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1.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-787141

RESUMO

Neuroinflammation is an important process underlying a wide variety of neurodegenerative diseases. Carvacrol (CAR) is a phenolic monoterpene commonly used as a food additive due to its antibacterial properties, but it has also been shown to exhibit strong antioxidative, anti-inflammatory, and neuroprotective effects. Here, we sought to investigate the effects of CAR on inflammation in the hippocampus and prefrontal cortex, as well as the molecular mechanisms underlying these effects. In our study, lipopolysaccharide was injected into the lateral ventricle of rats to induce memory impairment and neuroinflammation. Daily administration of CAR (25, 50, and 100 mg/kg) for 21 days improved recognition, discrimination, and memory impairments relative to untreated controls. CAR administration significantly attenuated expression of several inflammatory factors in the brain, including interleukin-1β, tumor necrosis factor-α, and cyclooxygenase-2. In addition, CAR significantly increased expression of brain-derived neurotrophic factor (BDNF) mRNA, and decreased expression of Toll-like receptor 4 (TLR4) mRNA. Taken together, these results show that CAR can improve memory impairment caused by neuroinflammation. This cognitive enhancement is due to the anti-inflammatory effects of CAR medicated by its regulation of BDNF and TLR4. Thus, CAR has significant potential as an inhibitor of memory degeneration in neurodegenerative diseases.


Assuntos
Animais , Encéfalo , Fator Neurotrófico Derivado do Encéfalo , Ciclo-Oxigenase 2 , Citocinas , Discriminação Psicológica , Aditivos Alimentares , Hipocampo , Inflamação , Ventrículos Laterais , Lipopolissacarídeos , Memória , Necrose , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Fenol , Córtex Pré-Frontal , Ratos , RNA Mensageiro , Receptor 4 Toll-Like
2.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-787140

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition.


Assuntos
Doença de Alzheimer , Amiloide , Animais , Plaquetas , Western Blotting , Encéfalo , Transtornos Cognitivos , Demência , Espinhas Dendríticas , Ensaio de Imunoadsorção Enzimática , Potenciais Pós-Sinápticos Excitadores , Aprendizagem , Memória , Metabolismo , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas , Neurônios , Fármacos Neuroprotetores , Extratos Vegetais , Plantas , Placa Amiloide , Aprendizagem Espacial
3.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-782263

RESUMO

BACKGROUND/OBJECTIVES: Oxidative stress causes cell damage and death, which contribute to the pathogenesis of neurodegenerative diseases. Urolithin A (UA), a gut microbial-derived metabolite of ellagitannins and ellagic acid, has high bioavailability and various health benefits such as antioxidant and anti-inflammatory effects. However, it is unknown whether it has protective effects against oxidative stress-induced cell death. We investigated whether UA ameliorates H₂O₂-induced neuronal cell death.MATERIALS/METHODS: We induced oxidative damage with 300 µM H₂O₂ after UA pretreatment at concentrations of 1.25, 2.5, and 5 µM in SK-N-MC cells. Cytotoxicity and cell viability were determined using the CCK-8 assay. The formation of reactive oxygen species (ROS) was measured using a 2,7-dichlorofluorescein diacetate assay. Hoechst 33342 staining was used to characterize morphological changes in apoptotic cells. The expressions of apoptosis proteins were measured using Western blotting.RESULTS: UA significantly increased cell viability and decreased intracellular ROS production in a dose-dependent manner in SK-N-MC cells. It also decreased the Bax/Bcl-2 ratio and the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3, and cleaved PARP. In addition, it suppressed the phosphorylation of the p38 mitogen-activated protein kinase (MAPK) pathway.CONCLUSIONS: UA attenuates oxidative stress-induced apoptosis via inhibiting the mitochondrial-related apoptosis pathway and modulating the p38 MAPK pathway, suggesting that it may be an effective neuroprotective agent.


