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1.
BMC Complement Altern Med ; 19(1): 339, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783843

RESUMO

BACKGROUND: The dried fruits of Forsythia suspensa has generally been used to clear heat and detoxify in traditional Korean and Chinese medicine. Oxaliplatin is a first-line treatment chemotherapeutic agent for advanced colorectal cancer, but it induces peripheral neuropathy as an adverse side effect affecting the treatment regimen and the patient's quality of life. The present study was conducted to evaluate the neuroprotective effects of an aqueous extract of F. suspensa fruits (EFSF) on oxaliplatin-induced peripheral neuropathy. METHODS: The chemical components from EFSF were characterized and quantified using the ultra-high performance liquid chromatography-diode array detector system. The cytotoxicities of anticancer drugs in cancer cells and PC12 cells were assessed by the Ez-Cytox viability assay. To measure the in vitro neurotoxicity, the neurite outgrowth was analyzed in the primary dorsal root ganglion (DRG) cells, and neural PC12 cells that were differentiated with nerve growth factor. To evaluate the in vivo neuroprotective activity, the von Frey test was performed in six-week-old male mice (C57BL/6) receiving EFSF (60-600 mg/kg) in the presence of 20-30 mg/kg cumulative doses of oxaliplatin. Thereafter, the mice were euthanized for immunohistochemical staining analysis with an antibody against PGP9.5. RESULTS: EFSF attenuated the cytotoxic activities of the various anticancer drugs in neural PC12 cells, but did not affect the anticancer activity of oxaliplatin in human cancer cells. Oxaliplatin remarkably induced neurotoxicities including cytotoxicity and the inhibited neurite outgrowth of DRG and neural PC12 cells. However, the co-treatment of EFSF (100 µg/ml) with oxaliplatin completely reversed the oxaliplatin-induced neurotoxicity. Forsythoside A, the major component of EFSF, also exerted remarkable neuroprotective effects against the oxaliplatin-induced neurotoxicity. In addition, EFSF (60-200 mg/kg) significantly alleviated the oxaliplatin-induced mechanical allodynia and loss of intra-epidermal nerve fiber to the levels of the vehicle control in the mouse peripheral neuropathy model. CONCLUSIONS: EFSF could be considered a useful herbal medicine for the treatment of peripheral neuropathy in cancer patients receiving chemotherapy with oxaliplatin.


Assuntos
Forsythia , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/toxicidade , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuritos/efeitos dos fármacos , Neurotoxinas/toxicidade , Células PC12 , Ratos
2.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509934

RESUMO

In addition to its role as an endocrine messenger, growth hormone (GH) also acts as a neurotrophic factor in the central nervous system (CNS), whose effects are involved in neuroprotection, axonal growth, and synaptogenic modulation. An increasing amount of clinical evidence shows a beneficial effect of GH treatment in patients with brain trauma, stroke, spinal cord injury, impaired cognitive function, and neurodegenerative processes. In response to injury, Müller cells transdifferentiate into neural progenitors and proliferate, which constitutes an early regenerative process in the chicken retina. In this work, we studied the long-term protective effect of GH after causing severe excitotoxic damage in the retina. Thus, an acute neural injury was induced via the intravitreal injection of kainic acid (KA, 20 µg), which was followed by chronic administration of GH (10 injections [300 ng] over 21 days). Damage provoked a severe disruption of several retinal layers. However, in KA-damaged retinas treated with GH, we observed a significant restoration of the inner plexiform layer (IPL, 2.4-fold) and inner nuclear layer (INL, 1.5-fold) thickness and a general improvement of the retinal structure. In addition, we also observed an increase in the expression of several genes involved in important regenerative pathways, including: synaptogenic markers (DLG1, NRXN1, GAP43); glutamate receptor subunits (NR1 and GRIK4); pro-survival factors (BDNF, Bcl-2 and TNF-R2); and Notch signaling proteins (Notch1 and Hes5). Interestingly, Müller cell transdifferentiation markers (Sox2 and FGF2) were upregulated by this long-term chronic GH treatment. These results are consistent with a significant increase in the number of BrdU-positive cells observed in the KA-damaged retina, which was induced by GH administration. Our data suggest that GH is able to facilitate the early proliferative response of the injured retina and enhance the regeneration of neurite interconnections.


