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1.
Biologicals ; 61: 61-67, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31262640

RESUMO

Stem cell transplantation is a new therapeutic strategy in the treatment of neurodegenerative disorders such as Parkinson's disease (PD). Therefore, in this study, the therapeutic effects of Trabecular Meshwork Mesenchymal Stem Cells (TM-MSCs) transplantation, as a new source of mesenchymal stem cells, were evaluated in the animal model of PD. After the development and confirmation of hemi-parkinsonian rats by administration of 6-hydroxy dopamine (6-OHDA) and apomorphine-induced rotation test, green fluorescent protein (GFP) labeled TM-MSCs (normal and induced cells) were transplanted in the striatum of rats. Next, the rotation test, rotarod test, open field, passive avoidance memory tests and immunohistochemistry for tyrosine hydroxylase (TH) were done. The results showed that the number of turns significantly decreased and the improvement of motor performance was achieved after cell transplantation. However, there was no significant difference in passive avoidance memory of animals documented by shuttle box test. The number of GFP- labeled cells expressing TH significantly is increased compared to the vehicle group. Collectively, it seems that TM-MSCs and induced TM-MSCs cell transplantation have positive effects on some aspects of the animal model of PD. Other studies may reveal the potentially positive aspects of these cells in the laboratory and clinical studies.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Atividade Motora , Doença de Parkinson Secundária , Malha Trabecular , Aloenxertos , Animais , Modelos Animais de Doenças , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/terapia , Ratos , Ratos Wistar , Malha Trabecular/metabolismo , Malha Trabecular/patologia
2.
Biomed Res Int ; 2019: 7654798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309116

RESUMO

This study aimed to screen the target miRNAs and to investigate the differential miR-3557/324-targeted signal mechanisms in the rats' model of Parkinson's disease (PD) with regular aerobic exercise. Rats were divided into sedentary control PD group (SED-PD, n = 18) and aerobic exercise PD group (EX-PD, n = 22). After 8 weeks of regular aerobic exercise, a 6-hydroxydopamine- (6-OHDA-) induced PD lesion model was constructed. Preregular aerobic exercises enhanced the injury resistance of rats with 6-OHDA-induced PD. The rotational behavior after injection of apomorphine hydrochloride was alleviated. Under the scanning electron microscopy, we found the neurons, axons, and villi of the striatum were clearly and tightly arranged, and neurons and axons significantly becoming larger. Tyrosine hydroxylase (TH) was increased significantly and α-synuclein protein expression was reduced in the EX-PD group compared to the SED-PD group. Screening from miRNA microarray chip, we further found upregulation of miR-3557 and downregulation of miR-324 were closely related to the calcium-modulating signaling pathway, remitting the progress of Parkinson's disease on aerobic exercise. Compared to the SED-PD group, Ca2+/calmodulin dependent protein kinase II (CaMK2α) was upregulated, but CaMKV and voltage-dependent anion-selective channel protein 1 (Vdac1) were significantly downregulated in the EX-PD group. Additionally, phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) expression were activated, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) expression was upregulated in the EX-PD group. Conclusions: the adaptive mechanism of regular aerobic exercise delaying neurodegenerative diseases and lesions was that miR-3557/324 was activated to regulate one of its targets CaMKs signaling pathways. CaMKs, coordinated with mTOR pathway-related gene expression, improved UCH-L1 level to favor for delaying neurodegeneration or improving the pathogenesis of PD lesions.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteínas de Ligação a Calmodulina/biossíntese , Corpo Estriado/metabolismo , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Doença de Parkinson Secundária/metabolismo , Condicionamento Físico Animal , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Perfilação da Expressão Gênica , Masculino , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Sprague-Dawley
3.
Chemosphere ; 233: 542-548, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31185338

RESUMO

Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine; ATR) is widely used as an herbicide, and its accumulation in the environment is a health risk to humans; for instance, it has been shown to cause dopaminergic neurotoxicity. MicroRNAs (miRNAs) are endogenous small RNAs that regulate gene expression in diverse physiological contexts; however, the extent of their involvement in the development of Parkinson's disease (PD) is not known. In this study, we carried out miRNA profiling of peripheral blood and brain tissue in a rat model of PD in order to identify factors that mediate PD pathogenesis. The miRNAmiR-7 is known to cause the downregulation of α-synuclein (α-syn), which is linked to the neuropathology of PD. Here we found that miR-7 was upregulated in brain tissue but downregulated in peripheral blood of rats with ATR-induced PD. We also found that miR-7 regulates the expression of brain-derived neurotrophic factor (BDNF) through an auto regulatory mechanism. These findings indicate that miRNA-7 regulates the BDNF/α-syn axis in the early stages of PD and can serve as a biomarker or therapeutic target for disease treatment.


