clínicas diferentes en pacientes oncohematológicos que se internaron entre los años 2018 y 2020. Dos de ellos presentaron recurrencia frente a la nueva administración del fármaco y todos evidenciaron lesiones en resonancia magnética nuclear.
Asunto(s)
Linfoma , Síndromes de Neurotoxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Metotrexato/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , Imagen por Resonancia Magnética , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Chronic exposure to aluminium (Al) can contribute to the progression of several neurological and neurodegenerative diseases. Al is a metal that promotes oxidative damage leading to neuronal death in different brain regions with behavior, cognition, and memory deficits. Chrysin is a flavonoid found mainly in honey, passion fruit, and propolis with antioxidant, anti-inflammatory, and cytoprotective properties. In this study, we used an integrated approach of in vitro and in vivo studies to evaluate the antioxidant and neuroprotective effects of chrysin against the neurotoxicity elicited by aluminium chloride (AlCl3). In in vitro studies, chrysin (5 µM) showed the ability to counteract the early oxidative stress elicited by tert-butyl hydroperoxide, an oxidant that mimics the lipid peroxidation and Fenton reaction in presence of AlCl3 as well as the late necrotic death triggered by AlCl3 in neuronal SH-SY5Y cells. In vivo studies in a mouse model of neurotoxicity induced by chronic exposure to AlCl3 (100 mg/kg/day) for ninety days then corroborated the antioxidant and neuroprotective effect of chrysin (10, 30, and 100 mg/kg/day) using the oral route. In particular, chrysin reduced the cognitive impairment induced by AlCl3 as well as normalized the acetylcholinesterase and butyrylcholinesterase activities in the hippocampus. In parallel, chrysin counteracted the oxidative damage, in terms of lipid peroxidation, protein carbonylation, catalase, and superoxide dismutase impairment, in the brain cortex and hippocampus. Lastly, necrotic cells frequency in the same brain regions was also decreased by chrysin. These results highlight the ability of chrysin to prevent the neurotoxic effects associated with chronic exposure to Al and suggest its potential use as a food supplement for brain health.
Asunto(s)
Encéfalo/efectos de los fármacos , Flavonoides/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/prevención & control , Acetilcolinesterasa/metabolismo , Cloruro de Aluminio , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Proteínas Ligadas a GPI/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Ratones , Necrosis , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica/efectos de los fármacos , Células THP-1RESUMEN
Over the years, most of the research concerning manganese exposure was restricted to the toxicity of neuronal cells. Manganese is an essential trace element that in high doses exerts neurotoxic effects. However, in the last two decades, efforts have shifted toward a more comprehensive approach that takes into account the involvement of glial cells in the development of neurotoxicity as a brain insult. Glial cells provide structural, trophic, and metabolic support to neurons. Nevertheless, these cells play an active role in adult neurogenesis, regulation of synaptogenesis, and synaptic plasticity. Disturbances in glial cell function can lead to neurological disorders, including neurodegenerative diseases. This review highlights the pivotal role that glial cells have in manganese-induced neurotoxicity as well as the most sounding mechanisms involved in the development of this phenomenon.
Asunto(s)
Manganeso/toxicidad , Neuroglía/patología , Neurotoxinas/toxicidad , Animales , Humanos , Modelos Biológicos , Neuroglía/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100ß content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100ß mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.