Assuntos
Hormônio do Crescimento/farmacologia , Ácido Caínico/toxicidade , Regeneração/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/genética , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurogênese/fisiologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Receptor Notch1/genética , Regeneração/genética , Regeneração/fisiologia , Retina/metabolismo , Retina/fisiopatologia , Fatores de Transcrição SOXB1/genética
3.
Dokl Biochem Biophys ; 487(1): 251-255, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559591

RESUMO

Three-finger snake neurotoxins are selective antagonists of some nicotinic acetylcholine receptor subtypes and are widely used to study these receptors. The peptide neurotoxin azemiopsin, recently isolated from the venom of Azemipos feae, is a selective blocker of muscle-type nicotinic acetylcholine receptor. In order to reduce their toxicity and increase resistance under physiological conditions, we have encapsulated these toxins into nanomaterials. The study of nanomaterials after interaction with neurotoxins by the methods of transmission electron microscopy and dynamic light scattering revealed an increase in the size of nanoparticles, which indicates the inclusion of neurotoxins in nanomaterials.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Neurotoxinas/química , Antagonistas Nicotínicos/química , Polissacarídeos/química , Receptores Nicotínicos/metabolismo , Sulfatos/química , Cápsulas , Neurotoxinas/toxicidade , Antagonistas Nicotínicos/toxicidade , Tamanho da Partícula , Venenos de Serpentes/química
4.
Artigo em Inglês | MEDLINE | ID: mdl-31546716

RESUMO

Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.


Assuntos
Doença de Alzheimer/induzido quimicamente , Manganês/toxicidade , Neurotoxinas/toxicidade , Doença de Parkinson/etiologia , Animais , Humanos , Mamíferos
5.
BMC Pharmacol Toxicol ; 20(1): 56, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500666

RESUMO

BACKGROUND: There are evidences that chlorogenic acid (CGA) has antidepressant effects, however the underlying molecular mechanism has not been well understood. The aim of the study was to explore the neuroprotective effect of CGA on corticosterone (CORT)-induced PC 12 cells and its mechanism, especially the autophagy pathway. METHODS: PC12 cells were incubated with CORT (0, 100, 200, 400 or 800 µM) for 24 h, cell viability was measured by MTT assay. PC12 cells were cultured with 400 µM of CORT in the absence or presence of CGA (25 µg/ml) for 24 h, morphologies and specific marker of autophagosome were observed by transmission electron microscope (TEM) and confocal immunofluorescence microscopy, respectively. In addition, PC12 cells were treated with different doses of CGA (0, 6.25, 12.5, 25 or 50 µg/ml) with or without CORT (400 µM) for 24 h, cell viability and changes in the morphology were observed, and further analysis of apoptotic and autophagic proteins, and expression of AKT/mTOR signaling pathway were carried out by Western blot. Specific inhibitors of autophagy 3-Methyladenine (3-MA) and chloroquine (CQ) were added to the PC12 cells cultures to explore the potential role of autophagy in CORT-induced neuronal cell apoptosis. RESULTS: Besides decreasing PC12 cell activity, CORT could also induce autophagy and apoptosis of PC12 cells, while CGA could reverse these effects. In addition, CGA treatment regulated AKT/mTOR signaling pathway in PC12 cells. CGA, similar to 3-MA and QC, significantly inhibited CORT-induced apoptosis in PC12 cells. CONCLUSIONS: Our results provide a new molecular mechanism for the treatment of CORT-induced neurotoxicity by CGA, and suggest CGA may be a potential substance which is can alleviate depression.


Assuntos
Ácido Clorogênico/farmacologia , Corticosterona/toxicidade , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Corticosterona/antagonistas & inibidores , Neurotoxinas/antagonistas & inibidores , Células PC12 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
6.
J Agric Food Chem ; 67(34): 9618-9629, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31381342

RESUMO

Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.


Assuntos
Astrócitos/efeitos dos fármacos , Hidroxianisol Butilado/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais , Astrócitos/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
7.
BMC Pharmacol Toxicol ; 20(1): 47, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383036

RESUMO

BACKGROUND: MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS: Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS: Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION: Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.


