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1.
Toxicol Lett ; 344: 34-45, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667609

RESUMO

ASP7962 is a small molecule inhibitor for the nerve growth factor (NGF) receptor, tropomyosin-related kinase A (TrkA). NGF contributes to the survival of sensory and sympathetic neurons through TrkA receptor activation. Gross, microscopic, and quantitative effects to the nervous system were evaluated following oral ASP7962 administration to Sprague Dawley rats for 4 weeks and 13 weeks and after a recovery period. Histopathological findings included reversible neuronal atrophy but no neuronal death in the sympathetic ganglia (cervicothoracic ganglion, cranial mesenteric ganglion or superior [cranial] cervical ganglion). Stereological analysis showed reversible decreased ganglion volume and/or decreased neuron size in the superior (cranial) cervical ganglion in both the 4-week and the 13-week repeated dose studies. There were no test article related changes in the brain, dorsal root ganglia with spinal nerve roots or trigeminal ganglia and no functional deficits. ASP7962 did not cause any detectable dysfunction of the sympathetic and sensory nervous system in either study.


Assuntos
Neurônios Aferentes/efeitos dos fármacos , Receptor trkA/antagonistas & inibidores , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Masculino , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , Ratos , Ratos Sprague-Dawley , Gânglio Estrelado/citologia , Gânglio Estrelado/efeitos dos fármacos , Gânglio Cervical Superior/citologia , Gânglio Cervical Superior/efeitos dos fármacos , Gânglio Trigeminal/efeitos dos fármacos
2.
Chem Biol Interact ; 340: 109431, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33716020

RESUMO

Parkinson's is a neurodegenerative disease, characterized by the loss of dopaminergic neurons, cholinergic alterations and oxidative damages. Lutein is widely known by its antioxidants properties. In the present study, we investigated whether lutein-loaded nanoparticles protects against locomotor damage and neurotoxicity induced by Parkinson's disease model in Drosophila melanogaster, as well as possible mechanisms of action. First, the nanoparticles were characterized by physicochemical methods, demonstrating that water affinity was improved by the encapsulation of lutein into the polymeric encapsulant matrix. The fruit flies of 1-4 days old were divided into four groups and exposed to a standard diet (control), a diet containing either rotenone (500 µM), lutein-loaded nanoparticles (6 µM) or rotenone (500 µM) and lutein-loaded nanoparticles (6 µM) for 7 days. The survival percentage was assessed, the flies were submitted to negative geotaxis, open field tasks and the determination of dopamine levels, tyrosine hydroxylase (TH) and acetylcholinesterase activities and oxidative stress indicators (superoxide dismutase, catalase, thiobarbituric acid reactive substances and glutathione S-transferase) were carried out. The exposure to lutein-loaded nanoparticles protected against locomotor damage and the decrease survival rate induced by rotenone, besides, it restored the dopamine levels, TH and acetylcholinesterase activities and oxidative stress indicators. These results provide evidence that lutein-loaded nanoparticles are an alternative treatment for rotenone-induced damage, and suggest the involvement of dopaminergic and cholinergic system and oxidative stress.


Assuntos
Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Luteína/farmacologia , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/metabolismo , Animais , Neurônios Colinérgicos/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Drosophila melanogaster/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Doença de Parkinson/metabolismo
3.
Ecotoxicol Environ Saf ; 208: 111570, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396099

RESUMO

Traditional brominated flame retardants (BFRs) negatively affect the environment and human health, especially in the sensitive (developing) nervous system. Considering the physicochemical similarities between novel brominated flame retardants (NBFRs) and BFRs, more and more evidence reveals the neurotoxic effects of NBFRs. We reviewed the neuro(endocrine) toxic effects of NBFRs in vivo and in vitro and discussed their action mechanisms based on the available information. The neurotoxic potential of NBFRs has been demonstrated through direct neurotoxicity and disruption of the neuroendocrine system, with adverse effects on neurobehavioral and reproductive development. Mechanistic studies have shown that the impact of NBFRs is related to the complex interaction of neural and endocrine signals. From disrupting the gender differentiation of the brain, altering serum thyroid/sex hormone levels, gene/protein expression, and so on, to interfere with the feedback effect between different levels of the HPG/HPT axis. In this paper, the mechanism of neurotoxic effects of NBFRs is explored from a new perspective-neuro and endocrine interactions. Gaps in the toxicity data of NBFRs in the neuroendocrine system are supplemented and provide a broader dataset for a complete risk assessment.