Asunto(s)
Encéfalo/patología , Cerebelo/patología , Contaminantes Ambientales/toxicidad , Vesículas Extracelulares/patología , Compuestos de Metilmercurio/toxicidad , Síndromes de Neurotoxicidad/patología , Animales , Encéfalo/efectos de los fármacos , Cerebelo/efectos de los fármacos , Vesículas Extracelulares/efectos de los fármacos , Masculino , Síndromes de Neurotoxicidad/etiología , Ratas , Ratas WistarRESUMEN
Intoxication by heavy metals such as methylmercury (MeHg) is recognized as a global health problem, with strong implications in central nervous system pathologies. Most of these neuropathological conditions involve vascular, neurotransmitter recycling, and oxidative balance disruption leading to accelerated decline in fine balance, and learning, memory, and visual processes as main outcomes. Besides neurons, astrocytes are involved in virtually all the brain processes and perform important roles in neurological response following injuries. Due to astrocytes' strategic functions in brain homeostasis, these cells became the subject of several studies on MeHg intoxication. The most heterogenous glial cells, astrocytes, are composed of plenty of receptors and transporters to dialogue with neurons and other cells and to monitor extracellular environment responding tightly through fluctuation of cytosolic ions. The overall toxicity of MeHg might be determined on the basis of the balance between MeHg-mediated injury to neurons and protective responses from astrocytes. Although the role of neurons in MeHg intoxication is relatively well-established, the role of the astrocytes is only beginning to be understood. In this review, we update the information on astroglial modulation of the MeHg-induced neurotoxicity, providing remarks on their protective and deleterious roles and insights for future studies.
Asunto(s)
Astrocitos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , Astrocitos/patología , Encéfalo/patología , Humanos , Neuronas/patologíaRESUMEN
Forty 1-2-y-old water buffaloes were simultaneously treated with trichlorfon and chlorpyrifos products in the recommended dose for cattle. After a week, 19 animals started presenting clinical signs characterized by apathy, diarrhea, aggressiveness, dehydration, and motor incoordination, followed by flaccid paralysis and permanent lateral recumbency. All affected buffaloes died after a clinical course of 1-4 days. Reduction of serum cholinesterase activity in three cases was indicative of significant exposure to organophosphorus compounds (OPs). Pathological examination of three buffaloes revealed no gross and histological lesions. By thin layer chromatography, chlorpyrifos residues and trace of trichlorfon residues were detected in fresh tissue samples. The epidemiological, clinical, pathological, and toxicological findings were highly compatible with OPs-induced delayed neurotoxicity, a neurological manifestation rarely described in domestic animals.(AU)
Quarenta búfalos foram simultaneamente tratados com clorpirifós e triclorfom na dose recomendada para bovinos. Após uma semana, 19 animais apresentaram sinais clínicos caracterizados por apatia, diarreia, agressividade, desidratação e incoordenação motora, seguidos por paralisia flácida e decúbito lateral permanente. Todos os búfalos afetados morreram após um curso clínico de 1-4 dias. Redução da atividade da colinesterase sérica em três casos foi indicativa de exposição significativa a organofosforados (OPs). O exame patológico de três búfalos não revelou lesões macroscópicas e histológicas. Por cromatografia em camada delgada, resíduos de clorpirifós e traços de resíduos de triclorfon foram detectados em amostras de tecidos frescos. Os achados epidemiológicos, clínicos, patológicos e toxicológicos foram compatíveis com neuropatia tardia induzida por OPs, uma manifestação neurológica raramente descrita em animais domésticos.(AU)
Asunto(s)
Animales , Bovinos , Enfermedades de los Bovinos/patología , Síndromes de Neurotoxicidad/complicaciones , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/veterinaria , Compuestos Organofosforados/toxicidadRESUMEN
Forty 1-2-y-old water buffaloes were simultaneously treated with trichlorfon and chlorpyrifos products in the recommended dose for cattle. After a week, 19 animals started presenting clinical signs characterized by apathy, diarrhea, aggressiveness, dehydration, and motor incoordination, followed by flaccid paralysis and permanent lateral recumbency. All affected buffaloes died after a clinical course of 1-4 days. Reduction of serum cholinesterase activity in three cases was indicative of significant exposure to organophosphorus compounds (OPs). Pathological examination of three buffaloes revealed no gross and histological lesions. By thin layer chromatography, chlorpyrifos residues and trace of trichlorfon residues were detected in fresh tissue samples. The epidemiological, clinical, pathological, and toxicological findings were highly compatible with OPs-induced delayed neurotoxicity, a neurological manifestation rarely described in domestic animals.