Assuntos
Atrazina/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Herbicidas/toxicidade , MicroRNAs/metabolismo , Doença de Parkinson Secundária/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Ratos , alfa-Sinucleína/genética
4.
Neuroscience ; 411: 1-10, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31129200

RESUMO

Parkinson's disease (PD) is a progressive aging disorder that affects millions worldwide, thus, disease-modifying-therapies are urgently needed. PD pathology includes α-synuclein (aSyn) accumulation as synucleinopathy. Loss of GM1 gangliosides occurs in PD brain, which is modeled in GM2 synthase transgenic mice. GM2+/- mice have low, not absent GM1 and develop age-onset motor deficits, making them an excellent PD drug testing model. FTY720 (fingolimod) reduces synucleinopathy in A53T aSyn mice and motor dysfunction in 6-OHDA and rotenone PD models, but no one has tested FTY720 in mice that develop age-onset PD-like motor problems. We confirmed that GM2+/-mice had equivalent rotarod, hindlimb reflexes, and adhesive removal functions at 9 mo. From 11 mo, GM2+/- mice received oral FTY720 or vehicle 3x/week to 16 mo. As bladder problems occur in PD, we also assessed GM2+/- bladder function. This allowed us to demonstrate improved motor and bladder function in GM2+/- mice treated with FTY720. By immunoblot, FTY720 reduced levels of proNGF, a biomarker of bladder dysfunction. In humans with PD, arm swing becomes abnormal, and brachial plexus modulates arm swing. Ultrastructure of brachial plexus in wild type and GM2 transgenic mice confirmed abnormal myelination and axons in GM2 transgenics. FTY720 treated GM2+/- brachial plexus sustained myelin associated protein levels and reduced aggregated aSyn and PSer129 aSyn levels. FTY720 increases brain derived neurotrophic factor (BDNF) and we noted increased BDNF in GM2+/- brachial plexus and cerebellum, which contribute to rotarod performance. These findings provide further support for testing low dose FTY720 in patients with PD.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Cloridrato de Fingolimode/uso terapêutico , Camundongos , Camundongos Transgênicos , Destreza Motora/efeitos dos fármacos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Doença de Parkinson Secundária/metabolismo , Teste de Desempenho do Rota-Rod , /uso terapêutico
5.
Neurosci Lett ; 706: 158-163, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31121284

RESUMO

Parkinson's disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NOx), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1ß and tumor necrosis factor alpha - TNF-α), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice.


Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Flavonoides/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Feminino , Flavonoides/farmacologia , Ácido Homovanílico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/psicologia , Espécies Reativas de Oxigênio/metabolismo
6.
Mol Cell Biochem ; 458(1-2): 71-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004306

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) is a technique protecting neurons against diverse neurodegenerative disorders by delivering magnetic stimuli into the brain through the intact scalp. In the current study, the protection effect of rTMS on Parkinson's disease (PD) and the associated mechanism driving the treatment were explored. The PD symptoms were induced using 6-OHDA in mice, and the effect of rTMS of two frequencies (1 Hz and 10 Hz) on the cognitive behaviors and neuron viability was detected. Afterwards, the level of Aß1-42 and activity of MKK7-ERK-Fos-APP axis under the administration of rTMS were recorded as well. The intracranial injection of 6-OHDA impaired the cognitive behaviors of the mice in the test of Morris water maze as well as reducing the viability and number of neurons in PD mice. After the treatment of rTMS of both frequencies, the cognitive function of mice was improved and the neuron viability and number were restored in mice brain tissues. The administration of rTMS also increased the cerebrospinal fluid (CSF) level of Aß1-42 in PD mice, which was accompanied by the suppressed levels of p-MKK7, p-ERK1/2, p-c-Fos, and APP. Moreover, the effect of rTMS on mice nerve system was all exerted in a frequency-dependent manner. In conclusion, the findings outlined in the current study affirmed the protection effect of rTMS against PD. The anti-PD function of rTMS was associated with the suppression of MKK7-ERK-Fos-APP axis, which subsequently resulted in the increased CSF Aß1-42 level and decreased brain Aß1-42 level.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo , Aprendizagem em Labirinto/efeitos dos fármacos , Oxidopamina/toxicidade , Doença de Parkinson Secundária , Fragmentos de Peptídeos/líquido cefalorraquidiano , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson Secundária/terapia , Estimulação Magnética Transcraniana
8.
Bull Exp Biol Med ; 166(6): 811-815, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020581