Assuntos
Sistema Endócrino/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Monitoramento Ambiental , Éteres Difenil Halogenados/análise , Humanos , Hidrocarbonetos Bromados/análise , Síndromes Neurotóxicas/metabolismo , Medição de Risco , Hormônios Tireóideos
4.
Neurosci Lett ; 740: 135482, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161106

RESUMO

It has been reported that many long noncoding RNAs (lncRNA) are abnormally expressed in Parkinson's disease (PD). However, the knowledge about the role of dysregulated lncRNA in the pathological process of PD and the potential molecular regulation mechanism is still limited. Our immunofluorescence data show that miR-126 enhances the aggregation and toxicity of synuclein, while lncRNA OIP5-AS1 reduces the aggregation and toxicity of MPP + induced α-synuclein by targeting miR-126. Luciferase experiments have found that miR-126 regulates α-synuclein by targeting PLK2. Western blot and IP experimental analysis showed that this process is achieved by regulating PLK2/α-synuclein autophagy. In conclusion, our data indicate that OIP5-AS1 promotes the autophagy of PLK2-α-synuclein by targeting the miR-126 axis with pathogenic factors, thus reducing the aggregation toxicity of α-synuclein, which It will help better to understand the mechanism of dopaminergic neuron loss in PD and provide novel treatment options.


Assuntos
MicroRNAs/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
5.
Toxicol Lett ; 338: 85-96, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309997

RESUMO

Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Neuritos/metabolismo , Neuritos/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Células PC12 , Ratos , Fatores de Tempo
6.
Sci Rep ; 10(1): 21889, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318563

RESUMO

Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.


Assuntos
Proteínas do Domínio Armadillo/metabolismo , Calpaína/metabolismo , Cisplatino/efeitos adversos , Proteínas do Citoesqueleto/metabolismo , Síndromes Neurotóxicas/metabolismo , Animais , Proteínas do Domínio Armadillo/genética , Calpaína/genética , Células Cultivadas , Cisplatino/farmacologia , Proteínas do Citoesqueleto/genética , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Camundongos , Camundongos Knockout , Síndromes Neurotóxicas/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Sprague-Dawley , Degeneração Walleriana/induzido quimicamente , Degeneração Walleriana/genética , Degeneração Walleriana/metabolismo
7.
Ecotoxicol Environ Saf ; 205: 111344, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32977283

RESUMO

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.


Assuntos
Genisteína/farmacologia , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Rotenona/toxicidade , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Citocinas/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Camundongos , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
Anticancer Res ; 40(7): 3685-3696, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620607

RESUMO

BACKGROUND/AIM: Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them. MATERIALS AND METHODS: Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M). RESULTS: All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib. CONCLUSION: Bortezomib-induced neuropathy might be ameliorated by antioxidants.


Assuntos
Antioxidantes/farmacologia , Bortezomib/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos
9.
Toxicol Lett ; 331: 152-158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522579

