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1.
C R Biol ; 342(5-6): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474522

RESUMO

Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements.


Assuntos
Corpo Estriado/patologia , Curcumina/análogos & derivados , Neurônios Dopaminérgicos/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/tratamento farmacológico , Intoxicação do Sistema Nervoso por Chumbo/patologia , Fármacos Neuroprotetores/uso terapêutico , Sistema Nervoso Parassimpático/patologia , Substância Negra/patologia , Administração Oral , Animais , Curcumina/uso terapêutico , Gerbillinae , Locus Cerúleo/patologia , Masculino , Transtornos dos Movimentos/psicologia , Área Tegmentar Ventral/patologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-31412628

RESUMO

Heavy metal exposure, in lead (Pb) particularly, is associated with severe neuronal impairment though oxidative stress mediated by reactive oxygen species, and antioxidants may be used to abolish these adverse effects. This study investigated the potential neuroprotective role of coenzyme Q10 (CoQ10) against lead acetate (PbAc)-induced neurotoxicity. Twenty-eight male Wistar albino rats were divided into four equal groups (n = 7) and treated as follows: the control group was injected with physiological saline (0.9% NaCl); the CoQ10 group was injected with CoQ10 (10 mg/kg); PbAc group was injected with PbAc (20 mg/kg); PbAc + CoQ10 group was injected first with PbAc, and after 1 h with CoQ10. All groups were injected intraperitoneally for seven days. PbAc significantly increased cortical lipid peroxidation, nitrate/nitrite levels, and inducible nitric oxide synthase expression, and decreased glutathione content, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase activity and mRNA expression, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and homoxygenase-1 (HO-1) expression. PbAc also promoted the secretion of interleukin-1ß and tumor necrosis factor-α, inhibited interleukin-10 production, triggered the activation of pro-apoptotic proteins, and suppressed anti-apoptotic proteins. Additionally, PbAc increased the cortical levels of serotonin, dopamine, norepinephrine, GABA, and glutamate, and decreased the level of ATP. However, treatment with CoQ10 rescued cortical neurons from PbAc-induced neurotoxicity by restoring the balance between oxidants and antioxidants, activating the Nrf2/HO-1 pathway, suppressing inflammation, inhibiting the apoptotic cascade, and modulating cortical neurotransmission and energy metabolism. Altogether, our findings indicate that CoQ10 has beneficial effects against PbAc-induced neuronal damage through its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/tratamento farmacológico , Compostos Organometálicos/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Modelos Animais de Doenças , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Compostos Organometálicos/administração & dosagem , Ratos , Ratos Wistar , Ubiquinona/farmacologia
3.
Toxicology ; 416: 23-29, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738087

RESUMO

Lead (Pb) is a widespread environmental heavy metal toxicant and chronic Pb exposure can have irreversible effects on memory and cognitive function, which is closely related to dendritic spines. Studies have shown that SNX6 and Homer1 can regulate the growth of dendritic spines. We aimed to investigate the effect of Pb exposure on the dendritic spines in hippocampus, the expression of SNX6 and Homer1 in rats and PC12 cells. The animals were randomly divided to three groups: control group, low lead group and high lead group. PC12 cells were divided into 3 groups: 0 µM, 1 µM and 100 µM Pb acetate. The results showed that the Pb levels in blood and hippocampus of all exposure groups were significantly higher than that of the control group. The morphology of dendritic spines in hippocampus after Pb treatment was changed and the density of dendritic spines was reduced. The expression of SNX6 and Homer1 was decreased in Pb exposed groups compared with the control group. Furthermore, up-regulation of SNX6 expression could reverse the down-regulation of Pb exposure on Homer1. These results indicate that Pb exposure can reduce the expression of SNX6 and lead to a decrease in Homer1 expression, which affects the changes in dendritic spines causing learning and memory impairment.