Quarenta búfalos foram simultaneamente tratados com clorpirifós e triclorfom na dose recomendada para bovinos. Após uma semana, 19 animais apresentaram sinais clínicos caracterizados por apatia, diarreia, agressividade, desidratação e incoordenação motora, seguidos por paralisia flácida e decúbito lateral permanente. Todos os búfalos afetados morreram após um curso clínico de 1-4 dias. Redução da atividade da colinesterase sérica em três casos foi indicativa de exposição significativa a organofosforados (OPs). O exame patológico de três búfalos não revelou lesões macroscópicas e histológicas. Por cromatografia em camada delgada, resíduos de clorpirifós e traços de resíduos de triclorfon foram detectados em amostras de tecidos frescos. Os achados epidemiológicos, clínicos, patológicos e toxicológicos foram compatíveis com neuropatia tardia induzida por OPs, uma manifestação neurológica raramente descrita em animais domésticos.
Asunto(s)
Animales , Bovinos , Compuestos Organofosforados/toxicidad , Enfermedades de los Bovinos/patología , Síndromes de Neurotoxicidad/complicaciones , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/veterinariaRESUMEN
The accumulation of amyloid protein aggregates in tissues is the basis for the onset of diseases known as amyloidoses. Intriguingly, many amyloidoses impact the central nervous system (CNS) and usually are devastating diseases. It is increasingly apparent that neurotoxic soluble oligomers formed by amyloidogenic proteins are the primary molecular drivers of these diseases, making them lucrative diagnostic and therapeutic targets. One promising diagnostic/therapeutic strategy has been the development of antibody fragments against amyloid oligomers. Antibody fragments, such as fragment antigen-binding (Fab), scFv (single chain variable fragments), and VHH (heavy chain variable domain or single-domain antibodies) are an alternative to full-length IgGs as diagnostics and therapeutics for a variety of diseases, mainly because of their increased tissue penetration (lower MW compared to IgG), decreased inflammatory potential (lack of Fc domain), and facile production (low structural complexity). Furthermore, through the use of in vitro-based ligand selection, it has been possible to identify antibody fragments presenting marked conformational selectivity. In this review, we summarize significant reports on antibody fragments selective for oligomers associated with prevalent CNS amyloidoses. We discuss promising results obtained using antibody fragments as both diagnostic and therapeutic agents against these diseases. In addition, the use of antibody fragments, particularly scFv and VHH, in the isolation of unique oligomeric assemblies is discussed as a strategy to unravel conformational moieties responsible for neurotoxicity. We envision that advances in this field may lead to the development of novel oligomer-selective antibody fragments with superior selectivity and, hopefully, good clinical outcomes.
Asunto(s)
Amiloide/inmunología , Amiloidosis/diagnóstico , Síndromes de Neurotoxicidad/diagnóstico , Agregación Patológica de Proteínas/diagnóstico , Amiloide/antagonistas & inhibidores , Amiloidosis/inmunología , Amiloidosis/patología , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos de Inmunoglobulinas/inmunología , Síndromes de Neurotoxicidad/inmunología , Síndromes de Neurotoxicidad/patología , Fragmentos de Péptidos/inmunología , Agregación Patológica de Proteínas/inmunología , Anticuerpos de Dominio Único , Relación Estructura-ActividadRESUMEN
Poisonous plants are a significant cause of death among adult cattle in Brazil. Plants that affect the central nervous system are widely spread throughout the Brazilian territory and comprise over 30 toxic species, including the genus Ipomoea, commonly associated with a lysosomal storage disease and a tremorgenic syndrome in livestock. We describe natural and experimental Ipomoea pes caprae poisoning in cattle from a herd in the Northside of Rio de Janeiro, Brazil. Affected cattle presented episodes of severe ataxia, abnormal posture followed by falling, muscular tremor, contraction, and spasticity, more prominent in the limbs, intensified by movement and forthcoming, and recumbence. Grossly, a substantial amount of leaves and petioles were found in the rumen. Histopathological