RESUMO

Chronic exposure to n-hexane, a widely used solvent in industry, causes sensorimotor neuropathy, which is mainly mediated by its toxic metabolite, 2,5-hexanedione (HD). However, the mechanisms remain unclear. This study is designed to investigate whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in HD-induced neurotoxicity. Results showed that HD intoxication significantly elevated NLRP3 expression, caspase-1 activation and interleukin-1ß (IL-1ß) maturation in the spinal cord of rats, indicating NLRP3 inflammasome activation. Glibenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, reduced HD-induced NLRP3 inflammasome activation, which was associated with mitigated gasdermin D (GSDMD) cleavage, neurofilament protein L (NF-L) reduction and demyelination as well as axon degeneration in the spinal cord of rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glibenclamide suppressed microglial activation and M1 polarization and simultaneously recovered M2 polarization in HD-intoxicated rats. Furthermore, glibenclamide treatment reduced the contents of malondialdehyde (MDA) as well as elevated glutathione (GSH) levels and total-antioxidative capacity in the spinal cord of HD-intoxicated rats, indicating attenuated oxidative stress. Collectively, our findings suggested that NLRP3 inflammasome activation contributed to HD-induced neurotoxicity by enhancing microglial M1 polarization and oxidative damage. Inhibition of NLRP3 inflammasome by glibenclamide might a potential avenue to combat n-hexane-induced neuropathy.


Assuntos
Glibureto/farmacologia , Hexanonas/toxicidade , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Masculino , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/imunologia , Ratos Sprague-Dawley , Medula Espinal/imunologia , Medula Espinal/metabolismo
10.
Toxicol Lett ; 331: 188-199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569805

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.


Assuntos
Astrócitos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Exossomos/metabolismo , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Hipocampo/citologia , Humanos , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/metabolismo , Síndromes Neurotóxicas/imunologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Cultura Primária de Células , Sinucleinopatias/imunologia , Sinucleinopatias/metabolismo
11.
Ecotoxicol Environ Saf ; 201: 110849, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32559690

RESUMO

Polybrominated diphenyl ethers (PBDEs) are extensively used as brominated flame retardants in various factory products. As environmental pollutants, the adverse effects of PBDEs on human health have been receiving considerable attention. However, the precise fundamental mechanisms of toxicity induced by PBDEs are still not fully understood. In this study, the mechanism of cytotoxicity induced by 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was investigated by combining Seahorse XFp analysis and mass spectrometry-based metabolomics and flux approaches in PC12 cells, one of the most widely used neuron-like cell lines for investigating cytotoxic effects. The Seahorse results suggest that BDE-47 significantly attenuated mitochondrial respiration and enhanced glycolysis in PC12 cells. Additionally, metabolomics results revealed the reduction of TCA metabolites such as citrate, succinate, aconitate, malate, fumarate, and glutamate after BDE-47 exposure. Metabolic flux analysis showed that BDE-47 exposure reduced the oxidative metabolic capacity of mitochondria in PC12 cells. Furthermore, various altered metabolites were found in multiple metabolic pathways, especially in glycine-serine-threonine metabolism and glutathione metabolism. A total of 17 metabolic features were determined in order to distinguish potentially disturbed metabolite markers of BDE-47 exposure. Our findings provide possible biomarkers of cytotoxic effects induced by BDE-47 exposure, and elicit a deeper understanding of the intramolecular mechanisms that could be used in further studies to validate the potential neurotoxicity of PBDEs in vivo. Based on our results, therapeutic approaches targeting mitochondrial function and the glycolysis pathway may be a promising direction against PBDE exposure.


Assuntos
Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Glicólise/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Mitocôndrias/efeitos dos fármacos , Animais , Fenômenos Bioquímicos , Biomarcadores/metabolismo , Humanos , Espectrometria de Massas , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Mitocôndrias/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Ratos
12.
Nat Commun ; 11(1): 3014, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541820

RESUMO

Formation of amyloid-beta (Aß) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer's disease (AD). Here, we present the three-dimensional structure of an Aß oligomer formed in a membrane mimicking environment, namely an Aß(1-42) tetramer, which comprises a six stranded ß-sheet core. The two faces of the ß-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aß(1-42) in the sample, Aß(1-42) octamers are also formed, made by two Aß(1-42) tetramers facing each other forming a ß-sandwich structure. Notably, Aß(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core ß-sheets edges of the oligomers.