Assuntos
Hipocampo/efeitos dos fármacos , Proteínas de Arcabouço Homer/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/etiologia , Compostos Organometálicos/toxicidade , Nexinas de Classificação/metabolismo , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Regulação para Baixo , Hipocampo/metabolismo , Hipocampo/patologia , Proteínas de Arcabouço Homer/genética , Intoxicação do Sistema Nervoso por Chumbo/genética , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Células PC12 , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Nexinas de Classificação/genética
4.
Toxicology ; 411: 101-109, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445054

RESUMO

A large number of studies have evidenced that developmental neurotoxicity induced by lead (Pb) is related to oxidative injury. Furthermore, recent studies have found that developmental Pb exposure can induce neurodegeneration in old age. Because of the common presence of Pb in the environment, humans are exposed to this metal throughout their lifetime. However, few studies have explored the changes in lifespan profiles of neurotoxicity, as well as oxidative stress following lifetime Pb exposure. In the present study, rats were exposed to lead acetate from their embryonic stage to old age. Dynamic changes in neurodegeneration, oxidative stress, and endoplasmic reticulum (ER) stress in the brains at postnatal week 3 (PNW3, weaning), 41 weeks (PNW41, adulthood) and 70 weeks (PNW70, old age) were investigated. Pb exposure resulted in neurodegeneration with decreased neuronal densities and brain volumes in PNW3 and PNW70 rats; however, no significant changes occurred in PNW41 rats based on thionine stain analysis and magnetic resonance imaging (MRI) scans. Expression of the ER stress protein glucose-regulated protein 78 (GRP78) increased in Pb-exposed rats, which was associated with high levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in rat brains after Pb exposure in PNW3 and PNW70 rats. Our findings suggested that lifetime Pb exposure induced neurodegenerative injuries that began to occur in infancy, were relieved in adulthood, but intensified in old age. The critical periods for prevention or intervention in neurodegenerative diseases induced by Pb exposure occurred in early life.


Assuntos
Encéfalo/patologia , Intoxicação do Sistema Nervoso por Chumbo/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento , Animais , Encéfalo/diagnóstico por imagem , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Chumbo/sangue , Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Neurônios/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley
5.
J Neuroinflammation ; 15(1): 263, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217162

RESUMO

BACKGROUND: Lead (Pb), a heavy metal, and quinolinic acid (QA), a metabolite of the kynurenine pathway of tryptophan metabolism, are known neurotoxicants. Both Pb and QA impair spatial learning and memory. Pb activates astrocytes and microglia, which in turn induce the synthesis of QA. We hypothesized increased QA production in response to Pb exposure as a novel mechanism of Pb-neurotoxicity. METHODS: Two experimental paradigms were used. In experiment one, Wistar rat pups were exposed to Pb via their dams' drinking water from postnatal day 1 to 21. Control group was given regular water. In the second protocol, QA (9 mM) or normal saline (as Vehicle Control) was infused into right lateral ventricle of 21-day old rats for 7 days using osmotic pumps. Learning and memory were assessed by Morris water maze test on postnatal day 30 or 45 in both Pb- and QA-exposed rats. QA levels in the Pb exposed rats were measured in blood by ELISA and in the brain by immunohistochemistry on postnatal days 45 and 60. Expression of various molecules involved in learning and memory was analyzed by Western blot. Means of control and experimental groups were compared with two-way repeated measure ANOVA (learning) and t test (all other variables). RESULTS: Pb exposure increased QA level in the blood (by ~ 58%) and increased (p < 0.05) the number of QA-immunoreactive cells in the cortex, and CA1, CA3 and dentate gyrus regions of the hippocampus, compared to control rats. In separate experiments, QA infusion impaired learning and short-term memory similar to Pb. PSD-95, PP1, and PP2A were decreased (p < 0.05) in the QA-infused rats, whereas tau phosphorylation was increased, compared to vehicle infused rats. CONCLUSION: Putting together the results of the two experimental paradigms, we propose that increased QA production in response to Pb exposure is a novel mechanism of Pb-induced neurotoxicity.


Assuntos
Intoxicação do Sistema Nervoso por Chumbo/complicações , Transtornos da Memória/induzido quimicamente , Ácido Quinolínico/toxicidade , Aprendizagem Espacial/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Proteína de Ligação a CREB/metabolismo , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Injeções Intraventriculares , Intoxicação do Sistema Nervoso por Chumbo/patologia , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeos/metabolismo , Ácido Quinolínico/sangue , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas tau/metabolismo
6.
Toxicol Lett ; 296: 173-183, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29908845

RESUMO

Lead exposure has been evidenced as a risk factor for Alzheimer's disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aß) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Encéfalo/patologia , Colesterol/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Chumbo/toxicidade , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Chumbo/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Ratos , Ratos Sprague-Dawley , Receptores de LDL/efeitos dos fármacos , Receptores de LDL/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Ligação a Elemento Regulador de Esterol/efeitos dos fármacos
7.
J Appl Toxicol ; 38(10): 1353-1364, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29797346

