RESUMO
Ureases are microbial virulence factors either because of the enzymatic release of ammonia or due to many other non-enzymatic effects. Here we studied two neurotoxic urease isoforms, Canatoxin (CNTX) and Jack Bean Urease (JBU), produced by the plant Canavalia ensiformis, whose mechanisms of action remain elusive. The neurotoxins provoke convulsions in rodents (LD50 â¼2 mg/kg) and stimulate exocytosis in cell models, affecting intracellular calcium levels. Here, electrophysiological and brain imaging techniques were applied to elucidate their mode of action. While systemic administration of the toxins causes tonic-clonic seizures in rodents, JBU injected into rat hippocampus induced spike-wave discharges similar to absence-like seizures. JBU reduced the amplitude of compound action potential from mouse sciatic nerve in a tetrodotoxin-insensitive manner. Hippocampal slices from CNTX-injected animals or slices treated in vitro with JBU failed to induce long term potentiation upon tetanic stimulation. Rat cortical synaptosomes treated with JBU released L-glutamate. JBU increased the intracellular calcium levels and spontaneous firing rate in rat hippocampus neurons. MicroPET scans of CNTX-injected rats revealed increased [18]Fluoro-deoxyglucose uptake in epileptogenesis-related areas like hippocampus and thalamus. Curiously, CNTX did not affect voltage-gated sodium, calcium or potassium channels currents, neither did it interfere on cholinergic receptors, suggesting an indirect mode of action that could be related to the ureases' membrane-disturbing properties. Understanding the neurotoxic mode of action of C. ensiformis ureases could help to unveil the so far underappreciated relevance of these toxins in diseases caused by urease-producing microorganisms, in which the human central nervous system is affected.
Assuntos
Canavalia/química , Síndromes Neurotóxicas/etiologia , Proteínas de Plantas/toxicidade , Toxinas Biológicas/toxicidade , Urease/toxicidade , Animais , Convulsivantes/isolamento & purificação , Convulsivantes/toxicidade , Feminino , Masculino , Camundongos , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Síndromes Neurotóxicas/fisiopatologia , Proteínas de Plantas/isolamento & purificação , Ratos , Ratos Wistar , Toxinas Biológicas/isolamento & purificação , Urease/isolamento & purificação , Xenopus laevisRESUMO
Exposure to fungicide ziram (zinc dimethyldithiocarbamate) has been associated with increased incidence of Parkinson's disease (PD). We recently demonstrated that the intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC, a more soluble salt than ziram) induces PD-like behavioral and neurochemical alterations in mice. We now investigated the putative neuroprotective effects of melatonin on behavioral dificits and neurochemical alterations induced by i.n. NaDMDC. Melatonin treatment (3, 10 or 30 mg/kg, i.p.) was given 1 h before NaDMDC administration (1 mg/nostril) during 4 consecutive days and we evaluated early (up to 7 days) and late (up to 35 days) NaDMDC-induced behavioral and neurochemical alterations. Melatonin treatment protected against early motor and general neurological impairments observed in the open field and neurological score of severity, respectively, and late deficits in rotarod test. Melatonin prevented the NaDMDC-induced alterations in the striatal tyrosine hydroxylase immunocontent. Melatonin also protected against increased levels of oxidative stress markers (4-hydroxynonenal and 3-nitrotyrosine) in the striatum, as well as the NaDMDC-induced increase of 4-hydroxynonenal and TNF, markers of oxidative stress and inflammation, respectively, in the olfactory bulb. These results further detail the mechanisms underlying NaDMDC toxicity and demonstrate the neuroprotective effects of melatonin against the neuronal damage induced by NaDMDC.