Assuntos
Meio Ambiente , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neurotoxinas/toxicidade , Serotoninérgicos/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Masculino , Síndromes Neurotóxicas/veterinária , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
8.
Neurotox Res ; 36(3): 602-611, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377995

RESUMO

The size and frequency of cyanobacterial blooms are increasing concomitantly with rising global temperatures and increased eutrophication, and this has implications for human health. Cyanotoxins, including L-BMAA, have been implicated in triggering neurodegenerative diseases such as ALS/PDC and Alzheimer's disease. L-BMAA is a water-soluble non-protein amino acid that can bioaccumulate up the food chain, in a free- and protein-bound form. While some data exists on the degree of environmental enrichment of L-BMAA in water bodies, cyanobacteria-derived supplements, fruit bats, and seafood, virtually nothing is known about the presence of L-BMAA in other foodstuffs. It has now been shown several times in laboratory settings that plants can absorb L-BMAA into their leaves and stems, but data from wild-grown plants is nascent. One of the mechanisms implicated in L-BMAA bioaccumulation is misincorporation into proteins in the place of the canonical amino acid L-serine. We first identified this as a mechanism of action of L-BMAA in 2013, and since then, several groups have replicated these findings, but others have not. Here, we discuss in detail the experimental approaches, why they may have produced negative findings and propose several ways forward for developing consistency within the field. We emphasize the need to standardize cell culture methods, using L-serine-free medium to study misincorporation of BMAA, and urge accurate reporting of the components present in cell culture media.


Assuntos
Diamino Aminoácidos/toxicidade , Contaminação de Alimentos , Doenças Transmitidas por Alimentos/etiologia , Neurotoxinas/toxicidade , Cianobactérias , Cadeia Alimentar , Doenças Transmitidas por Alimentos/epidemiologia , Proliferação Nociva de Algas , Humanos
9.
Aquat Toxicol ; 214: 105258, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31374405

RESUMO

A vast variety of substances currently reaches the aquatic environment, including newly developed chemicals and products. Lack of appropriate analytical methods for trace determinations in aquatic ecosystem compartments and lack of information regarding their toxicity explains existing regulation gaps. However, suspicion of their toxicity assigned them as Contaminants of Emerging Concern (CECs). Among CECs are Pharmaceuticals including Salicylic Acid (SA), which is the active metabolite of acetylsalicylic acid (ASA; aspirin). The aim of the present study was to evaluate the potential effects of SA on the mussel Mytilus galloprovincialis. For this, organisms were exposed for 28 days to different concentrations of SA (0.005; 0.05; 0.5 and 5 mg/L), resembling low to highly polluted sites, after which different physiological and biochemical parameters were evaluated to assess organism's respiration rate, neurotoxic, metabolic and oxidative stress status. Our results clearly showed that SA strongly reduced the respiration capacity of mussels. Also, SA inhibited the activity of superoxide dismutase (SOD) and catalase (CAT) enzymes, but increased the activity of glutathione peroxidase (GPx) and glutathione-S-transferases (GSTs), which prevented the occurrence of lipid peroxidation (LPO). Nevertheless, oxidative stress was confirmed by the strong decrease of the ratio between reduce glutathione (GSH) and oxidized (GSSG) glutathione in contaminated mussels. Moreover, neurotoxicity was observed in mussels exposed to SA. Overall, this study demonstrates the metabolic, neurotoxic and oxidative stress impacts of SA in M. galloprovincialis, which may result in negative consequences at the population level.


Assuntos
Mytilus/fisiologia , Ácido Salicílico/efeitos adversos , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Biotransformação , Catalase/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Mytilus/efeitos dos fármacos , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Respiração , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/toxicidade
10.
Dokl Biochem Biophys ; 486(1): 171-174, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31367814

RESUMO

Under conditions of the experimental model of Parkinson's disease at the preclinical (early) and clinical stage-injection of mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 5 and 10 weeks-the toxic effects of MPTP was evaluated (the content of catecholamines and their metabolites in the heart, which receives the most extensive sympathetic innervation, was determined). The obtained data indicated the beginning of desympathization of the heart at the preclinical stage of PD and its progression at the clinical stage of the disease.