RESUMO

The neurotoxicity of lead (Pb) is well established, and oxidative stress is strongly associated with Pb-induced neurotoxicity. Heme oxygenase 1 (HO-1) is an important antioxidative enzyme for protection against oxidative stress in many disease models. In this study, we applied hemin, the substrate and a well-known inducer of HO-1, to investigate the possible role of HO-1 in protecting against Pb neurotoxicity. Hemin can significantly attenuate Pb acetate-induced cell death and oxidative stress in the hippocampus and frontal cortex of developmental rats. Consistent with in vivo results, the protective effects of hemin were also observed in SH-SY5Y cells after inducing cell survival and maintaining redox balance. However, knocking down HO-1 could significantly abolish the cytoprotective action of hemin against Pb toxicity, confirming HO-1 contributed to the protection. Finally, the HO-1-derived production of carbon monoxide, but not of bilirubin or Fe2+ , mediated the protective effects of HO-1 activation induced by hemin treatment against Pb-induced cell death and oxidative stress in SHSY5Y cells. Overall, this study showed that hemin provided protection against Pb neurotoxicity by HO-1/carbon monoxide activation.


Assuntos
Heme Oxigenase-1/metabolismo , Hemina/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Inativação de Genes , Heme Oxigenase-1/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley
8.
Toxicol Sci ; 162(2): 688-701, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29301062

RESUMO

Lead (Pb) prevails among the environmental hazards against human health. Although increasing evidence highlights the epigenetic roles underlying the Pb-induced neurotoxicity, the exact mechanisms concerning histone acetylation and its causative agents are still at its infancy. In the present study, the roles of histone deacetylases 1 and 2 (HDAC1/2), as well as acetylation of Lys9 on histone H3 (Ac-H3K9), in Pb-induced neurotoxicity were investigated. Pb was administered to PC12 cells at 10 µM for 24 h. And Sprague Dawley rats were chronically exposed to Pb through drinking water containing 250 ppm Pb for 2 months. Owing to Pb exposure, it indicated that HDAC2 was up-regulated accompanied by Ac-H3K9 down-regulation. Meanwhile, chromatin immunoprecipitation assay revealed that the changes in HDAC2 were attributed to histone H3 Lys27 trimethylation occupancy on its promoter. Blockade of HDAC2 with either Trichostatin A or HDAC2-knocking down construct (shHDAC2) resulted in amelioration of neurite outgrowth deficits via increasing Ac-H3K9 levels. It implied that HDAC2 plays essential regulatory roles in Pb-induced neurotoxicity. And, coimmunoprecipitation trials revealed that HDAC2 colocalized with HDAC1, forming a so-called HDAC1/2 complex. Subsequently, it was shown that HDAC1/2 repression could markedly prevent neurite outgrowth impairment and rescue the spatial memory deficits caused by Pb exposure, unequivocally implicating this complex in the studied toxicological process. Furthermore, Notch2 maybe the functional target of the HDAC1/2 and Ac-H3K9 alterations. Our study provided insight into the precise roles of HDAC1/2 in Pb-induced neurotoxicity, and thereby provided a promising molecular target for medical intervention of neurological disorders with environmental etiology.


Assuntos
Poluentes Ambientais/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Intoxicação do Sistema Nervoso por Chumbo/enzimologia , Chumbo/toxicidade , Animais , Técnicas de Cultura de Células , Técnicas de Silenciamento de Genes , Intoxicação do Sistema Nervoso por Chumbo/genética , Intoxicação do Sistema Nervoso por Chumbo/patologia , Crescimento Neuronal/efeitos dos fármacos , Crescimento Neuronal/genética , Células PC12 , Ratos , Ratos Sprague-Dawley , Regulação para Cima
9.
Neurotoxicol Teratol ; 66: 35-45, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29353014

RESUMO

Lead (Pb) intoxication is a prevalent type of environmental toxicity as well as minimal amount of lead exposure is liable for neurobehavioral or perhaps intelligence defects. The present study was undertaken to investigate the beneficial effects of morin in protecting the lead acetate (PbAc)-induced oxidative stress in rat brain. PbAc intoxication resulted in motor deficit, memory impairment and oxidative stress Further, PbAc administration alters Bax/Bcl-2 expression thereby increases cytochrome c release from the mitochondria. Treatment with morin at a dose of 40 mg/kg b.wt. significantly restored back the abnormal changes that were noticed in PbAc intoxicated rats. Histopathological sections of cortex, cerebellum and hippocampus showed the extent of neuronal loss in PbAc induced rats and its restoration upon administration of morin. These outcomes imply that morin might be employed therapeutically to chelate toxic metals like Pb, thus possibly lowering PbAc-induced neurotoxicity and tissue damage.