RESUMO

We assessed changes of olfactory bulbs in rata with 6-hydroxydopamine destruction of the substantia nigra. The expression of marker proteins of immature and differentiated neurons and glia (vimentin, PSA-NCAM, tyrosine hydroxylase, and S100) was analyzed by immunohistochemical and morphometric methods. The number of periglomerular dopamine neurons and astroglia in the olfactory bulbs increased on the side of toxin injection and expression of PSA-NCAM and vimentin increased in the rostral migratory stream. Destruction of the substantia nigra shifted differentiation of neuronal progenitors towards the dopaminergic phenotype and increased their survival in the olfactory bulbs, which can be explained by increased expression of PSA-NCAM.


Assuntos
Neuroglia/patologia , Neurônios/patologia , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/patologia , Adaptação Fisiológica , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Atividade Motora/fisiologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/metabolismo , Oxidopamina/administração & dosagem , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Ratos , Ratos Wistar , Proteínas S100/genética , Proteínas S100/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Vimentina/genética , Vimentina/metabolismo
9.
Environ Toxicol ; 34(6): 699-707, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30835941

RESUMO

BACKGROUND: The insecticide exposure has been linked to Parkinson's disease (PD). In the present study, we used a most widely used cell line in study of PD, the SH-SY5Y cells, to investigate mechanisms of chlorpyrifos (CPF) induced cell toxicity and the possible roles of cell pyroptosis and oxidative stress in SH-SY5Y cells, as well as role of miR-181/SIRT1/PGC-1α/Nrf2 signaling pathway in this process. METHODS: SH-SY5Y cells were treated with different concentrations of CPF. Cell viability was measured using CCK-8 assay. Cell pyroptosis was determined by immunofluorescence of caspase-1 and TUNEL assay. The miR-181 (has-miR-181-5p) level was determined by qRT-PCR. Expression of SIRT1, PGC-1α, Nrf2, and pyroptosis related proteins NLRP3, caspase-1, IL-1ß, and IL-18 was determined by both qRT-PCR and Western blotting. RESULTS: Cell viability was found to be decreased with the increased CPF concentrations. The pyroptosis related proteins, ROS levels, as well as level of caspase-1 and the TUNEL positive cells were all significantly up-regulated by CPF. Meanwhile, expression of miR-181 and pyroptosis proteins was also enhanced, while the SIRT1/PGC-1α/Nrf2 signaling was inhibited by CPF. Knockdown of Nrf2 significantly up-regulated the expression of pyroptosis related proteins, ROS level, caspase-1, and the TUNEL positive cells, while over-expression of Nrf2 resulted in opposite results. The expression of PGC-1α and Nrf2 was significantly down-regulated when SIRT1 was inhibited, while over-expressed SIRT1 led to increased PGC-1α and Nrf2 levels. Besides, miR-181 promoted the CPF induced activation of pyroptosis and oxidative stress, as well as down-regulated SIRT1/PGC-1α/Nrf2 signaling, while inhibition of miR-181 led to opposite results. CONCLUSIONS: Chlorpyrifos could inhibit cell proliferation, activate cell pyroptosis and increase susceptibility on oxidative stress-induced toxicity by elevating miR-181 through down-regulation of the SIRT1/PGC-1α/Nrf2 pathway in human neuroblastoma SH-SY5Y cells. This study might give deeper insights for mechanisms of CPF induced toxicity and might give some novel research targets for PD treatment.