Assuntos
Catecolaminas/metabolismo , Neurotoxinas/toxicidade , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Animais , Coração/efeitos dos fármacos , Coração/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
J Trace Elem Med Biol ; 56: 146-155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470248

RESUMO

BACKGROUND: Calcium is an essential macronutrient that is involved in many cellular processes. Homeostatic control of intracellular levels of calcium ions [Ca2+] is vital to maintaining cellular structure and function. Several signaling molecules are involved in regulating Ca2+ levels in cells and perturbation of calcium signaling processes is implicated in several neurodegenerative and neurologic conditions. Manganese [Mn] is a metal which is essential for basic physiological functions. However, overexposure to Mn from environmental contamination and workplace hazards is a global concern. Mn overexposure leads to its accumulation in several human organs particularly the brain. Mn accumulation in the brain results in a manganism, a Parkinsonian-like syndrome. Additionally, Mn is a risk factor for several neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. Mn neurotoxicity also affects several neurotransmitter systems including dopaminergic, cholinergic and GABAergic. The mechanisms of Mn neurotoxicity are still being elucidated. AIM: The review will highlight a potential role for calcium signaling molecules in the mechanisms of Mn neurotoxicity. CONCLUSION: Ca2+ regulation influences the neurodegenerative process and there is possible role for perturbed calcium signaling in Mn neurotoxicity. Mechanisms implicated in Mn-induced neurodegeneration include oxidative stress, generation of free radicals, and apoptosis. These are influenced by mitochondrial integrity which can be dependent on intracellular Ca2+ homeostasis. Nevertheless, further elucidation of the direct effects of calcium signaling dysfunction and calcium-binding proteins activities in Mn neurotoxicity is required.


Assuntos
Sinalização do Cálcio , Manganês/toxicidade , Neurotoxinas/toxicidade , Animais , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Biosci Biotechnol Biochem ; 83(11): 2016-2026, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31272310

RESUMO

Exposure of PC12 cells to 10 mM glutamate caused significant viability loss, cell apoptosis, decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as increased levels of malondialdehyde (MDA). In parallel, glutamate significantly increased the intracellular levels of ROS and intracellular calcium. However, pretreatment of the cells with acteoside and isoacteoside significantly suppressed glutamate-induced cellular events. Moreover, acteoside and isoacteoside reduced the glutamate-induced increase of caspase-3 activity and also ameliorated the glutamate-induced Bcl-2/Bax ratio reduction in PC12 cells. Furthermore, acteoside and isoacteoside significantly inhibited glutamate-induced DNA damage. In the mouse model, acteoside significantly attenuated cognitive deficits in the Y maze test and attenuated neuronal damage of the hippocampal CA1 regions induced by glutamate. These data indicated that acteoside and isoacteoside play neuroprotective effects through anti-oxidative stress, anti-apoptosis, and maintenance of steady intracellular calcium.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Ácido Glutâmico/toxicidade , Glicosídeos/química , Glicosídeos/farmacologia , Neurotoxinas/toxicidade , Álcool Feniletílico/química , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Artif Cells Nanomed Biotechnol ; 47(1): 2948-2956, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317779

RESUMO

Neurotoxicity of local anesthetics is often reported in the clinic, more and more people pay attention to them. CaMKIIß, a subtype of CaMKII, is detected in the central nervous system. Previous study found that CaMKIIß mRNA are up-regulated in DRG neurons treated with ropivacaine hydrochloride, as well as inhibition of Cav3.2 and Cav3.3 expression can improve the local anesthetics neurotoxicity. In this study, we observed the effect of CaMKIIß on neurotoxicity injury induced by ropivacaine hydrochloride with DRG cell in vitro. We first constructed the pAd-shRNA-CaMKIIß-DRG to inhibit CaMKIIß mRNA expression and detected the cell viability, cell apoptosis rate, CaMKIIß, Cav3.2 and Cav3.3 expression. The results showed that ropivacaine hydrochloride caused the DRG cell injury with cell viability decreased and cell apoptosis rate increased, CaMKIIß, Cav3.2 and Cav3.3 expression up-regulated. Interestingly, inhibition of CaMKIIß expression protected the DRG cell from the neurotoxicity injury induced by ropivacaine hydrochloride, increased the cell viability and decreased the apoptosis rate, as well as inhibition of CaMKIIß expression down-regulated Cav3.2 and Cav3.3 expression. In other words, CaMKIIß is involved with the DRG injury induced by ropivacaine hydrochloride. Inhibition CaMKIIß expression improved DRG injury, increased the cell viability and decreased cell apoptosis rate.