Assuntos
Apoptose/efeitos dos fármacos , Citocromos c/metabolismo , Flavonoides/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Compostos Organometálicos/toxicidade , Proteína X Associada a bcl-2/metabolismo , Animais , Antioxidantes/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Intoxicação do Sistema Nervoso por Chumbo/etiologia , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar
10.
J Appl Toxicol ; 37(4): 400-407, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27535807

RESUMO

Developmental lead (Pb) exposure is suggested in laboratory studies to be a trigger for neurodegenerative diseases such as Alzheimer's disease (AD). Sortilin-related receptor, L (DLR class) A repeats-containing (SORL1) is a recently identified AD genetic risk factor. SORL1 has limited characterization in vertebrate models in comparison to other AD genetic risk factors. To characterize SORL1 further, protein sequence homology between humans, mice and zebrafish was analyzed and showed conservation of functional repeats and domain orientation. Next, spatial expression of sorl1 in zebrafish larvae was completed and diffuse expression in neural tissue that was not restricted to the brain was observed. Influences of sex and age on quantitative expression of sorl1 in the brain of adult zebrafish were then assessed. Sex-specific alteration of sorl1 expression transpired during the aging process in females. The zebrafish was then utilized to investigate the impacts of a 100 ppb embryonic Pb exposure on sorl1 expression and other known AD genetic risk factors. Sex-specific quantitative gene expression analysis was completed with adult zebrafish brain to compare those developmentally exposed to Pb or a control treatment, but no significant difference in sorl1 expression or other AD genetic risk factors was observed. Overall, this study provided characterization of sorl1 with changes in brain expression during aging being female-specific. This finding is in agreement with females being more prone to the onset of AD, but analysis of additional AD genetic risk factors is needed to facilitate our understanding of the impact of a 100 ppb embryonic Pb exposure. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Embrião não Mamífero/patologia , Proteínas Relacionadas a Receptor de LDL/genética , Intoxicação do Sistema Nervoso por Chumbo/genética , Proteínas de Peixe-Zebra/genética , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Feminino , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Sinais Direcionadores de Proteínas/genética , Fatores de Risco , Caracteres Sexuais , Peixe-Zebra
11.
Neuroreport ; 27(4): 264-71, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26836461

RESUMO

Substantial evidence supports the neurochemical vulnerability to lead (Pb) as one of the most potent neurotoxic heavy metals. In the present study, we aimed to assess: (i) The subcommissural organ (SCO) responsiveness as a secretory circumventricular organ to chronic and acute Pb intoxication together with its serotoninergic innervation. (ii) The possible restorative effect of curcumin against Pb intoxication under the same pathological conditions. We used immunohistochemistry with antibodies against Reissner's fiber and serotonin [5-hydroxytryptophan (5-HT)] in Wistar rats following chronic as well as acute Pb administration, respectively, at 25 mg/kg intraperitoneally for 3 days and 0.3% in drinking water from the intrauterine stage until 2 months of adult age. Our data showed a significant decrease in Reissner's fiber material immunoreactivity concomitant with an overall increased 5-HT innervation of the SCO and the ventricular borders. Coadministration of curcumin (50 mg/kg body weight) restores this impairment by reversing the effect of chronic and acute Pb on the secretory activity and the 5-HTergic innervation of the SCO. The investigation showed, on the one hand, the involvement of the SCO in the response to heavy metals, especially Pb, and on the other, the beneficial corrector role of curcumin. As a part of the circumventricular organ, known as a privileged area of brain-blood exchanges, the SCO may play a key role in the mechanism of brain defense against heavy metal neurotoxicity in rats.


Assuntos
Curcumina/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/tratamento farmacológico , Intoxicação do Sistema Nervoso por Chumbo/patologia , Fármacos Neuroprotetores/farmacologia , Órgão Subcomissural/efeitos dos fármacos , Órgão Subcomissural/patologia , Doença Aguda , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Masculino , Ratos Wistar , Serotonina/metabolismo , Órgão Subcomissural/metabolismo
12.
Nutr Neurosci ; 19(9): 396-405, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26005885

RESUMO

BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65-fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead-induced neurotoxicity and associated human health risk.