Assuntos
Apoptose , Disponibilidade Biológica , Western Blotting , Caspase 3 , Caspase 9 , Morte Celular , Sobrevivência Celular , Citocromos c , Ácido Elágico , Taninos Hidrolisáveis , Benefícios do Seguro , Doenças Neurodegenerativas , Neurônios , Fármacos Neuroprotetores , Estresse Oxidativo , Proteínas Quinases p38 Ativadas por Mitógeno , Fosforilação , Proteínas Quinases , Espécies Reativas de Oxigênio , Sincalida
5.
Salud trab. (Maracay) ; 27(1): 65-75, jun. 2019. tab, ilus
Artigo em Espanhol | LILACS (Américas), LIVECS | ID: biblio-1103760

RESUMO

La enfermedad de Parkinson (EP) es el segundo trastorno neurodegenerativo más frecuente del envejecimiento y el trastorno del movimiento más común. En Chile, de un total de 17.514.003 habitantes un 11,4% de la población es adulto mayor, y aproximadamente un 1-2% de la población de 65 años vive con EP, cifra que se eleva a un 3-5% en aquellos mayores de 85 años. Dentro de las alteraciones del movimiento que genera, se describen trastornos de la marcha y caídas, afectando la calidad de vida de los pacientes, por lo tanto, es fundamental generar estrategias que combatan estas alteraciones. La investigación tuvo como objetivo evaluar la efectividad de un plan de entrenamiento sensoriomotor para mejorar el balance, deambulación y calidad de vida en personas con Parkinson de la ciudad de Valdivia. Estudio cuasiexperimental con medida pre-post test tras 18 sesiones de entrenamiento sensoriomotor de 45 minutos, 3 veces por semana en días no consecutivos, durante 6 semanas. Se evaluó 8 participantes utilizando los test Timed Up and Go (TUG), Gait Speed (GS), Sharpened Romberg (SR) y la escala Unified Parkinson's Disease Rating Scale (UPDRS). Los resultados revelaron que se obtuvo una mejora significativa en las pruebas TUG y GS, con un porcentaje de cambio de 32,1% y 84,61% respectivamente, disminución de compensaciones en test SR y disminución de 2 puntos en la UPDRS. Se concluye que el entrenamiento sensoriomotor a corto plazo logra mejoras significativas en las variables de balance deambulación y calidad de vida(Au)


Introduction. Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging and the most common movement disorder. In Chile, there is a total of 17,574,003 inhabitants, where 11.4% of the total population is older adult, and approximately 1-2% of the population of 65 years lives with PD, a figure that rises to 3-5% in those over 85 years old. Within the alterations of the movement that it generates, disorders of the gait and falls are described, affecting the quality of life of the patients, therefore, it is fundamental to generate strategies that combat these alterations. Objective: Evaluate the effectiveness of a sensorimotor training plan to improve balance, walking and quality of life in people with Parkinson's disease in the city of Valdivia. Methods: Quasi-experimental study with pre-post measurement after 18 sessions of sensorimotor training of 45 minutes, 3 times a week on nonconsecutive days, for 6 weeks. Eight 2 participants were evaluated using the Timed Up and Go (TUG), Gait Speed (GS), Sharpened Romberg (SR) and the escalation of the Unified Parkinson's Disease Classification Scale (UPDRS). Results: A significant improvement was obtained in the TUG and GS tests, with a percentage of change of 32.1% and 84.61% respectively, decrease of compensations in SR test and decrease of 2 points in the UPDRS. Conclusion: Short-term sensorimotor training in the short term achieved significant improvement in variables of balance, ambulation and quality of life(AU)


Assuntos
Humanos , Doença de Parkinson/prevenção & controle , Qualidade de Vida , Chile , Doenças Neurodegenerativas , Equilíbrio Postural , Exercícios em Circuitos , Testes de Estado Mental e Demência
7.
Experimental Neurobiology ; : 547-553, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763791

RESUMO

Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.


Assuntos
Animais , Autofagia , Demência , Imunoterapia , Corpos de Lewy , Camundongos , Doenças Neurodegenerativas , Neuroglia , Neurônios , Neuropatologia , Doença de Parkinson , Receptor 2 Toll-Like , Receptores Toll-Like
8.
Experimental Neurobiology ; : 554-567, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763790

RESUMO

Parkinson's disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.


Assuntos
Envelhecimento , Esclerose Amiotrófica Lateral , Aterosclerose , Circulação Sanguínea , Barreira Hematoencefálica , Encéfalo , Colesterol , Metabolismo , Mitocôndrias , Doenças Neurodegenerativas , Doença de Parkinson
9.
Experimental Neurobiology ; : 504-515, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763777

RESUMO

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.