Assuntos
Clorpirifos/toxicidade , Inseticidas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-30870786

RESUMO

Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or ß-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of ß-sheet-rich fibrils from α-helix-rich fibrils of PLL.


Assuntos
Amiloide/metabolismo , Antipsicóticos/efeitos adversos , Doença de Parkinson Secundária/etiologia , Fenotiazinas/efeitos adversos , Polilisina/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Estrutura Secundária de Proteína/efeitos dos fármacos , Amiloide/química , Amiloide/ultraestrutura , Antipsicóticos/química , Dicroísmo Circular , Humanos , Modelos Moleculares , Doença de Parkinson Secundária/metabolismo , Fenotiazinas/química , Polilisina/química , Agregação Patológica de Proteínas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Neurotherapeutics ; 16(2): 465-479, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30756361

RESUMO

Pridopidine is a small molecule in clinical development for the treatment of Huntington's disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Piperidinas/farmacologia , Receptores sigma/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Oxidopamina , Doença de Parkinson Secundária/metabolismo , Piperidinas/uso terapêutico , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
12.
Cells ; 8(1)2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625984

RESUMO

Human neuroblastoma SH-SY5Y cells are a widely-used human neuronal cell model in the study of neurodegeneration. A recent study shows that, 1-methyl-4-phenylpyridine ion (MPP), which selectively causes dopaminergic neuronal death leading to Parkinson's disease-like symptoms, can reduce SH-SY5Y cell viability by inducing H2O2 generation and subsequent TRPM2 channel activation. MPP-induced cell death is enhanced by increasing the TRPM2 expression. By contrast, increasing the TRPM2 expression has also been reported to support SH-SY5Y cell survival after exposure to H2O2, leading to the suggestion of a protective role for the TRPM2 channel. To clarify the role of reactive oxygen species (ROS)-induced TRPM2 channel activation in SH-SY5Y cells, we generated a stable SH-SY5Y cell line overexpressing the human TRPM2 channel and examined cell death and cell viability after exposure to H2O2 in the wild-type and TRPM2-overexpressing SH-SY5Y cells. Exposure to H2O2 resulted in concentration-dependent cell death and reduction in cell viability in both cell types. TRPM2 overexpression remarkably augmented H2O2-induced cell death and reduction in cell viability. Furthermore, H2O2-induced cell death in both the wild-type and TRPM2-overexpressing cells was prevented by 2-APB, a TRPM2 inhibitor, and also by PJ34 and DPQ, poly(ADP-ribose) polymerase (PARP) inhibitors. Collectively, our results show that increasing the TRPM2 expression renders SH-SY5Y cells to be more susceptible to ROS-induced cell death and reinforce the notion that the TRPM2 channel plays a critical role in conferring ROS-induced cell death. It is anticipated that SH-SY5Y cells can be useful for better understanding the molecular and signaling mechanisms for ROS-induced TRPM2-mediated neurodegeneration in the pathogenesis of neurodegenerative diseases.


Assuntos
Neuroblastoma , Doenças Neurodegenerativas/induzido quimicamente , Espécies Reativas de Oxigênio/toxicidade , Canais de Cátion TRPM/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Compostos de Boro/química , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/toxicidade , Modelos Biológicos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Fenantrenos/química , Espécies Reativas de Oxigênio/química , Canais de Cátion TRPM/genética
13.
Int J Med Sci ; 16(1): 84-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662332

RESUMO

Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study. METHODS: Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching. RESULTS: The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process. CONCLUSIONS: Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.