Assuntos
Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Barreira Hematoencefálica , Encéfalo/metabolismo , Encéfalo/patologia , Óleos de Peixe/uso terapêutico , Chumbo/sangue , Chumbo/metabolismo , Chumbo/toxicidade , Intoxicação do Sistema Nervoso por Chumbo/sangue , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Compostos Organometálicos/administração & dosagem , Distribuição Aleatória , Ratos Wistar , Distribuição Tecidual , Toxicocinética , Vitamina E/uso terapêutico
13.
Synapse ; 70(3): 87-97, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26562488

RESUMO

Lead exposure has been implicated in the impairment of synaptic plasticity in the hippocampal dentate gyrus (DG) areas of rats. However, whether the degradation of physiological properties is based on the morphological alteration of granule neurons in DG areas remains elusive. Here, we examined the dendritic branch extension and spine formation of granule neurons after lead exposure during development in rats. Dendritic morphology was studied using Golgi-Cox stain method, which was followed by Sholl analysis at postnatal days 14 and 21. Our results indicated that, for both ages, lead exposure significantly decreased the total dendritic length and spine density of granule neurons in the DG of the rat hippocampus. Further branch order analysis revealed that the decrease of dendritic length was observed only at the second branch order. Moreover, there were obvious deficits in the proportion and size of mushroom-type spines. These deficits in spine formation and maturity were accompanied by a decrease in Arc/Arg3.1 expression. Our present findings are the first to show that developmental lead exposure disturbs branch and spine formation in hippocampal DG areas. Arc/Arg3.1 may have a critical role in the disruption of neuronal morphology and synaptic plasticity in lead-exposed rats.


Assuntos
Dendritos/patologia , Giro Denteado/patologia , Intoxicação do Sistema Nervoso por Chumbo/patologia , Animais , Western Blotting , Proteínas do Citoesqueleto/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Chumbo/toxicidade , Intoxicação do Sistema Nervoso por Chumbo/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/fisiologia
14.
Neurotoxicology ; 48: 142-51, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25845299

RESUMO

Understanding the interaction between dietary protein deficits and neurotoxicants such as lead (Pb) is critical since oxidative stress is a common denominator under such conditions. The Drosophila system is an extensively used model to investigate the interaction between nutrients and environmental toxicants. Accordingly, we have examined the hypothesis that casein (CSN) enrichment has the propensity to attenuate Pb-associated phenotype, oxidative stress and neurotoxicity in Drosophila melanogaster. Exposure of young (2-3 d) and adult flies (10-12 d old) to Pb acetate (0-20 mM, 7 d) in the medium resulted in a concentration dependent mortality and the survivors exhibited a hyperactive phenotype. While males showed higher susceptibility to Pb among both age groups, young flies were relatively more susceptible than adults. Pb exposure (5-10 mM, 5 d) among young flies caused robust oxidative stress as evidenced by markedly elevated levels of reactive oxygen species with concomitant perturbations in the activities of antioxidant enzymes (diminished SOD and elevated thioredoxin reductase) and altered redox state. Further, Pb caused significant elevation in the activity of acetylcholinesterase and dopamine levels. In a satellite study, we assessed the modulatory effect of CSN-enriched diet (1-2%) on Pb intoxication in terms of lethality, hyperactivity, oxidative stress and neurotoxicity. CSN markedly offset Pb-induced lethality and diminished the hyperactivity response. While CSN enrichment among Pb (5 mM) treated flies caused further elevation in ROS levels and thioredoxin reductase activity, the SOD levels were restored to normalcy. Further, CSN improved the activity levels of complex I-III and restored the dopamine levels. Our data suggest that Pb-induced toxicity in the Drosophila system may be predominantly mediated through oxidative stress mechanisms and the propensity of casein-enriched diet to abrogate such responses. Hence, we propose that enrichment of diet with protein such as casein may be a useful approach to alleviate Pb associated adverse effects in children.