Assuntos
Acetilação , Animais , Sobrevivência Celular , Neurônios Dopaminérgicos , Epigenômica , Expressão Gênica , Histona Desacetilases , Histonas , Corpos de Lewy , Camundongos , Camundongos Transgênicos , Microglia , Modelos Genéticos , Transtornos dos Movimentos , Doenças Neurodegenerativas , Neurônios , Neuroproteção , RNA Mensageiro , Substância Negra , Tirosina 3-Mono-Oxigenase , Ácido Valproico
10.
Experimental Neurobiology ; : 311-319, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763773

RESUMO

Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.


Assuntos
Axônios , Efrinas , Inflamação , Sistema Nervoso , Doenças Neurodegenerativas , Neuroglia , Semaforinas
11.
Experimental Neurobiology ; : 329-336, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763771

RESUMO

Alzheimer's Disease (AD) is a progressive neurodegenerative disease, which is pathologically defined by the accumulation of amyloid plaques and hyper-phosphorylated tau aggregates in the brain. Mitochondrial dysfunction is also a prominent feature in AD, and the extracellular Aβ and phosphorylated tau result in the impaired mitochondrial dynamics. In this study, we generated an induced pluripotent stem cell (iPSC) line from an AD patient with amyloid precursor protein (APP) mutation (Val715Met; APP-V715M) for the first time. We demonstrated that both extracellular and intracellular levels of Aβ were dramatically increased in the APP-V715M iPSC-derived neurons. Furthermore, the APP-V715M iPSC-derived neurons exhibited high expression levels of phosphorylated tau (AT8), which was also detected in the soma and neurites by immunocytochemistry. We next investigated mitochondrial dynamics in the iPSC-derived neurons using Mito-tracker, which showed a significant decrease of anterograde and retrograde velocity in the APP-V715M iPSC-derived neurons. We also found that as the Aβ and tau pathology accumulates, fusion-related protein Mfn1 was decreased, whereas fission-related protein DRP1 was increased in the APP-V715M iPSC-derived neurons, compared with the control group. Taken together, we established the first iPSC line derived from an AD patient carrying APP-V715M mutation and showed that this iPSC-derived neurons exhibited typical AD pathological features, including a distinct mitochondrial dysfunction.


Assuntos
Doença de Alzheimer , Amiloide , Encéfalo , Carisoprodol , Humanos , Imuno-Histoquímica , Dinâmica Mitocondrial , Neuritos , Doenças Neurodegenerativas , Neurônios , Patologia , Placa Amiloide , Células-Tronco Pluripotentes
12.
Experimental Neurobiology ; : 362-375, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763768

RESUMO

Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that associated with repetitive head trauma. CTE is neuropathologically defined by the perivascular accumulation of abnormally phosphorylated tau protein in the depths of the sulci in the cerebral cortices. In advanced CTE, hyperphosphorylated tau protein deposits are found in widespread regions of brain, however the mechanisms of the progressive neurodegeneration in CTE are not fully understood. In order to identify which proteomic signatures are associated with CTE, we prepared RIPA-soluble fractions and performed quantitative proteomic analysis of postmortem brain tissue from individuals neuropathologically diagnosed with CTE. We found that axonal guidance signaling pathwayrelated proteins were most significantly decreased in CTE. Immunohistochemistry and Western blot analysis showed that axonal signaling pathway-related proteins were down regulated in neurons and oligodendrocytes and neuron-specific cytoskeletal proteins such as TUBB3 and CFL1 were reduced in the neuropils and cell body in CTE. Moreover, oligodendrocyte-specific proteins such as MAG and TUBB4 were decreased in the neuropils in both gray matter and white matter in CTE, which correlated with the degree of axonal injury and degeneration. Our findings indicate that deregulation of axonal guidance proteins in neurons and oligodendrocytes is associated with the neuropathology in CTE. Together, altered axonal guidance proteins may be potential pathological markers for CTE.


Assuntos
Axônios , Western Blotting , Lesão Encefálica Crônica , Encéfalo , Corpo Celular , Córtex Cerebral , Traumatismos Craniocerebrais , Proteínas do Citoesqueleto , Substância Cinzenta , Humanos , Imuno-Histoquímica , Doenças Neurodegenerativas , Neurônios , Neuropatologia , Neurópilo , Oligodendroglia , Proteínas tau , Substância Branca
13.
Experimental Neurobiology ; : 404-413, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763765

RESUMO

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.