examination showed degenerative neuronal changes, mostly in cerebellar Purkinje cells, which were confirmed with Bielschowsky silver. The characteristic clinical changes and mild histological lesion strongly suggested a tremorgenic syndrome. Lectin- immunohistochemistry evaluation reinforced this hypothesis; all lectins tested failed to react with affect neurons and Purkinje cells, which ruled out an underlying lysosomal storage disease. One calf given I. pes caprae leaves experimentally developed clinical signs similar to natural cases. On the 28th day of the experiment, the plant administration was suspended, and the calf recovered within four days. I. pes caprae's spontaneous tremorgenic syndrome in cattle is conditioned to exclusive feeding for several months. We were able to experimentally reproduce toxic clinical signs 12 days following the ingestion.(AU)
A intoxicação por plantas tóxicas está entre as três causas de morte mais importantes em bovinos adultos no Brasil. O grupo das plantas que causam alterações neurológicas, muito bem representada no país, encerra mais de trinta espécies tóxicas, entre as quais do gênero Ipomoea, amplamente distribuídas no território brasileiro. As plantas tóxicas desse gênero podem causar doenças do armazenamento ou síndrome tremorgênica. Descrevem-se a intoxicação natural e reprodução experimental por Ipomoea pes caprae em bovinos, verificada no norte do Estado do Rio de Janeiro. Foram observados episódios de intensa ataxia locomotora, postura anormal seguida de queda, incapacidade de levantar-se, tremores, contrações, espasticidades musculares nos membros, intensificados após estimulação ou a simples aproximação e decúbito. Nos bovinos afetados há mais de 6 meses, os sinais clínicos tornavam-se permanentes. À necropsia havia apenas significativa quantidade de folhas e pecíolos da planta no rúmen. O estudo histopatológico evidenciou lesões neuronais degenerativas principalmente nos neurônios de Purkinje. A impregnação argêntica pela técnica de Bielschowsky ratificou esses achados microscópicos. As lesões histológicas sutis associadas ao quadro clínico indicam que trata-se de intoxicação tremorgênica. O fato de não haver nenhum armazenamento intracitoplasmático, confirmado pelo resultado do estudo lectino-histoquímico (não houve afinidade das lectinas Con-A, WGA e sWGA e de outras lectinas empregadas aos neurônios de Purkinje e outros neurônios afetados), é suficiente para descartar a possibilidade de tratar-se de doença do armazenamento. No bezerro intoxicado experimentalmente verificaram-se sinais clínicos semelhantes, entretanto, com a interrupção do fornecimento da planta no 28º dia, os sinais clínicos desapareceram após quatro dias. I. pes caprae causa síndrome tremorgênica espontânea em bovinos, quando ingerida como alimentação exclusiva durante períodos prolongados (muitos meses). Experimentalmente, os primeiros sinais clínicos da intoxicação foram reproduzidos após 12 dias de ingestão da planta.(AU)
Asunto(s)
Animales , Bovinos , Intoxicación por Plantas/veterinaria , Intoxicación por Plantas/epidemiología , Enfermedades de los Bovinos , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Ipomoea/envenenamiento , Temblor/etiología , Temblor/veterinaria , Síndromes de Neurotoxicidad/veterinariaRESUMEN
Poisonous plants are a significant cause of death among adult cattle in Brazil. Plants that affect the central nervous system are widely spread throughout the Brazilian territory and comprise over 30 toxic species, including the genus Ipomoea, commonly associated with a lysosomal storage disease and a tremorgenic syndrome in livestock. We describe natural and experimental Ipomoea pes caprae poisoning in cattle from a herd in the Northside of Rio de Janeiro, Brazil. Affected cattle presented episodes of severe ataxia, abnormal posture followed by falling, muscular tremor, contraction, and spasticity, more prominent in the limbs, intensified by movement and forthcoming, and recumbence. Grossly, a substantial amount of leaves and petioles were found in the rumen. Histopathological examination showed degenerative neuronal changes, mostly in cerebellar Purkinje cells, which were confirmed with Bielschowsky silver. The characteristic clinical changes and mild histological lesion strongly suggested a tremorgenic syndrome. Lectin- immunohistochemistry evaluation reinforced this hypothesis; all lectins tested failed to react with affect neurons and Purkinje cells, which ruled out an underlying lysosomal storage disease. One calf given I. pes caprae leaves experimentally developed clinical signs similar to natural cases. On the 28th day of the experiment, the plant administration was suspended, and the calf recovered within four days. I. pes caprae's spontaneous tremorgenic syndrome in cattle is conditioned to exclusive feeding for several months. We were able to experimentally reproduce toxic clinical signs 12 days following the ingestion.(AU)