Assuntos
Anestésicos Locais/toxicidade , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Gânglios Espinais/citologia , Neurotoxinas/toxicidade , Ropivacaina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Sobrevivência Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley
14.
Elife ; 82019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31318331

RESUMO

Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.


Assuntos
Drosophila melanogaster/fisiologia , Retroalimentação Fisiológica , Ácido Glutâmico/toxicidade , Neurônios Motores/fisiologia , Neurotoxinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Estresse Oxidativo/efeitos dos fármacos
15.
J Environ Sci Health B ; 54(11): 883-891, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311415

RESUMO

The characterization of soluble cholinesterases (ChEs) together with carboxylesterases (CEs) in Ficopomatus enigmaticus as suitable biomarkers of neurotoxicity was the main aim of this study. ChEs of F. enigmaticus were characterized considering enzymatic activity, substrate affinity (acetyl-, butyryl-, propionylthiocholine), kinetic parameters (Km and Vmax) and in vitro response to model inhibitors (eserine hemisulfate, iso-OMPA, BW284C51), and carbamates (carbofuran, methomyl, aldicarb, and carbaryl). CEs were characterized based on enzymatic activity, kinetic parameters and in vitro response to carbamates (carbofuran, methomyl, aldicarb, and carbaryl). Results showed that cholinesterases from F. enigmaticus showed a substrate preference for acetylthiocholine followed by propionylthiocholine; butyrylthioline was not hydrolyzed differently from other Annelida species. CE activity was in the same range of cholinesterase activity with acetylthiocholine as substrate; the enzyme activity showed high affinity for the substrate p-nytrophenyl butyrate. Carbamates inhibited ChE activity with propionylthiocholine as substrate to a higher extent than with acetylthiocoline. Also CE activity was inhibited by all tested carbamates except carbaryl. In vitro data highlighted the presence of active forms of ChEs and CEs in F. enigmaticus that could potentially be inhibited by pesticides at environmentally relevant concentration.


Assuntos
Anelídeos/enzimologia , Inibidores da Colinesterase/toxicidade , Colinesterases/química , Neurotoxinas/toxicidade , Animais , Anelídeos/efeitos dos fármacos , Biomarcadores/química , Carbamatos/química , Carbaril/química , Carbaril/toxicidade , Carbofurano/química , Carbofurano/toxicidade , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Cinética , Metomil/química , Metomil/toxicidade , Neurotoxinas/química
16.
Int J Nanomedicine ; 14: 4167-4186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239675

RESUMO

Engineered nanomaterials (ENMs) have been widely used in various fields due to their novel physicochemical properties. However, the use of ENMs has led to an increased exposure in humans, and the safety of ENMs has attracted much attention. It is universally acknowledged that ENMs could enter the human body via different routes, eg, inhalation, skin contact, and intravenous injection. Studies have proven that ENMs can cross or bypass the blood-brain barrier and then access the central nervous system and cause neurotoxicity. Until now, diverse in vivo and in vitro models have been developed to evaluate the neurotoxicity of ENMs, and oxidative stress, inflammation, DNA damage, and cell death have been identified as being involved. However, due to various physicochemical properties of ENMs and diverse study models in existing studies, it remains challenging to establish the structure-activity relationship of nanomaterials in neurotoxicity. In this paper, we aimed to review current studies on ENM-induced neurotoxicity, with an emphasis on the molecular and cellular mechanisms involved. We hope to provide a rational material design strategy for ENMs when they are applied in biomedical or other engineering applications.