Assuntos
Doença de Parkinson/metabolismo , Inibidores de Proteassoma/farmacologia , Proteômica , Proteínas 14-3-3/metabolismo , Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Proteínas de Choque Térmico/metabolismo , Humanos , Corpos de Inclusão/efeitos dos fármacos , Laminina/metabolismo , Doença de Parkinson Secundária/metabolismo , Fosfoglicerato Desidrogenase/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
14.
Hum Exp Toxicol ; 38(3): 303-310, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30350722

RESUMO

Abnormality in Src PSD-95 NR2B signaling complex assemble occurs in levodopa-induced dyskinesia (LID). N-methyl-D-aspartate receptor (NMDAR) subunit NR2B tyrosine phosphorylation mediated by Src family protein tyrosine kinases is closely associated with dyskinesia. Src autophosphorylation (p-Src) is an important part of Src-catalyzed phosphorylation of NR2B. In addition, the neuronal nitric oxide synthase (nNOS)-derived NO (nNOS/NO) signal which was also involved in dyskinesia recently was proved to participate in the regulation of Src function. Yet, the detailed signal mechanism about the interactions of NR2B, nNOS, and Src is still unknown. In the present study, we investigated the influences of nNOS on Src activation and NR2B tyrosine phosphorylation in dyskinetic rat model by immunoblotting and immunoprecipitation. The results demonstrated that chronic levodopa treatment resulted in downregulation of p-nNOS-S847, one marker of nNOS overactivation. Coinstantaneously, the S-nitrosylation (SNO-Src) and autophosphorylation (p-Src) of Src and NR2B tyrosine phosphorylation were upregulated in dyskinetic rat model. Conversely, administration of 7-NI, one nNOS inhibitor, reversed all these effects of levodopa treatment. Besides, NR2B-containing NMDAR (NR2B/NMDAR) antagonist CP-101,606 could upregulate p-nNOS-S847 and thus attenuate nNOS activation and simultaneously reduce the SNO-Src, p-Src, and NR2B tyrosine phosphorylation. Taken together, the S-nitrosylation of Src is caused by nNOS/NO signal, which is overactivated via Ca2+ influx dependent on NR2B/NMDAR, and subsequently facilitates Src auto-tyrosine phosphorylation and further phosphorylates NR2B. The "NR2B/NMDAR-nNOS/NO-SNO-Src-p-Src-NR2B/NMDAR" signaling cycle may be the molecular basis of NR2B tyrosine phosphorylation upward positive feedback, which demonstrates the possibility as one latent target for dyskinesia therapy.


Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Doença de Parkinson Secundária/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Quinases da Família src/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Levodopa , Doença de Parkinson Secundária/induzido quimicamente , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Tirosina/metabolismo
15.
Int J Neurosci ; 129(6): 534-539, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30433834

RESUMO

BACKGROUND: Parkinson's disease is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to excitotoxicity, oxidative stress and many other factors may contribute to MPTP- and PD-related neurodegeneration. The present study deals with the neuroprotective effect of Naringenin (NGN), a bioflavonoid against MPTP-induced Parkinson's disease in the mouse model. METHODS: Healthy male C57BL/6J mice (18-22 g b wt) were pretreated with NGN [25, 50, 100 mg/kg/b.wt, p.o] once daily for 5 days. Thereafter, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (80 mg/kg b.wt, i.p) was given in two divided doses (2 × 40 mg/kg at 16 h interval). The animals were observed for motor functions 48 h after the first MPTP injection. After completion of behaviour tasks, all animals were euthanized to dissect out the brain and used for biochemical, molecular and histopathological investigations. RESULTS: Pretreatment of NGN significantly reversed the toxic effects of MPTP by reducing LPO levels and increasing the activities of glutathione reductase and catalase along with improved behavioural performance. Interestingly, pre-treatment with NGN down-regulated iNOS expression level in MPTP intoxicated mice brain. In addition, the histopathological evaluation revealed that NGN decreased the nuclear pigmentation and cytoplasmic vacuolation in the substantia nigra and striatal regions when compared to MPTP-intoxicated mice brain. DISCUSSION: The present study showed that NGN exerts neuroprotection by suppressing oxidative stress via antioxidant mechanisms. The above finding suggests that NGN may act as a potential target in the management of PD.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Flavanonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/prevenção & controle , Animais , Catalase/biossíntese , Corpo Estriado/patologia , Relação Dose-Resposta a Droga , Glutationa Redutase/biossíntese , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/biossíntese , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Substância Negra/patologia
16.
Phytother Res ; 33(2): 309-318, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30421460