Assuntos
Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Melatonina/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Administração Intranasal , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Dimetilditiocarbamato , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Aluminum (Al) is a neurotoxicant agent implicated in several behavioral, neuropathological and neurochemical changes associated with cognitive impairments. Nevertheless, mechanisms of damage and safety concentrations are still very discussed. Thus, the main purpose of this study was to investigate whether two aluminum low doses were able to produce deleterious effects on cognition of adult rats, including oxidative stress in hippocampus and prefrontal cortex, two important areas for cognition. For this, thirty adult Wistar rats were divided into three groups: Al1 (8.3 mg/kg/day), Al2 (32 mg/kg/day) and Control (Ultrapure Water), in which all three groups received their solutions containing or not AlCl3 by intragastric gavage for 60 days. After the experimental period, the short- and long-term memories were assessed by the object recognition test and step-down inhibitory avoidance. After euthanizing, prefrontal cortex and hippocampus samples were dissected for Al levels measurement and evaluation of oxidative biochemistry. Only Al2 increased Al levels in hippocampal parenchyma significantly; both concentrations did not impair short-term memory, while long-term memory was affected in Al1 and Al2. In addition, oxidative stress was observed in prefrontal and hippocampus in Al1 and Al2. Our results indicate that, in a translational perspective, humans are subjected to deleterious effects of Al over cognition even when exposed to low concentrations, by triggering oxidative stress and poor long-term memory performance.
Assuntos
Cloreto de Alumínio/toxicidade , Alumínio/toxicidade , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas , Córtex Pré-Frontal/efeitos dos fármacos , Alumínio/administração & dosagem , Alumínio/análise , Cloreto de Alumínio/administração & dosagem , Cloreto de Alumínio/análise , Animais , Hipocampo/química , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos WistarRESUMO
One of the tissues of the central nervous system most affected by diabetes is the retina. Despite a growing understanding of the biochemical processes involved in glucose toxicity, little is known about the physiological consequences of chronic high glucose (HG) on individual neurons and neuronal circuits. Electroretinogram recordings suggest that retinal bipolar cells (BCs), which filter and transmit photoreceptor output to the inner retina, are among the first cells affected by diabetic conditions, and may therefore serve as sensitive early biomarkers for incipient neuronal damage caused in diabetes. Here, we comparatively assessed retinal integrity, calcium responses, and the electrophysiological profiles of specific BC types of mouse and rat organotypic retinal explants after 1 to 3 weeks in tissue culture, under moderate glucose (MG) and HG conditions. While the retinal layers of both rodent species displayed a progressively reduced thickness in culture, BCs retained their electrophysiological profiles and remained morphologically identifiable for up to 2 weeks. Responses to glutamate and endogenous inhibitory responses were routinely observed, indicating that the retinal circuitry remained intact during this period. Significant physiological differences between MG and HG conditions were evident in calcium signals and in the time course of responses to glutamate, but the voltage-gated current profiles of BCs displayed only minor variations. Overall, rat retina appeared slightly more sensitive to HG levels compared with mouse. In conclusion, electrophysiological analysis of neuronal function in rodent retinal explants is useful for the study of early damage due to HG neurotoxicity.
Assuntos
Glucose/toxicidade , Síndromes Neurotóxicas/fisiopatologia , Retina/efeitos dos fármacos , Retina/fisiopatologia , Animais , Retinopatia Diabética/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-DawleyRESUMO
The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF3-PhSe)2 elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF3-PhSe)2 developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF3-PhSe)2 attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100â¯mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF3-PhSe)2 (5 and 10â¯mg/kg, ig) or methadone (5â¯mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30â¯min after the last administration of (m-CF3-PhSe)2. Although short-term treatment with (m-CF3-PhSe)2 at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF3-PhSe)2 per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF3-PhSe)2 modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF3-PhSe)2 downregulated the proBDNF/p-75NTR/JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF3-PhSe)2 treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice.