A intoxicação por plantas tóxicas está entre as três causas de morte mais importantes em bovinos adultos no Brasil. O grupo das plantas que causam alterações neurológicas, muito bem representada no país, encerra mais de trinta espécies tóxicas, entre as quais do gênero Ipomoea, amplamente distribuídas no território brasileiro. As plantas tóxicas desse gênero podem causar doenças do armazenamento ou síndrome tremorgênica. Descrevem-se a intoxicação natural e reprodução experimental por Ipomoea pes caprae em bovinos, verificada no norte do Estado do Rio de Janeiro. Foram observados episódios de intensa ataxia locomotora, postura anormal seguida de queda, incapacidade de levantar-se, tremores, contrações, espasticidades musculares nos membros, intensificados após estimulação ou a simples aproximação e decúbito. Nos bovinos afetados há mais de 6 meses, os sinais clínicos tornavam-se permanentes. À necropsia havia apenas significativa quantidade de folhas e pecíolos da planta no rúmen. O estudo histopatológico evidenciou lesões neuronais degenerativas principalmente nos neurônios de Purkinje. A impregnação argêntica pela técnica de Bielschowsky ratificou esses achados microscópicos. As lesões histológicas sutis associadas ao quadro clínico indicam que trata-se de intoxicação tremorgênica. O fato de não haver nenhum armazenamento intracitoplasmático, confirmado pelo resultado do estudo lectino-histoquímico (não houve afinidade das lectinas Con-A, WGA e sWGA e de outras lectinas empregadas aos neurônios de Purkinje e outros neurônios afetados), é suficiente para descartar a possibilidade de tratar-se de doença do armazenamento. No bezerro intoxicado experimentalmente verificaram-se sinais clínicos semelhantes, entretanto, com a interrupção do fornecimento da planta no 28º dia, os sinais clínicos desapareceram após quatro dias. I. pes caprae causa síndrome tremorgênica espontânea em bovinos, quando ingerida como alimentação exclusiva durante períodos prolongados (muitos meses). Experimentalmente, os primeiros sinais clínicos da intoxicação foram reproduzidos após 12 dias de ingestão da planta.(AU)
Asunto(s)
Animales , Bovinos , Intoxicación por Plantas/veterinaria , Intoxicación por Plantas/epidemiología , Enfermedades de los Bovinos , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Ipomoea/envenenamiento , Temblor/etiología , Temblor/veterinaria , Síndromes de Neurotoxicidad/veterinariaRESUMEN
Pesticides are proposed as one reason for the worldwide decline in the reptile. Effects of pesticides on food intake and organ toxicity could affect wildlife populations dynamics. To explore the hepatotoxicity of alpha-cypermethrin (ACP) in reptiles, we designed a tri-trophic food chain with three concentrations (0, 2, and 20 mg/kgwet weight). Although the enzymes changes were similar between male and female lizards, the significant variations in anti-oxidative enzymes' activities, lactic dehydrogenase activities and acetylcholine esterase activities in liver and kidney suggesting that oxidative stress, decreased metabolic ability and neurotoxicity on lizards. The results of hepatic metabolomics showed that ACP could affect amino acid, energy and lipid metabolism on lizards. Comparing with female lizards, there were more significant changes of metabolites in male lizards. The histopathology analysis in the liver (such as hepatic lobule congestion and hepatocyte vacuolation) and kidney (such as renal tubule necrosis and glomerulus necrosis), dose- and gender dependent changes of lesions suggested the functions of organ were damaged. In summary, the reduction of detoxification and elimination capacities of the liver and kidney showed dose/gender-dependent in lizards.