Assuntos
Nanoestruturas/toxicidade , Nanotecnologia , Neurotoxinas/toxicidade , Morte Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Dano ao DNA , Humanos , Nanoestruturas/química
17.
Biomed Environ Sci ; 32(4): 281-290, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31217064

RESUMO

OBJECTIVE: The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant, is harmful to the nervous system, but its effects on the brain are still unclear. This study aimed to investigate the effects of TCDD on astrocytes proliferation and underlying molecular mechanism. METHODS: The cell proliferation was measured by EdU-based proliferation assay and PI staining by flow cytometry. Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of signal transducer and activator of transcription 3 (STAT3). RESULTS: C6 cells treated with 10 and 50 nmol/L TCDD for 24 h showed significant promotion of the proliferation of. The exposure to TCDD resulted in the upregulation in the expression levels of phosphorylated protein kinase B (p-Akt), phosphorylated STAT3, and cyclin D1 in a dose- and time-dependent manner. The inhibition of Akt expression with LY294002 or STAT3 expression with AG490 abolished the TCDD-induced cyclin D1 upregulation and cell proliferation. Furthermore, LY294002 suppressed the activation of STAT3. Finally, TCDD promoted the translocation of STAT3 from the cytoplasm to the nucleus, and LY294002 treatment blocked this effect. CONCLUSION: TCDD exposure promotes the proliferation of astrocyte cells via the Akt/STAT3/cyclin D1 pathway, leading to astrogliosis.


Assuntos
Astrócitos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Neurotoxinas/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Animais , Animais Recém-Nascidos , Ciclina D1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo
18.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
19.
J Neuroinflammation ; 16(1): 118, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170999

RESUMO

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1ß), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage. METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1ß prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes. RESULTS: NMDA-induced damage included neuronal cell death, microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1ß-signaling in different types of retinal neurons and glia. Expression of the IL1ß receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Müller glia, and OFF bipolar cells. Ablation of microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1ß stimulated the proliferation and reactivity of microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1ß failed to provide neuroprotection in the IL-1R1-null retina, but IL1ß-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes. CONCLUSIONS: We conclude that reactive microglia provide protection to retinal neurons, since the absence of microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of microglia may be mediated by IL1ß, IL-1R1, and interactions of microglia and other macroglia.


Assuntos
Interleucina-1beta/metabolismo , Microglia/metabolismo , Neuroproteção/fisiologia , Receptores Tipo I de Interleucina-1/metabolismo , Retina/patologia , Animais , Agonistas de Aminoácidos Excitatórios/toxicidade , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , N-Metilaspartato/toxicidade , Neurotoxinas/toxicidade , Receptores Tipo I de Interleucina-1/imunologia , Retina/imunologia
20.
J Biol Chem ; 294(26): 10336-10348, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31113867

RESUMO

Parkinson's disease (PD) is a major human disease associated with degeneration of the central nervous system. Evidence suggests that several endogenously formed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mimicking chemicals that are metabolic conversion products, especially ß-carbolines and isoquinolines, act as neurotoxins that induce PD or enhance progression of the disease. We have demonstrated previously that mitochondrially targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the conversion of MPTP to the toxic 1-methyl-4-phenylpyridinium ion. In this study, we show that the mitochondrially targeted CYP2D6 can efficiently catalyze MPTP-mimicking compounds, i.e. 2-methyl-1,2,3,4-tetrahydroisoquinoline, 2-methyl-1,2,3,4-tetrahydro-ß-carboline, and 9-methyl-norharmon, suspected to induce PD in humans. Our results reveal that activity and respiration in mouse brain mitochondrial complex I are significantly affected by these toxins in WT mice but remain unchanged in Cyp2d6 locus knockout mice, indicating a possible role of CYP2D6 in the metabolism of these compounds both in vivo and in vitro These metabolic effects were minimized in the presence of two CYP2D6 inhibitors, quinidine and ajmalicine. Neuro-2a cells stably expressing predominantly mitochondrially targeted CYP2D6 were more sensitive to toxin-mediated respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Exposure to these toxins also induced the autophagic marker Parkin and the mitochondrial fission marker Dynamin-related protein 1 (Drp1) in differentiated neurons expressing mitochondrial CYP2D6. Our results show that monomethylamines are converted to their toxic cationic form by mitochondrially directed CYP2D6 and result in neuronal degradation in mice.


Assuntos
Citocromo P-450 CYP2D6/fisiologia , Modelos Animais de Doenças , Metilaminas/toxicidade , Mitocôndrias/patologia , Neuroblastoma/patologia , Neurônios/patologia , Doença de Parkinson/patologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroblastoma/etiologia , Neuroblastoma/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotoxinas/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Células Tumorais Cultivadas
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