Assuntos
Caseínas/administração & dosagem , Dieta , Drosophila melanogaster/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Sistema Nervoso/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Acetilcolinesterase/metabolismo , Fatores Etários , Animais , Antioxidantes/metabolismo , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Drosophila melanogaster/metabolismo , Enzimas/metabolismo , Feminino , Voo Animal/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Estresse Oxidativo , Fatores Sexuais , Fatores de Tempo
15.
Toxicol Mech Methods ; 25(2): 120-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25496357

RESUMO

Exposure to aluminum (Al) and lead (Pb) can cause brain damage. Also, Pb and Al exposure alters N-methyl-d-aspartate receptor (NMDAR) subunit expression. Polyphenols such as tannic acid and curcumin are very efficient chelator for metals. The effects of curcumin and tannic acid (polyphenols) on Al(3+)- and Pb(2+)-induced oxidative stress were examined by investigating lipid peroxidation (LPO) levels, antioxidant enzyme activities, acetyl cholinesterase (AChE) activity and also NMDA receptor subunits 2A and 2B concentrations in the brain tissue of rats sub-chronically. Rats were divided into seven groups as control, Al, Pb, aluminum-tannic acid treatment (AlT), aluminum-curcumin treatment (AlC), lead-tannic acid treatment (PbT) and lead-curcumin treatment (PbC). After 16 weeks of treatment, LPO levels in the brain and hippocampus were higher in Al(3+)-exposed rats than that of Pb(2+)-exposed group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in brain tissue of Al- and Pb-exposed rats increased significantly compared with control, while catalase (CAT) and AChE activities decreased. It was observed that metal exposure affected NR2A concentrations more than NR2B concentrations and also that polyphenol treatments increased these receptor protein concentrations.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Curcumina/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Taninos/farmacologia , Acetatos , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/etiologia , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Compostos Organometálicos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Superóxido Dismutase/metabolismo , Regulação para Cima
16.
Toxicol Mech Methods ; 25(2): 128-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25496477

RESUMO

In recent years, the use of stem cells as a new tool to create an in vitro model for toxicological studies has been considered. Adipose tissue-derived stem cells (ADSCs) are mesenchymal stem cells which have been extracted from adipose tissue by a less invasive method and rapidly propagated in culture medium compared with other sources. These cells have the capacity to differentiate into different cell lineage in vitro including neural cells. The aim of this study was to investigate the effect of lead exposure at various stages of differentiation on the neural differentiation of ADSCs. Third-passaged ADSCs were differentiated to neural cell in differentiation medium during 16 d. The ADSCs were exposed to lead (0.1-100 µg/ml) before differentiation and during differentiation on days 1, 7 and 14. The cell viability was assessed by MTT assay after 48 h. Also expression of ß-tubulin III protein and Nestin, NeuN, NF70, Synaptophysin genes were evaluated at the end of differentiation in all treated groups. The results showed that lead had no effect on viability of undifferentiated ADSCs but differentiating cells showed various sensitivities to lead exposure and cells were more vulnerable to lead exposure at early stage of differentiation. Also, lead exposure at different stages of differentiation had various effects on gene expressions. Our study indicated that neural cells differentiated from ADSCs in vitro are sensitive to neurotoxic effect of lead as well-known developmental neurotoxicant, and then ADSCs could be a candidate as an alternative method for assessing neurodevelopmental toxicity potential of chemicals.


Assuntos
Tecido Adiposo/citologia , Intoxicação do Sistema Nervoso por Chumbo , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Animais , Separação Celular/métodos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/genética , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Camundongos Endogâmicos BALB C , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fatores de Tempo
17.
Neurotoxicology ; 39: 95-101, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23973560

RESUMO

Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aß) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Intoxicação do Sistema Nervoso por Chumbo/complicações , Intoxicação do Sistema Nervoso por Chumbo/patologia , Proteínas tau/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Estudos de Coortes , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Macaca fascicularis , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Proteínas tau/genética
18.
J Inorg Biochem ; 126: 70-5, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23777747

RESUMO

PbS nanoparticles (NPs) is an important nanomaterial for biomedical imaging in living tissues. However, concerning the high toxicity, especially neurotoxicity, of Pb element, it is crucial that the toxicity assessment of "naked" PbS NPs should be adequately studied. In the current study, we systematically explored the neurotoxicity of PbS NPs in rats by measuring the body weight and brain coefficient changes, testing memory behaviors in Y-electric maze, and studying the neuronal ultrastructure and pathology in hippocampus. Furthermore, in order to study the toxic mechanism, we performed Pb and Ca content measurements in various organs, and investigated Ca(2+)-ATPase activity and L-type calcium channel subunit expression. Our results confirmed that PbS NPs showed high neurotoxicity, while a possible mechanism was suggested to be due to the PbS NPs-induced calcium homeostasis disorder which was caused by the abnormal calcium transportation.