Assuntos
Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Morfina , Entorpecentes , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/fisiopatologia , Compostos de Organossilício/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia , Adaptação Fisiológica , Animais , Comportamento Animal , Depressão/tratamento farmacológico , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
Methylmercury (MeHg) is a well-known toxic pollutant. However, little is known about the effects of this toxic agent in an adult as a consequence of a parental or preimaginal exposure. This study used Drosophila melanogaster to investigate whether a parental or a preimaginal (eggs-larvae-pupae stages) exposure could impact parameters as viability, locomotor activity, and sleep patterns of fruit flies. Thus, we performed two exposure protocols. One where just parents were exposed to MeHg (0-12 µM) during 24 h, then flies were transferred to lay eggs in a healthy medium (without MeHg). In the other, flies were set to lay eggs in a MeHg medium, same concentrations, and discarded after this (preimaginal exposure). Viability was evaluated from egg to adult flies. F1 progeny was collected within 24 h and transferred to a fresh healthy medium. Sleep behavior analysis was performed using Drosophila Active Monitoring System (DAMS), and the locomotor activity was evaluated by climbing assay. Results have shown that the parental exposure had a significant impact on F1 progeny reducing viability and locomotor activity performance, but no significant circadian rhythm alterations. Whereas the preimaginal exposure had a stronger effect decreasing viability and locomotor activity, it also disrupted sleep patterns. MeHg preimaginal exposure showed a longer sleep duration and lower daily activity. Results corroborate the hypothesis that low MeHg exposure could trigger subclinical symptoms related to a 'neurotoxicological development effect'. Complementary investigations could clarify the underlying mechanisms of MeHg effects in neural functions due to parental and early development exposure to this toxicant.
Assuntos
Ritmo Circadiano/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Locomoção/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Animais , Drosophila melanogaster/efeitos dos fármacos , Feminino , Estágios do Ciclo de Vida , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Sono/efeitos dos fármacosRESUMO
Aluminum (Al) is a neurotoxin and is associated with the etiology of neurodegenerative diseases, such as Alzheimer's disease (AD). The Al-free ion (Al3+) is the biologically reactive and toxic form. However, the underlying mechanisms of Al toxicity in the brain remain unclear. Here, we evaluated the effects of Al3+ (in the chloride form-AlCl3) at different concentrations (0.1-100 µM) on the morphology, proliferation, apoptosis, migration and differentiation of neural progenitor cells (NPCs) isolated from embryonic telencephalons, cultured as neurospheres. Our results reveal that Al3+ at 100 µM reduced the number and diameter of neurospheres. Cell cycle analysis showed that Al3+ had a decisive function in proliferation inhibition of NPCs during neural differentiation and induced apoptosis on neurospheres. In addition, 1 µM Al3+ resulted in deleterious effects on neural phenotype determination. Flow cytometry and immunocytochemistry analysis showed that Al3+ promoted a decrease in immature neuronal marker ß3-tubulin expression and an increase in co-expression of the NPC marker nestin and glial fibrillary acidic protein. Thus, our findings indicate that Al3+ caused cellular damage and reduced proliferation and migration, resulting in global inhibition of NPC differentiation and neurogenesis.