Assuntos
Peptídeos beta-Amiloides/química , Membrana Celular/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Conformação Proteica , Multimerização Proteica , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Membrana Celular/metabolismo , Condutividade Elétrica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Bicamadas Lipídicas/metabolismo , Síndromes Neurotóxicas/metabolismo , Fragmentos de Peptídeos/metabolismo , Água/metabolismo
13.
Sci Rep ; 10(1): 7283, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350290

RESUMO

Earlier studies showed that endogenous estrogens have neuroprotective effect against oxidative damage. The present study seeks to investigate the protective effect of various endogenous estrogen metabolites against oxidative neurotoxicity in vitro and in vivo. Using immortalized mouse hippocampal neuronal cells as an in vitro model, 4-hydroxyestrone, an estrone metabolite with little estrogenic activity, is found to have the strongest neuroprotective effect against oxidative neurotoxicity among 25 endogenous estrogen metabolites tested, and its protective effect is stronger than 17ß-estradiol. Similarly, 4-Hydroxyestrone also exerts a stronger protective effect than 17ß-estradiol against kanic acid-induced hippocampal oxidative damage in rats. Neuroprotection by 4-hydroxyestrone involves increased cytoplasmic translocation of p53 resulting from SIRT1-mediated deacetylation of p53. Analysis of brain microsomal enzymes shows that estrogen 4-hydroxylation is the main metabolic pathway in the central nervous system. Together, these results show that 4-hydroxyestrone is an endogenous neuroestrogen that can strongly protect against oxidative neuronal damage.


Assuntos
Hipocampo/metabolismo , Hidroxiestronas/farmacologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular Transformada , Estradiol/farmacologia , Hipocampo/patologia , Masculino , Camundongos , Neurônios/patologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos , Ratos Sprague-Dawley
14.
Environ Toxicol ; 35(9): 922-929, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32293791

RESUMO

Excessive fluoride exposure contributes to neurotoxic effects. Emodin exhibits antioxidative functions in the central nervous system (CNS); however, its neuroprotective mechanism against fluoride remains to be elucidated. Our aim was to explore the neuroprotective efficacy and the possible mechanisms of emodin. In our study, synaptic proteins and oxidative stress damage were examined after human neuroblastoma SH-SY5Y cells were treated with high doses of NaF for 24 hours. Moreover, pretreatment with emodin was used to shed light on the neuroprotective effects in NaF-induced toxicity in SH-SY5Y cells. We found that NaF significantly lowered the protein expressions of SNAP 25, synaptophysin and PSD 95 in SH-SY5Y cells. In addition, NaF exposure increased the protein expression of p-ERK1/2 and decreased the protein expressions of Nrf2 and HO-1, as well as facilitated increasing ROS, 4-hydroxynonenal (4-HNE), and 8-Hydroxy-2'-deoxyguanosine (8-OHdG). Pretreatment with emodin significantly recovered these alterations caused by NaF. These data implied that the neuroprotective effects of emodin and pointed to the promising utilization for protecting against neurotoxicity induced by fluoride.


Assuntos
Emodina/farmacologia , Fluoretos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neuroblastoma/metabolismo , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Sinaptofisina/metabolismo
15.
Toxicology ; 438: 152461, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32278788

RESUMO

The α-Synuclein (α-syn) and tau have synergistic effects on neurodegenerative diseases induced by environmental factors or genetic mutation. Thus, we investigated the role of α-syn and tau in neurodegeneration induced by chronic methamphetamine (METH) exposure (1.0∼20.0 mg/kg/d body weight, for 14 consecutive days). Here, we present a mice model with evidences of α-syn and tau participating in toxicology in chronic METH. METH increased α-syn level in the stratum oriens, pyramidal layer, stratum radiatum and stratum moleculare of hippocampal CA1, CA2 and CA3, polymorph layer of hippocampal dentate gyrus (DG), and substantia nigra (SN). The subcellular locations of the upregulated α-syn were mainly found in mitochondria and axons. The METH upregulated α-syn may directly induce mitochondrial damage, myelin sheath destruction, and synaptic failure. Also, the excess α-syn might indirectly promote tau phosphorylation through tau kinase GSK3ß and CDK5, leading to microtubule depolymerization and eventually fusion deficit of autophagosome and lysosome. In the in vitro experiment, the autophagic vacuoles failed to fuse with the lysosome. The neuropathology induced by both the direct and indirect effects of α-syn could be alleviated by α-syn knockout. Taking together, these results indicate that the α-syn mediates the neurodegenerative process induced by chronic METH and that reducing α-syn might be a potential approach to protect the toxic effects of METH and also be, to a broader view, of therapeutic value in neurodegenerative diseases.