RESUMO

Parkinson is the second common neurodegenerative disease. The characteristics of Parkinson's disease (PD) are the dopamin neurons loss caused by neuroinflammation responses. C alycosin, an isoflavone phytoestrogen isolated from Astragalus membranaceus, has multiple pharmacological activities, such as anti-inflammation, anti-tumor, and neuroprotective effects. However, it is unknown whether calycosin can mitigate PD symptoms. This study aims to explore whether calycosin can alleviate PD symptoms and the underlying mechanisms. PD was induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, and calycosin was given intracerebroventricularly to these mice. A cell model of nerve inflammation was established by BV2 microglia cells injected with lipopolysaccharide (LPS). The motor states were evaluated by stepping, whisker, and cylinder experiments. The states of dopaminergic neurons and microglia were detected by immunostainning of tyrosine hydroxylase and cluster of differentiation molecule 11b (CD11b). The expression levels of inflammatory factors were detected by qPCR. Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were investigated by western blot. We found that calycosin treatment mitigated the behavioral dysfunctions and inflammatory responses in MPTP-induced PD mice. The TLR/NF-κB and MAPK pathways in MPTP-induced PD mice were inhibited by calycosin treatment, which was coincident with experiments in LPS-induced BV2 cells. Above all, calycosin mitigates PD symptoms through TLR/NF-κB and MAPK pathways in mice and cell lines.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Isoflavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/prevenção & controle , Animais , Células Cultivadas , Neurônios Dopaminérgicos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Isoflavonas/uso terapêutico , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Microglia/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Ratos , Receptores Toll-Like/metabolismo
17.
J Cell Biol ; 218(1): 267-284, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30538141

RESUMO

Mutations in ATP13A2 cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied ATP13A2 to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment. ATP13A2 deficiency impaired autophagosome-lysosome fusion in cultured cells and in in vitro reconstitution assays. In ATP13A2-deficient cells or Drosophila melanogaster or mouse tissues, lysosomal localization and activity of HDAC6 were reduced, with increased acetylation of tubulin and cortactin. Wild-type HDAC6, but not a deacetylase-inactive mutant, restored autophagosome-lysosome fusion, antagonized cortactin hyperacetylation, and promoted lysosomal localization of cortactin in ATP13A2-deficient cells. Mechanistically, ATP13A2 facilitated recruitment of HDAC6 and cortactin to lysosomes. Cortactin overexpression in cultured cells reversed ATP13A2 deficiency-associated impairment of autophagosome-lysosome fusion. PD-causing ATP13A2 mutants failed to rescue autophagosome-lysosome fusion or to promote degradation of protein aggregates and damaged mitochondria. These results suggest that ATP13A2 recruits HDAC6 to lysosomes to deacetylate cortactin and promotes autophagosome-lysosome fusion and autophagy. This study identifies ATP13A2 as an essential molecular component for normal autophagy flux in vivo and implies potential treatments targeting HDAC6-mediated autophagy for PD.


Assuntos
Autofagossomos/metabolismo , Cortactina/genética , Desacetilase 6 de Histona/genética , Lisossomos/metabolismo , Doença de Parkinson Secundária/genética , ATPases Translocadoras de Prótons/genética , Sequência de Aminoácidos , Anilidas/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Autofagia/genética , Cortactina/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster , Regulação da Expressão Gênica , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Leupeptinas/farmacologia , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/ultraestrutura , Masculino , Fusão de Membrana/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , ATPases Translocadoras de Prótons/deficiência , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
18.
Mol Neurobiol ; 56(2): 1221-1232, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29881944