Assuntos
Cloreto de Alumínio/toxicidade , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células-Tronco Embrionárias/patologia , Feminino , Masculino , Camundongos , Células-Tronco Neurais/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Fenótipo , Telencéfalo/efeitos dos fármacos , Telencéfalo/embriologiaRESUMO
Molecules exhibiting antioxidant, neuroprotective, and regulatory properties inherent to natural products consumed by humans are gaining attention in biomedical research. Ferulic acid (FA) is a phenolic compound possessing antioxidant and cytoprotective properties. It is found in several vegetables, including sugarcane, where it serves as the main antioxidant component. Here, we compared the antioxidant and cytoprotective effects of FA with those of the total sugarcane aqueous extract (SCAE). Specifically, we assessed biochemical markers of cell dysfunction in rat cortical brain slices and markers of physiological stress in Caenorhabditis elegans upon exposure to toxins evoking different mechanisms of neurotoxicity, including direct oxidative stress and/or excitotoxicity. In rat cortical slices, FA (250 and 500 µM), but not SCAE (~ 270 µM of total polyphenols), prevented the loss of reductive capacity induced by the excitotoxin quinolinic acid (QUIN, 100 µM), the pro-oxidant agent ferrous sulfate (FeSO4, 25 µM), and the dopaminergic pro-oxidant 6-hydroxydopamine (6-OHDA, 100 µM). In wild-type (N2) C. elegans, FA (38 mM) exerted protective effects on decreased survival induced by FeSO4 (15 mM) and 6-OHDA (25 mM), and the motor alterations induced by QUIN (100 mM), FeSO4, and 6-OHDA. In contrast, SCAE (~ 13.5 mM of total polyphenols) evoked protective effects on the decreased survival induced by the three toxic agents, the motor alterations induced by FeSO4, and the reproductive deficit induced by FeSO4. In addition, FA was unable to reverse the decreased survival induced by all these toxins in the skn-1-/- strain (VC1772), which lacks the homolog of mammalian Nrf2, a master antioxidant gene. Altogether, our results suggest that (1) both FA and SCAE afford protection against toxic conditions, (2) not all the effects inherent to SCAE are due to FA, and (3) FA requires the skn-1 pathway to exert its protective effects in C. elegans.
Assuntos
Ácidos Cumáricos/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Saccharum/química , Análise de Variância , Animais , Animais Geneticamente Modificados , Coeficiente de Natalidade , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Compostos Ferrosos/toxicidade , Técnicas In Vitro , Ferro/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Oxidopamina/toxicidade , Extratos Vegetais/química , Ácido Quinolínico/toxicidade , Ratos , Ratos WistarRESUMO
Ilex paraguariensis, yerba mate is a native plant from the southern region of Brazil. Studies showed that yerba mate has an antioxidant potential, which could help to reduce the risk of developing neurodegenerative diseases, as Alzheimer's Disease (AD). It's known that I. paraguariensis grows in acid soils with aluminium (Al), which is bioavailable in these soils. Al has a neurotoxic potential related with the progression of neurological disorders. This study aim was to evaluate the potential of I. paraguariensis in the etiology of AD using strains of Caenorhabditis elegans and the concentration of Al and antioxidants in the yerba mate extract. The results of the I. paraguariensis infusions made at 65°C and at 75° C show that there was no significant difference between both temperatures when preparing the tea infusion in relation to the presence of Al, methylxanthines, phenolic compounds and flavonoids. Additionally, in the case of Al, there was no difference between the extracts prepared at both temperatures. The behavioral parameters of C. elegans were altered after a long-term exposure to both factors: I. paraguariensis extract and Al. Through the antioxidant levels results along with the Al content on the Acetylcholinesterase (AChE) activity it is possible to observe that the acute and chronic exposure to Al and I. paraguariensis leaves extract are very similar to wild-type worms. Moreover, we can observe that the results in both the transgenic strains long-term exposed to I. paraguariensis leaves extract and to the Al concentrations presented an increase in the AChE activity.
Assuntos
Alumínio/toxicidade , Doença de Alzheimer/etiologia , Modelos Animais de Doenças , Contaminação de Alimentos , Ilex paraguariensis/química , Poluentes do Solo/toxicidade , Chás de Ervas/efeitos adversos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Alumínio/análise , Doença de Alzheimer/prevenção & controle , Animais , Animais Geneticamente Modificados , Antioxidantes/análise , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Brasil , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/agonistas , Proteínas de Caenorhabditis elegans/metabolismo , Flavonoides/análise , Flavonoides/uso terapêutico , Ilex paraguariensis/crescimento & desenvolvimento , Síndromes Neurotóxicas/fisiopatologia , Fenóis/análise , Fenóis/uso terapêutico , Folhas de Planta/química , Folhas de Planta/crescimento & desenvolvimento , Poluentes do Solo/análise , Chás de Ervas/análise , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Xantinas/análise , Xantinas/química , Xantinas/uso terapêuticoRESUMO
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.