Assuntos
Animais , Ansiedade , Tronco Encefálico , Transtornos Cognitivos , Marcha , Humanos , Imuno-Histoquímica , Locomoção , Camundongos , Camundongos Transgênicos , Modelos Animais , Doenças Neurodegenerativas , Emaranhados Neurofibrilares , Patologia , Fenótipo , Prosencéfalo , Rombencéfalo , Tauopatias
14.
Experimental Neurobiology ; : 414-424, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763764

RESUMO

Mitochondria continuously fuse and divide to maintain homeostasis. An impairment in the balance between the fusion and fission processes can trigger mitochondrial dysfunction. Accumulating evidence suggests that mitochondrial dysfunction is related to neurodegenerative diseases such as Parkinson's disease (PD), with excessive mitochondrial fission in dopaminergic neurons being one of the pathological mechanisms of PD. Here, we investigated the balance between mitochondrial fusion and fission in the substantia nigra of a non-human primate model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. We found that MPTP induced shorter and abnormally distributed mitochondria. This phenomenon was accompanied by the activation of dynamin-related protein 1 (Drp1), a mitochondrial fission protein, through increased phosphorylation at S616. Thereafter, we assessed for activation of the components of the cyclin-dependent kinase 5 (CDK5) and extracellular signal-regulated kinase (ERK) signaling cascades, which are known regulators of Drp1(S616) phosphorylation. MPTP induced an increase in p25 and p35, which are required for CDK5 activation. Together, these findings suggest that the phosphorylation of Drp1(S616) by CDK5 is involved in mitochondrial fission in the substantia nigra of a non-human primate model of MPTP-induced PD.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes , Neurônios Dopaminérgicos , Homeostase , Mitocôndrias , Dinâmica Mitocondrial , Doenças Neurodegenerativas , Doença de Parkinson , Fosforilação , Fosfotransferases , Primatas , Substância Negra
15.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763718

RESUMO

Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.


Assuntos
Adipogenia , Doença de Alzheimer , Aminoácidos de Cadeia Ramificada , Aminoácidos Essenciais , Doenças Cardiovasculares , Doença Crônica , Insuficiência Cardíaca , Insulina , Metabolismo , Leite , Doenças Neurodegenerativas , Obesidade , Sirolimo
16.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763303

RESUMO

OBJECTIVES.: Sodium salicylate (SS) is well known for its ototoxic properties that induce functional and morphological changes in the cochlea and brain. Ginkgo biloba extract (GBE) has been widely used for treatment of various neurodegenerative diseases; however, its effects on salicylate-induced ototoxicity remain unclear. Herein, we examined the effects of EGb 761 (EGb), a standard form of GBE, on the plasticity of the N-methyl-D-aspartate receptor subunit 2B (GluN2B) in the inferior colliculus (IC) following SS administration. METHODS.: Seven-week-old Sprague Dawley rats (n=24) were randomly allocated to control, SS, EGb, and EGb+SS groups. The SS group received a single intraperitoneal SS injection (350 mg/kg), the EGb group received EGb orally for 5 consecutive days (40 mg/kg), and the EGb+SS group received EGb for 5 consecutive days, followed by an SS injection. The auditory brainstem responses (ABRs) were assessed at baseline and 2 hours after SS administration. GluN2B expression was examined by Western blot and immunohistochemistry. RESULTS.: There were no significant differences in ABR threshold shifts among the groups. The expression of the GluN2B protein normalized by which of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was significantly lower in the EGb+SS group, as compared to the SS group (P=0.012). Weak and diffused GluN2B immunoreactivity was detected in the IC neural cells of the EGb+SS group, while those of the SS group exhibited strong and diffused GluN2B positivity. CONCLUSION.: EGb may play a role in regulating the GluN2B expression in the IC of salicylate-induced ototoxicity model.


Assuntos
Western Blotting , Encéfalo , Cóclea , Potenciais Evocados Auditivos do Tronco Encefálico , Ginkgo biloba , Gliceraldeído 3-Fosfato , Imuno-Histoquímica , Colículos Inferiores , N-Metilaspartato , Doenças Neurodegenerativas , Oxirredutases , Plásticos , Ratos Sprague-Dawley , Salicilato de Sódio
17.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763048

RESUMO

Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated β-galactosidase (SA-β-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-β-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including Phospho-Histone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.