RESUMO

Parkinson's disease (PD) is a neurodegenerative pathology characterized by resting tremor, rigidity, bradykinesia, and loss of dopamine-producing neurons in the pars compacta of the substantia nigra in the central nervous system (CNS) that result in dopamine depletion in the striatum. Oxidative stress has been documented as a key pathological mechanism for PD. Epidemiological studies have shown that smokers have a lower incidence of PD. In this aspect, different studies have shown that nicotine, a chemical compound found in cigarette, is capable of exerting beneficial effects in PD patients, but it can hardly be used as a therapeutic agent because of its inherent toxicity. Several studies have suggested that the use of nicotine analogs can have the same benefits as nicotine but lack its toxicity. In this study, we assessed the effects of two nicotine analogs, (E)-nicotinaldehyde O-cinnamyloxime and 3-(pyridin-3-yl)-3a,4,5,6,7,7a-hexahidrobenzo[d]isoxazole, in an in vitro model of PD. Initially, we performed a computational prediction of the molecular interactions between the nicotine analogs with the α7 nicotinic acetylcholine receptor (nAChR). Furthermore, we evaluated the effect of nicotine, nicotine analogs and rotenone on cell viability and reactive oxygen species (ROS) production in the SH-SY5Y neuronal cell line to validate possible protective effects. We observed that pre-treatment with nicotine or (E)-nicotinaldehyde O-cinnamyloxime (10 µM) improved cell viability and diminished ROS production in SH-SY5Y cells insulted with rotenone. These findings suggest that nicotine analogs have a potential protective effect against oxidative damage in brain pathologies.


Assuntos
Morte Celular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nicotina/análogos & derivados , Doença de Parkinson Secundária/tratamento farmacológico , Rotenona/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neurônios/metabolismo , Nicotina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Neurotox Res ; 35(4): 945-954, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30569287

RESUMO

Parkinson's disease (PD) remarks its pathology by affecting the patient's movements and postural instability by dopaminergic loss in the substantia nigra of midbrain. The disease is characterized by the accumulation of alpha-synuclein protein followed by dementia symptoms. Moreover, the pathology enhances the production of monoamine oxidases A and B (MAO A and B), leucine-rich repeat kinase 2 (LRRK2), phosphate and tensin homolog (PTEN), PTEN-induced putative kinase 1 (PINK1), and PARK7 (deglycase 1 (DJ-1)). Hinokitiol (HIN), a tropolone-related compound, has widely been reported as an antioxidant, antineuralgic as well as a neuroprotective agent. Hence, in this study, we have examined the effect of hinokitol to act as a neuroprotective agent against 6-OHDA-induced toxicity in SH-SY5Y neuroblastoma cells through downregulation of the mRNA expression of PD pathological proteins like alpha-synuclein, MAO A and B, LRRK2, PTEN, PINK1, and PARK7 (deglycase 1 (DJ-1)). The study revealed that the 6-OHDA-induced elevation in the mRNA expression of the pathology marker proteins was subsequently downregulated by the treatment with HIN and was referenced with the positive control, amantadine (AMA), widely used nowadays as a treatment drug for PD symptoms. Thus, the study suggests that hinokitiol could be a drug of choice against 6-OHDA-induced neurotoxicity in SH-SY5Y neuroblastoma cells.


Assuntos
Monoterpenos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/metabolismo , Tropolona/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Monoaminoxidase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Doença de Parkinson/prevenção & controle , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Proteína Desglicase DJ-1/metabolismo , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Tropolona/administração & dosagem , alfa-Sinucleína/metabolismo
20.
Hum Exp Toxicol ; 38(2): 173-184, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30001633

RESUMO

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and nonmotor symptoms. The neuropathological hallmarks of PD are well reported, but the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, and neuroinflammation play vital roles in the progress of the disease. The current study was established to investigate the neuroprotective effect of agmatine on a rotenone (ROT)-induced experimental model of PD. Adult male Sprague Dawley rats were subcutaneously injected with ROT at a dose of 2 mg/kg body weight for 35 days. Agmatine was injected intraperitoneally at 50 and 100 mg/kg body weight, 1 h prior to ROT administration. ROT-treated rats that received agmatine showed better performance on beam walking and an elevated number of rears within the cylinder test. In addition, agmatine reduced midbrain malondialdehyde as an indication of lipid peroxidation, pro-inflammatory cytokines including tumor necrosis factor alpha and interleukin-1ß, and glial fibrillary acidic protein. Moreover, agmatine was responsible for preventing loss of tyrosine hydroxylase-positive neurons. In conclusion, our study showed that agmatine possesses a dose-dependent neuroprotective effect through its antioxidant and anti-inflammatory activities. These findings need further clinical investigations of agmatine as a promising neuroprotective agent for the future treatment of PD.


Assuntos
Agmatina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Agmatina/farmacologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Ratos Sprague-Dawley , Rotenona , Tirosina 3-Mono-Oxigenase/metabolismo
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