Assuntos
Hipocampo/metabolismo , Degeneração Neural , Neurônios/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Substância Negra/metabolismo , alfa-Sinucleína/deficiência , Animais , Autofagia , Axônios/metabolismo , Axônios/ultraestrutura , Células Cultivadas , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/ultraestrutura , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Masculino , Metanfetamina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/ultraestrutura , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Fosforilação , Substância Negra/ultraestrutura , Fatores de Tempo , alfa-Sinucleína/genética , Proteínas tau/metabolismo
16.
Environ Toxicol ; 35(8): 840-848, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32167238

RESUMO

Oxidative stress may play critically important roles in the etiology of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a physiological neurotoxin reported to induce oxidative-induced apoptosis of dopaminergic neurons in PD mice models. Valproic acid (VPA), a clinical mood stabilizer, is a HDAC inhibitor with neuroprotective capacities. In the study, we aim at examining the feasibility of VPA as a protector for dopaminergic neurons against damage from 6-OHDA, and the intracellular mechanisms. The 6-OHDA-induced neurotoxicity to the human dopaminergic cell line SH-SY5Y was applied for examining VPA protective effects. Pretreatment with VPA was able to improve cell viability and reduce 6-OHDA-induced reactive oxygen species. Furthermore, a significant suppression of apoptotic caspases including cleaved caspase-3, caspase-7, and caspase-9 was observed. The results also revealed VPA decreased the 6-OHDA-induced Bax/Bcl2 ratio, as measured at protein level. These novel findings indicate that VPA may be capable of protecting the SH-SY5Y dopaminergic neuronal cells from 6-OHDA-induced toxicity via the deceasing of apoptotic caspases (cleaved caspase-3, caspase-7, and caspase-9) and reducing of the Bax/Bcl2 ratio. Very possibly, VPA could serve as not only a mood stabilizer but also a potential antidote for PD prevention.


Assuntos
Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Ácido Valproico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dopamina/metabolismo , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/metabolismo , Oxidopamina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ácido Valproico/metabolismo
17.
Ecotoxicol Environ Saf ; 194: 110382, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146195

RESUMO

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


Assuntos
Encéfalo/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Neurotransmissores/metabolismo , Tricotecenos/toxicidade , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Dieta , Masculino , Síndromes Neurotóxicas/metabolismo , Oxirredução , Suínos , Desmame
18.
Curr Pharm Biotechnol ; 21(12): 1259-1268, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196446

RESUMO

BACKGROUND: Ginkgo biloba extract (GbE) is known to contain several bioactive compounds and exhibits free radical scavenging activity. Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and is associated with oxidative stress, neuroinflammation and apoptosis. OBJECTIVE: The current study aimed to investigate the neuroprotective effect of GbE in a rat model of PD induced by rotenone (ROT; a neurotoxin). METHODS: Twenty-four male albino rats were randomly divided into four groups of six rats each: normal control, GbE treated, toxin control (ROT treated) and GbE+ROT group. RESULTS: Oral administration of ROT (2.5 mg/kg b.w.) for 50 days caused an increased generation of lipid peroxidation products and significant depletion of reduced glutathione, total thiol content and activities of enzymatic antioxidants, i.e., superoxide dismutase and glutathione peroxidase in the brains of treated rats. Furthermore, ROT caused an elevation in acetylcholinesterase, interleukin-1ß, interleukin- 6 and tumor necrosis factor-α and a significant reduction in dopamine in the stratum and substantia nigra. Immunohistochemical results illustrated that ROT treatment reduced the expression of tyrosine hydroxylase (TH). GbE treatment (150 mg/kg b.w./day) significantly reduced the elevated oxidative stress markers and proinflammatory cytokines and restored the reduced antioxidant enzyme activities, DA level and TH expression. These results were confirmed by histological observations that clearly indicated a neuroprotective effect of GbE against ROT-induced PD. CONCLUSION: GbE mitigated ROT-induced PD via the inhibition of free-radical production, scavenging of ROS, and antioxidant enhancement.