Assuntos
Envelhecimento , Animais , Astrócitos , Encéfalo , Senescência Celular , Ciclo Celular , Linhagem Celular , DNA , Etoposídeo , Proteínas da Matriz Extracelular , Homeostase , Interleucina-6 , Potencial da Membrana Mitocondrial , Mitocôndrias , Mitofagia , Dinâmica Mitocondrial , Doenças Neurodegenerativas , Neurônios , Neuroproteção , Consumo de Oxigênio , Fagocitose , Fenótipo , Ratos , Fatores de Risco , Cicatrização
18.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763016

RESUMO

Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that SIRT1 and SIRT2 play certain roles in cellular senescence in peripheral systems. Both SIRT1 and SIRT2 inhibitors delay tumor growth in vivo without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of SIRT1 and SIRT2, on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence-associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including IL-6 and IL-1β, and cell cycle-related proteins like phospho-histone H3 and CDK2. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting SIRT1 and SIRT2, which may play particular roles in brain aging and neurodegenerative conditions.


Assuntos
Envelhecimento , Animais , Astrócitos , Barreira Hematoencefálica , Encéfalo , Senescência Celular , Contagem de Células , Pontos de Checagem do Ciclo Celular , Interleucina-6 , Idioma , Memória , Doenças Neurodegenerativas , Neurônios , Permeabilidade , Fenótipo , Ratos , Cicatrização
19.
Laboratory Animal Research ; : 124-131, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-786395

RESUMO

Cerebral ischemia is a major cause of neurodegenerative disease. It induces neuronal vulnerability and susceptibility, and leads to neuronal cell death. Resveratrol is a polyphenolic compound that acts as an anti-oxidant. It exerts a neuroprotective effect against focal cerebral ischemic injury. Akt signaling pathway is accepted as a representative cell survival pathway, including proliferation, growth, and glycogen synthesis. This study investigated whether resveratrol regulates Akt/glycogen synthase kinase-3β (GSK-3β) pathway in a middle cerebral artery occlusion (MCAO)-induced ischemic brain injury. Adult male rats were intraperitoneally injected with vehicle or resveratrol (30 mg/kg) and cerebral cortices were isolated 24 h after MCAO. Neurological behavior test, corner test, brain edema measurment, and 2,3,5-triphenyltetrazolium chloride staining were performed to elucidate the neuroprotective effects of resveratrol. Phospho-Akt and phospho-GSK-3β expression levels were measured using Western blot analysis. MCAO injury led to severe neurobehavioral deficit, infraction, and histopathological changes in cerebral cortex. However, resveratrol treatment alleviated these changes caused by MCAO injury. Moreover, MCAO injury induced decreases in phospho-Akt and phospho-GSK-3β protein levels, whereas resveratrol attenuated these decreases. Phosphorylations of Akt and GSK-3β act as a critical role for the suppression of apoptotic cell death. Thus, our finding suggests that resveratrol attenuates neuronal cell death in MCAO-induced cerebral ischemia and Akt/GSK-3β signaling pathway contributes to the neuroprotective effect of resveratrol.


Assuntos
Adulto , Animais , Escala de Avaliação Comportamental , Western Blotting , Edema Encefálico , Lesões Encefálicas , Isquemia Encefálica , Morte Celular , Sobrevivência Celular , Córtex Cerebral , Glicogênio , Humanos , Infarto da Artéria Cerebral Média , Masculino , Artéria Cerebral Média , Doenças Neurodegenerativas , Neurônios , Fármacos Neuroprotetores , Fosforilação , Ratos
20.
Experimental Neurobiology ; : 643-657, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-785792

RESUMO

Macroautophagy/autophagy is a conserved degradation system that engulfs intracytoplasmic contents, including aggregated proteins and organelles, which is crucial for cellular homeostasis. During aging, cellular factors suggested as the cause of aging have been reported to be associated with progressively compromised autophagy. Dysfunctional autophagy may contribute to age-related diseases, such as neurodegenerative disease, cancer, and metabolic syndrome, in the elderly. Therefore, restoration of impaired autophagy to normal may help to prevent age-related disease and extend lifespan and longevity. Therefore, this review aims to provide an overview of the mechanisms of autophagy underlying cellular aging and the consequent disease. Understanding the mechanisms of autophagy may provide potential information to aid therapeutic interventions in age-related diseases.


Assuntos
Idoso , Envelhecimento , Autofagia , Senescência Celular , Dano ao DNA , Homeostase , Humanos , Longevidade , Doenças Neurodegenerativas , Organelas , Estresse Oxidativo , Encurtamento do Telômero
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