Assuntos
Cálcio/metabolismo , Hipocampo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Chumbo/toxicidade , Nanopartículas/toxicidade , Neurônios/efeitos dos fármacos , Sulfetos/toxicidade , Administração por Inalação , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , ATPases Transportadoras de Cálcio/genética , ATPases Transportadoras de Cálcio/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Transporte de Íons/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/patologia , Intoxicação do Sistema Nervoso por Chumbo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Subunidades Proteicas/agonistas , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Neurotoxicology ; 33(3): 370-83, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22387731

RESUMO

Serine/threonine protein phosphatases regulate several key cellular events in the brain, including learning and memory. These enzymes, when over-activated, are known to function as a constraint on learning and memory. We investigated whether these phosphatases are implicated in lead (Pb)-induced deficits in learning and memory. Wistar rat pups were exposed to 0.2% Pb-acetate via their dams' drinking water from postnatal day (PND) 1-21 and directly in drinking water until PND 30. Pb levels in blood, brain and hippocampus were measured and expression of PP1, PP2A, PP2B and PP5 in hippocampus was analyzed. Total phosphatase activity, and PP1 and PP2A activities were determined. Tau phosphorylation at various epitopes was determined by Western blot. Spatial learning and memory was determined by Morris water maze test. Pb exposure significantly increased levels of Pb in blood, brain and hippocampus, reduced the number of synapses in hippocampus and impaired learning and long-term memory (LTM). Short-term memory (STM) was only affected in rats at PND21. Pb exposure increased the expression and activity of PP1 and decreased phosphorylation of tau at threonine-231 in hippocampus at both PND21 and PND30. Pb-induced phosphorylation of tau at serine-199/202 (AT8) paralleled with PP2A activity; at PND21 PP2A activity increased and AT8 phosphorylation decreased; at PND30 PP2A activity decreased and AT8 phosphorylation increased. Increased PP1 activity in hippocampus by Pb is associated with learning and LTM impairment, whereas, increased PP2A activity is associated with STM impairment. These findings suggest the overactivation of PP1 and PP2A, together with changes in tau phosphorylation, as a potential mechanism of lead-induced deficits in learning and memory.


Assuntos
Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/enzimologia , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 2/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Western Blotting , Modelos Animais de Doenças , Ativação Enzimática , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Intoxicação do Sistema Nervoso por Chumbo/etiologia , Intoxicação do Sistema Nervoso por Chumbo/patologia , Intoxicação do Sistema Nervoso por Chumbo/fisiopatologia , Intoxicação do Sistema Nervoso por Chumbo/psicologia , Transtornos da Memória/enzimologia , Transtornos da Memória/psicologia , Testes Neuropsicológicos , Compostos Organometálicos/sangue , Fosforilação , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/patologia , Fatores de Tempo , Proteínas tau/metabolismo
20.
Neurotoxicology ; 33(3): 280-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22342836

RESUMO

The role of green tea in protection against neurotoxicity induced by lead acetate was investigated in rats. Five equal groups, each of ten rats were used. The first group was served as control, the second, third, and fourth groups were given lead acetate, lead acetate and green tea, and green tea only, respectively, for one month, the fifth group was administered lead acetate for one month followed by green tea for 15 days. Lead acetate was given orally at a dose of 100 mg/kg b. wt, while green tea was given in drinking water at a concentration of 5 g/L. Lead acetate administration induced loss of body weight and decreased concentration of reduced glutathione and SOD activity in brain tissues as well as significantly high DNA fragmentation and pathological changes. Co-administration of green tea with lead acetate significantly alleviated these adverse effects.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Dano ao DNA , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá , Animais , Antioxidantes/isolamento & purificação , Encéfalo/metabolismo , Encéfalo/patologia , Citoproteção , Fragmentação do DNA , Modelos Animais de Doenças , Glutationa/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/etiologia , Intoxicação do Sistema Nervoso por Chumbo/genética , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Masculino , Fármacos Neuroprotetores/isolamento & purificação , Tamanho do Órgão/efeitos dos fármacos , Compostos Organometálicos , Extratos Vegetais/isolamento & purificação , Ratos , Superóxido Dismutase/metabolismo , Chá/química , Fatores de Tempo , Perda de Peso/efeitos dos fármacos
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