Assuntos
Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Administração Oral , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Ratos , Rotenona/toxicidade , Superóxido Dismutase/metabolismo
19.
Oxid Med Cell Longev ; 2020: 2963020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215171

RESUMO

Organophosphorus insecticides including chlorpyrifos (CPF) are mainly used for agriculture, household, and military purposes; their application is associated with various adverse reactions in animals and humans. This study was conducted to evaluate the potential neuroprotective effect of red beetroot methanolic extract (RBR) against CPF-induced cortical damage. Twenty-eight adult male Wistar albino rats were divided into 4 groups (n = 7 in each group): the control group was administered physiological saline (0.9% NaCl), the CPF group was administered CPF (10 mg/kg), the RBR group was administered RBR (300 mg/kg), and the RBR+CPF group was treated with RBR (300 mg/kg) 1 hr before CPF (10 mg/kg) supplementation. All groups were treated for 28 days. Rats exposed to CPF exhibited a significant decrease in cortical acetylcholinesterase activity and brain-derived neurotrophic factor and a decrease in glial fibrillary acidic protein. CPF intoxication increased lipid peroxidation, inducible nitric oxide synthase expression, and nitric oxide production. This was accompanied by a decrease in glutathione content and in the activities of glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the cortical tissue. Additionally, CPF enhanced inflammatory response, indicated by increased levels and expression of interleukin-1ß and tumor necrosis factor-α. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. However, RBR reversed the induced neuronal alterations following CPF intoxication. Our findings suggest that RBR can minimize and prevent CPF neurotoxicity through its antioxidant, anti-inflammatory, and antiapoptotic activities.


Assuntos
Antioxidantes/administração & dosagem , Beta vulgaris/química , Clorpirifos/toxicidade , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/prevenção & controle , Extratos Vegetais/administração & dosagem , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Inflamação , Inseticidas/toxicidade , Masculino , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Ratos , Ratos Wistar
20.
Ecotoxicol Environ Saf ; 195: 110479, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32199213

RESUMO

Cypermethrin (CYP), a class II synthetic pyrethroid, is used to control household insects. CYP can cross the blood-brain barrier to exert neurotoxicity through changes in sodium ion channels. Selenium is an essential component of glutathione peroxidise enzyme; in addition, it shows a potential anti-inflammatory property. The present study aimed to investigate the neuroprotective role of Nano-Se on CYP-induced neurotoxicity. Twenty-four adult male Wister rats were randomly divided into three groups: a) control, b) CYP (1mg/kg) administered orally for 21 days, c) CYP (1mg/kg) administered orally for 21 days and Nano-Se (2.5 mg/kg) given once a day three times a week for three weeks). Locomotor activity was assessed using open field test then rats were sacrificed under anaesthesia, and their brains were dissected out and processed for biochemical and histopathological studies. Histological examination of CYP-treated rats demonstrated some degenerative changes; besides, CYP affected rat locomotor activity. CYP-treated rats showed increased levels of malondialdehyde (MDA), TNF-α and IL-1ß in addition to the reduction of glutathione (GSH) levels and gamma-Aminobutyric acid (GABA). Nano-Se restored normal behavioural function and significantly attenuated CYP-evoked degenerative changes. Nano-Se increased levels of GABA and glutathione; on the other hand, it significantly prevented the rise in the levels of MDA, TNF-α and IL-1ß. Therefore, Nano-Se demonstrated both anti-oxidant and anti-inflammatory potential. Nano-Se may be suggested to be a prospective candidate to ameliorate CYP-induced neurotoxicity.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piretrinas/toxicidade , Selênio/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos , Ratos Wistar , Selênio/uso terapêutico , Ácido gama-Aminobutírico/metabolismo
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