Asunto(s)
Plaguicidas/toxicidad , Piretrinas/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Relación Dosis-Respuesta a Droga , Femenino , Cadena Alimentaria , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Lagartos/metabolismo , Masculino , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/fisiología , Plaguicidas/metabolismoRESUMEN
Cassava (Manihot esculenta Crantz) is a tropical plant that is used as fresh food, processed food, or raw material for the preparation of flours with high nutritional value. However, cassava contains cyanogenic glycosides, such as linamarin and lotaustralin, that can trigger severe toxic effects and some neurological disorders, including motor impairment, cognitive deterioration, and symptoms that characterize tropical ataxic neuropathy and spastic epidemic paraparesis (Konzo). These alterations that are associated with the consumption of cassava or its derivatives have been reported in both humans and experimental animals. The present review discusses and integrates preclinical and clinical evidence that indicates the toxic and neurological effects of cassava and its derivatives by affecting metabolic processes and the central nervous system. An exhaustive review of the literature was performed using specialized databases that focused on the toxic and neurological effects of the consumption of cassava and its derivatives. We sought to provide structured information that will contribute to understanding the undesirable effects of some foods and preventing health problems in vulnerable populations who consume these vegetables. Cassava contains cyanogenic glycosides that contribute to the development of neurological disorders when they are ingested inappropriately or for prolonged periods of time. Such high consumption can affect neurochemical and neurophysiological processes in particular brain structures and affect peripheral metabolic processes that impact wellness. Although some vegetables have high nutritional value and ameliorate food deficits in vulnerable populations, they can also predispose individuals to the development of neurological diseases.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Manihot/toxicidad , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Neurotoxinas/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enfermedades del Sistema Nervioso/patología , Síndromes de Neurotoxicidad/patología , Neurotoxinas/administración & dosificación , Neurotoxinas/aislamiento & purificaciónRESUMEN
Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF. The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.
Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Encéfalo/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Gliosis/inducido químicamente , Locomoción/efectos de los fármacos , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Gliosis/metabolismo , Locomoción/fisiología , Masculino , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas WistarRESUMEN
Parkinson's disease (PD) is a major neurodegenerative disorder that affects 1-2% of the total global population. Despite its high prevalence and publication of several studies focused on understanding its pathology, an effective treatment that stops and/or reverses the damage to dopaminergic neurons is unavailable. Similar to other neurodegenerative disorders, PD etiology may be linked to several factors, including genetic susceptibility and environmental elements. Regarding environmental factors, several neurotoxic pollutants, including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been identified. Moreover, some pesticides/herbicides, such as rotenone, paraquat (PQ), maneb (MB), and mancozeb (MZ), cause neurotoxicity and induce a PD-like pathology. Based on these findings, several in vitro and in vivo PD-like models have been developed to understand the pathophysiology of PD and evaluate different therapeutic strategies to fight dopaminergic neurodegeneration. 6-OHDA and MPTP are common models used in PD research, and pesticide-based approaches have become secondary models of study. However, some herbicides, such as PQ, are commonly used by farming laborers in developing countries. Thus, the present review summarizes the relevant scientific background regarding the use and effects of chronic exposure to PQ in the context of PD. Similarly, we discuss the relevance of PD-like models developed using this agrochemical compound.
Asunto(s)
Síndromes de Neurotoxicidad/tratamiento farmacológico , Paraquat/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Sustancia Negra/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Dopamina/farmacología , Síndromes de Neurotoxicidad/patología , Enfermedad de Parkinson/patologíaRESUMEN
Pesticide exposure has been linked to the pathogenesis of neurodevelopmental and neurodegenerative disorders including autism spectrum disorders, attention deficit/hyperactivity, and Parkinson's disease (PD). Developmental exposure to pesticides, even at low concentrations not harmful for the adult brain, can lead to neuronal loss and functional deficits. It has been shown that prenatal or early postnatal exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB), alone or in combination, causes permanent toxicity in the nigrostriatal dopamine system, supporting the idea that early exposure to these pesticides may contribute to the pathophysiology of PD. However, the mechanisms mediating PQ and MB developmental neurotoxicity are not yet understood. Therefore, we investigated the neurotoxic effect of low concentrations of PQ and MB in primary cultures of rat embryonic neural stem cells (NSCs), with particular focus on cell proliferation and oxidative stress. Exposure to PQ alone or in combination with MB (PQ + MB) led to a significant decrease in cell proliferation, while the cell death rate was not affected. Consistently, PQ + MB exposure altered the expression of major genes regulating the cell cycle, namely cyclin D1, cyclin D2, Rb1, and p19. Moreover, PQ and PQ + MB exposures increased the reactive oxygen species (ROS) production that could be neutralized upon N-acetylcysteine (NAC) treatment. Notably, in the presence of NAC, Rb1 expression was normalized and a normal cell proliferation pattern could be restored. These findings suggest that exposure to PQ + MB impairs NSCs proliferation by mechanisms involving alterations in the redox state.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Maneb/toxicidad , Células-Madre Neurales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Paraquat/toxicidad , Plaguicidas/toxicidad , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Relación Dosis-Respuesta a Droga , Herbicidas/toxicidad , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/fisiología , Ratas Sprague-DawleyRESUMEN
Thiamethoxam is a broad-spectrum pesticide widely used in agricultural practice throughout the world. Worryingly, this pesticide is considered a potential contaminant on the surface and underground water, being a significant risk to aquatic ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of immune and inflammatory responses. Such as the neurotoxic effects of thiamethoxam remain poorly understood, the aim of this study was to evaluate whether purinergic signaling may be considered a potential target of thiamethoxam-induced neurotoxicity in silver catfish (Rhamdia quelen). Brain ectonucleoside triphosphate diphosphohydrolase (ATP as substrate) and 5'-nucleotidases activities were inhibited at 3.75 µg L-1 after 24 h of exposure and at 1.125 and 3.75 µg L-1 after 96 h of exposure compared with the control group. On the other hand, brain adenosine deaminase activity was stimulated at 3.75 µg L-1 after 24 h of exposure and at 1.125 and 3.75 µg L-1 after 96 h of exposure compared with the control group. Brain ATP levels increased at 3.75 µg L-1 after 24 h of exposure and at 1.125 and 3.75 µg L-1 after 96 h of exposure compared with the control group, while the Ado levels decreased. The enzymatic activity of the purinergic signaling did not return to control levels after a 48-h recovery period, revealing the potential neurotoxic effects of thiamethoxam. In summary, the brain purinergic signaling may be considered a potential target for thiamethoxam-induced neurotoxicity in silver catfish.
Asunto(s)
Adenosina Trifosfato/metabolismo , Adenosina/metabolismo , Encéfalo/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Transducción de Señal/efectos de los fármacos , Tiametoxam/efectos adversos , Animales , Encéfalo/patología , Bagres , Modelos Animales de Enfermedad , Proteínas de Peces/metabolismo , Síndromes de Neurotoxicidad/patología , Tiametoxam/farmacologíaRESUMEN
Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.
Asunto(s)
Antineoplásicos/toxicidad , Compuestos Organoplatinos/toxicidad , Oxalatos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Animales , Antineoplásicos/química , Masculino , Ratones , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Compuestos Organoplatinos/química , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction.