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1.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
2.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
3.
Neurochem Res ; 44(11): 2590-2605, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560103

RESUMO

Increased number of newly-born neurons produced at latent stage after status epilepticus (SE) contribute to aberrant rewiring of hippocampus and are hypothesized to promote epileptogenesis. Although physical training (PT) was reported to cause further increase in neurogenesis after SE, how PT affect their integration pattern is still elusive, whether they integrate into normal circuits or increase aberrant integrations is yet to be determined. To understand this basic mechanism by which PT effects SE and to elaborate the possible role of neuronal integrations in prognosis of SE, we evaluated the effect of 4 weeks of treadmill PT in adult male mice after pilocarpine-induced SE on behavioral and aberrant integrations' parameters. Changes in BDNF gene methylation and its protein level in hippocampus was also measured at latent stage (2-weeks) to explore underlying pathways involved in increasing neurogenesis. Our results demonstrated that although PT increased proliferation and maturation of neurons in dentate gyrus, they showed reduced aberrant integrations into hippocampal circuitry assessed through a decrease in the number of ectopic granular cells, hilar basal dendrites and mossy fiber sprouting as compared to non-exercised SE mice. While SE decreased the percentage methylation of specific CpGs of BDNF gene's promoter, PT did not yield any significant difference in methylation of BDNF CpGs as compared to non-exercised SE mice. In conclusion, PT increases hippocampal neurogenesis through increasing BDNF levels by some pathways other than demethylating BDNF CpGs and causes post SE newly-born neurons to integrate into normal circuits thus resulting in decreased spontaneous recurrent seizures and enhanced spatial memory.


Assuntos
Giro Denteado/metabolismo , Hipocampo/metabolismo , Neurogênese/fisiologia , Condicionamento Físico Animal , Estado Epiléptico/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/fisiologia , Ilhas de CpG , DNA/metabolismo , Metilação de DNA , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Regulação para Cima
4.
Exp Neurol ; 321: 113029, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31377403

RESUMO

Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is associated with epilepsy, autism and brain growth abnormalities in humans. mTOR hyperactivation often results from developmental somatic mutations, producing genetic lesions and associated dysfunction in relatively restricted populations of neurons. Disrupted brain regions, such as those observed in focal cortical dysplasia, can contain a mix of normal and mutant cells. Mutant cells exhibit robust anatomical and physiological changes. Less clear, however, is whether adjacent, initially normal cells are affected by the presence of abnormal cells. To explore this question, we used a conditional, inducible mouse model approach to delete the mTOR negative regulator phosphatase and tensin homolog (PTEN) from <1% to >30% of hippocampal dentate granule cells. We then examined the morphology of PTEN-expressing granule cells located in the same dentate gyri as the knockout (KO) cells. Despite the development of spontaneous seizures in higher KO animals, and disease worsening with increasing age, the morphology and physiology of PTEN-expressing cells was only modestly affected. PTEN-expressing cells had smaller somas than cells from control animals, but other parameters were largely unchanged. These findings contrast with the behavior of PTEN KO cells, which show increasing dendritic extent with greater KO cell load. Together, the findings indicate that genetically normal neurons can exhibit relatively stable morphology and intrinsic physiology in the presence of nearby pathological neurons and systemic disease.


Assuntos
Giro Denteado/metabolismo , Giro Denteado/patologia , Neurônios/metabolismo , Neurônios/patologia , PTEN Fosfo-Hidrolase/deficiência , Animais , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina-Treonina Quinases TOR/metabolismo
5.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426356

RESUMO

Halitosis and submandibular abscesses are examples of mouth-related diseases with the possible bacterial origin. Salivary volatile organic compounds (VOCs) are potential biomarkers of them, once they can be addressed as metabolites of bacterial activity. Healthy patients (n = 15), subjects with submandibular abscesses located in fascial deep space (n = 10), and subjects with halitosis (n = 5) were enrolled in the study. Saliva samples were subjected to headspace solid-phase microextraction (HS-SPME) and gas chromatography coupled to mass spectrometry (GC/MS) analysis. A total number of 164 VOCs was detected by the developed methodology, 23 specific for halitosis and 41 for abscess. Halitosis' profiles were characterized by a larger number of sulfur compounds, while for abscess they had a higher variety of alcohols, aldehydes, and hydrocarbons-biomarkers of inflammatory processes. Principal components analysis allowed visualization of clusters formed according to the evaluated conditions. Kruskal-Wallis test indicated that 39 VOCs presented differentiated responses between the studied groups, with statistical relevance (p < 0.05). Random forest was applied, and a prediction model based on eight VOCs (2-butanone, methyl thioacetate, 2-methylbutanoic acid, S-methyl pentanethioate, dimethyl tetrasulfide, indolizine, pentadecane, and octadecanal) provided 100% of sensitivity, 82% of specificity, and 91% of balanced accuracy, indicating the specific presence of submandibular abscess.


Assuntos
Abscesso/diagnóstico , Álcoois/isolamento & purificação , Aldeídos/isolamento & purificação , Halitose/diagnóstico , Hidrocarbonetos/isolamento & purificação , Compostos de Enxofre/isolamento & purificação , Abscesso/metabolismo , Abscesso/patologia , Adulto , Idoso , Álcoois/classificação , Aldeídos/classificação , Biomarcadores/análise , Estudos de Casos e Controles , Giro Denteado/metabolismo , Giro Denteado/patologia , Diagnóstico Diferencial , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Halitose/metabolismo , Halitose/patologia , Humanos , Hidrocarbonetos/classificação , Masculino , Mandíbula/metabolismo , Mandíbula/patologia , Pessoa de Meia-Idade , Análise de Componente Principal , Saliva/química , Sensibilidade e Especificidade , Microextração em Fase Sólida/métodos , Compostos de Enxofre/classificação , Compostos Orgânicos Voláteis
6.
Neurochem Res ; 44(8): 1924-1938, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203481

RESUMO

Inflammatory reactions and oxidative stress play critical roles in cerebral ischemic injuries. Microglia are activated after ischemic injury. Activated microglia produce neurotoxic proinflammatory factors and reactive oxygen species (ROS), which have been demonstrated closely related TLR2/4-NF-κB signal pathways. This study was to evaluate the effect of JLX001 against ischemic injury and investigate the mechanisms. The permanent middle cerebral artery occlusion (pMCAO) model was employed in rats. The neurobehavioral score, brain infarction rate, brain water content, pathological changes, immunohistochemical staining, biochemical index (T-AOC, SOD, and MDA), proinflammatory factors (IL-1ß, TNF-α, and NO), expression of TLR2/4 and nuclear translocation of NF-κB p65 were determined. To explore probable underlying mechanism of the neuroprotective effect of JLX001, BV-2 cells were exposed to in oxygen-glucose deprivation (OGD) for 4 h to mimic ischemic injury in vitro. The result showed that JLX001 significantly decreased neurological deficit score, infarct size, and brain edema, attenuated pathological changes, inhibited the activation of microglia, improved the process of oxidative stress, reduced the release of proinflammatory cytokines and downregulated TLR2/4-NF-κB signal pathway. Moreover, OGD reduced BV2 cell viability, induced oxidative damage, increased the release of proinflammatory factors and activated TLR2/4-NF-κB signal pathway, which was significantly reversed by the intervention of JLX001. This study demonstrates that JLX001 is effective in protecting the brain from ischemic injury, which may be mediated by regulating oxidative stress, inflammation and inhibiting TLR2/4-NFκB signal pathway.


Assuntos
Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Hipóxia Celular/fisiologia , Linhagem Celular , Giro Denteado/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
7.
Behav Neurosci ; 133(5): 508-516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31204826

RESUMO

Thousands of new neurons are produced each day in the dentate gyrus of the adult mammalian hippocampus. However, the majority of those cells die within weeks of their birth. The most effective way to prevent this cell death is through effortful and successful learning. Myriad studies have revealed that classical conditioning and spatial learning can prevent this cell death. However, little research has examined whether acquisition of an operant conditioning task with an appetitive reward also increases the number of surviving cells. Therefore, the current study was conducted to determine whether conditioning with an operant procedure would prevent the death of adult-born hippocampal cells. Adult male rats were trained with 50 trials of an operant discrimination procedure per day for four consecutive days. In order to motivate animals to perform the task, they were food restricted prior to conditioning, and food pellets were used as an appetitive reward during training. Additional control animals were food restricted but not trained, or not food restricted and not trained. In order to ensure that exposure to food reward pellets did not alter cell survival, all animals received equal exposure to the food pellets. Stereological analysis conducted approximately two weeks after training revealed that food restriction decreased the number of surviving cells in the dentate gyrus (p < .05). However, training with the operant task prevented that decrease (p < .05). Together, these results indicate that food restriction decreased the number of surviving cells in the dentate gyrus, and training with an operant procedure was sufficient to attenuate that decrease. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Morte Celular/fisiologia , Condicionamento Operante/fisiologia , Giro Denteado/patologia , Animais , Sobrevivência Celular/fisiologia , Condicionamento Clássico/fisiologia , Giro Denteado/fisiologia , Alimentos , Hipocampo/fisiologia , Aprendizagem/fisiologia , Masculino , Neurogênese/fisiologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Recompensa
8.
Transl Psychiatry ; 9(1): 143, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028242

RESUMO

Chronic stress, a suggested precipitant of brain pathologies, such as depression and Alzheimer's disease, is known to impact on brain plasticity by causing neuronal remodeling as well as neurogenesis suppression in the adult hippocampus. Although many studies show that stressful conditions reduce the number of newborn neurons in the adult dentate gyrus (DG), little is known about whether and how stress impacts on dendritic development and structural maturation of these newborn neurons. We, herein, demonstrate that chronic stress impacts differentially on doublecortin (DCX)-positive immature neurons in distinct phases of maturation. Specifically, the density of the DCX-positive immature neurons whose dendritic tree reaches the inner molecular layer (IML) of DG is reduced in stressed animals, whereas their dendritic complexity is increased. On the contrary, no change on the density of DCX-positive neurons whose dendritic tree extends to the medial/outer molecular layer (M/OML) of the DG is found under stress conditions, whereas the dendritic complexity of these cells is diminished. In addition, DCX+ cells displayed a more complex and longer arbor in the dendritic compartments located in the granular cell layer of the DG under stress conditions; on the contrary, their dendritic segments localized into the M/OML were shorter and less complex. These findings suggest that the neuroplastic effects of chronic stress on dendritic maturation and complexity of DCX+ immature neurons vary based on the different maturation stage of DCX-positive cells and the different DG sublayer, highlighting the complex and dynamic stress-driven neuroplasticity of immature neurons in the adult hippocampus.


Assuntos
Dendritos/patologia , Hipocampo/citologia , Neurônios/patologia , Estresse Psicológico/fisiopatologia , Animais , Giro Denteado/patologia , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/fisiologia , Neurogênese , Plasticidade Neuronal
9.
J Affect Disord ; 252: 152-159, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986730

RESUMO

BACKGROUND: Smaller hippocampus volume represents a consistent finding in major depression (MDD). Hippocampal neuroplasticity due to chronic stress might have differential effect on hippocampal subfields. We investigated the effects of the rs1360780 polymorphism of the hypothalamic-pituitary-axis related gene FKBP5 in combination with early life stress (ELA) on the structure of hippocampal subfields in MDD. METHODS: We assessed the hippocampal subfields volumes in 85/67 MDD/healthy controls. We investigated the effects of diagnosis, FKBP5 allelic status and their interaction as predictors of hippocampal subfield volumes as well as the effect of ELA and its interaction with FKBP5. RESULTS: MDD patients had smaller hippocampal volumes, in particular within the cornu ammonis (CA) and dentate gyrus (DG) regions. Patients exposed to ELA had larger hippocampi, in particular within the CA and DG. Among the patients exposed to ELA, the T allele carriers displayed lower volumes within the hippocampus-amygdala-transition-area (HATA) as those subjects homozygous for the C allele. LIMITATIONS: We pooled the subjects from 2 centers in order to increase the sample size. We did not include the cumulative lifetime exposure to medication. CONCLUSIONS: Hippocampal volume reductions in MDD were present particularly in the CA and DG. MDD with ELA display differential volume changes compared to MDD without ELA. The significant interaction between ELA and the rs1360780 polymorphism in HATA suggests a role of FKBP5 in the pathophysiology of structural alterations in depression.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Estresse Psicológico/genética , Proteínas de Ligação a Tacrolimo/genética , Adulto , Tonsila do Cerebelo/patologia , Giro Denteado/patologia , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/genética , Tamanho do Órgão , Lobo Temporal/patologia
10.
Oxid Med Cell Longev ; 2019: 8639618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918581

RESUMO

Background: The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. Methods: In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. Results: The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. Conclusion: These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.


Assuntos
Compostos de Bifenilo/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/metabolismo , Inflamassomos/metabolismo , Lignanas/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Complicações Pós-Operatórias/tratamento farmacológico , Sevoflurano/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Disfunção Cognitiva/etiologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Feminino , Hipocampo/ultraestrutura , Lignanas/farmacologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Complicações Pós-Operatórias/etiologia , Espécies Reativas de Oxigênio/metabolismo
11.
Int J Dev Neurosci ; 74: 18-26, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822517

RESUMO

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-ß injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-ß on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.


Assuntos
Antioxidantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Giro Denteado/patologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Quercetina/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neuropeptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Wistar
12.
Nat Med ; 25(4): 554-560, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911133

RESUMO

The hippocampus is one of the most affected areas in Alzheimer's disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.


Assuntos
Doença de Alzheimer/patologia , Hipocampo/patologia , Neurogênese , Adulto , Biomarcadores/metabolismo , Diferenciação Celular , Giro Denteado/patologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo
13.
Int J Mol Sci ; 20(4)2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30781689

RESUMO

Aging is characterized by increased inflammation and deterioration of the cellular stress responses such as the oxidant/antioxidant equilibrium, DNA damage repair fidelity, and telomeric attrition. All these factors contribute to the increased radiation sensitivity in the elderly as shown by epidemiological studies of the Japanese atomic bomb survivors. There is a global increase in the aging population, who may be at increased risk of exposure to ionizing radiation (IR) as part of cancer therapy or accidental exposure. Therefore, it is critical to delineate the factors that exacerbate age-related radiation sensitivity and neurocognitive decline. The transcription factor CCAAT enhancer binding protein delta (C/EBPδ) is implicated with regulatory roles in neuroinflammation, learning, and memory, however its role in IR-induced neurocognitive decline and aging is not known. The purpose of this study was to delineate the role of C/EBPδ in IR-induced neurocognitive decline in aged mice. We report that aged Cebpd-/- mice exposed to acute IR exposure display impairment in short-term memory and spatial memory that correlated with significant alterations in the morphology of neurons in the dentate gyrus (DG) and CA1 apical and basal regions. There were no significant changes in the expression of inflammatory markers. However, the expression of superoxide dismutase 2 (SOD2) and catalase (CAT) were altered post-IR in the hippocampus of aged Cebpd-/- mice. These results suggest that Cebpd may protect from IR-induced neurocognitive dysfunction by suppressing oxidative stress in aged mice.


Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/deficiência , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Radiação Ionizante , Envelhecimento , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Dendritos/metabolismo , Giro Denteado/patologia , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto , Memória de Curto Prazo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Memória Espacial , Extratos de Tecidos
14.
Neurol Res ; 41(5): 429-436, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30762490

RESUMO

OBJECTIVE: Rats treated with progesterone (P4) after ischemia show an adequate functional performance despite a significant loss of hippocampal pyramidal neurons, suggesting that P4 could favour a permissive microenvironment for cerebral plasticity mechanisms. The possibility of P4 treatment promoting the survival of newly generated hippocampal neurons, in relation to the performance of ischemic rats in a spatial learning task, was assessed in this study. METHODS: Adult male rats were subjected to a severe global cerebral ischemia episode (30 min) and treated with P4 or its vehicle at 15 min, 2, 6, 24, 48 and 72 h of reperfusion. From day 4 to 8 post-ischemia 5-bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells. Twenty-one days post-ischemia, the rats were exposed to the Morris water maze to assess behavioral parameters of spatial learning and memory. Subsequently, the brain was perfusion-fixed and immunofluorescence procedures were performed to quantify the number of new mature neurons (BrdU+/NeuN+) in the dentate gyrus (DG) of the hippocampus. RESULTS: Rats subjected to severe global cerebral ischemia and treated with P4 had a significantly better performance in spatial learning-memory tests, than those treated with vehicle, and a significantly higher number of new mature neurons (BrdU+/NeuN+) in the DG. CONCLUSION: These findings show that post-ischemia P4 treatment, following an episode of severe global cerebral ischemia, promotes the survival of newly generated hippocampal neurons in the DG, which may be one of the mechanisms of cerebral plasticity induced by the hormone, that underlie a successful functional performance in learning and memory tests.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Giro Denteado/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
15.
Cell Mol Neurobiol ; 39(3): 435-449, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30771197

RESUMO

Cyclohexane (CHX) is an organic solvent commonly used as a drug-of-abuse. This drug increases the oxidative stress and glial reactivity in the hippocampus, which suggests that this brain region is vulnerable to CHX effects. This study aimed to establish the behavioral changes and the pathological alterations that occur in the Cornu Ammonis 3 (CA3) and Dentate Gyrus (DG) after a long-lasting exposure to CHX. We exposed CD1 mice to a recreational-like dose of CHX (~ 30,000 ppm) for 30 days and explored its consequences in motor skills, reward-seeking behavior, and the CA3 and DG hippocampal subfields. Twenty-four hours after the last administration of CHX, we found a significant decrease in the number of c-Fos+ cells in the hippocampal CA3 and DG regions. This event coincided with an increased in NMDAR1 expression and apoptotic cells in the CA3 region. At day 13th without CHX, we found a persistent reduction in the number of c-Fos+ and TUNEL+ cells in DG. At both time points, the CHX-exposed mice showed a strong overexpression of neuropeptide Y (NPY) in the CA3 stratum lucidum and the hippocampal hilus. In parallel, we used an operant-based task to assess motor performance and operant conditioning learning. The behavioral analysis indicated that CHX did not modify the acquisition of operant conditioning tasks, but affected some motor skills and increased the reward-seeking behavior. Altogether, this evidence reveals that CHX exposure provokes long-lasting changes in the hippocampal subfields, induces motor impairments and increases the motivation-guided behavior. These findings can help understand the deleterious effect of CHX into the adult hippocampus and unveil its potential to trigger addiction-like behaviors.


Assuntos
Envelhecimento/patologia , Comportamento Animal , Cicloexanos/administração & dosagem , Hipocampo/patologia , Recompensa , Administração por Inalação , Animais , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Contagem de Células , Giro Denteado/metabolismo , Giro Denteado/patologia , Hipocampo/metabolismo , Masculino , Camundongos , Motivação , Atividade Motora , Neuropeptídeo Y/metabolismo , Postura , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Análise e Desempenho de Tarefas
16.
Mol Neurobiol ; 56(8): 5856-5865, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30685843

RESUMO

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus allows the continuous generation of new neurons. This cellular process can be disturbed under specific environmental conditions, such as epileptic seizures; however, the underlying mechanisms responsible for their control remain largely unknown. Although different studies have linked the JNK (c-Jun-N-terminal-kinase) activity with the regulation of cell proliferation and differentiation, the specific function of JNK in controlling adult hippocampal neurogenesis is not well known. The purpose of this study was to analyze the role of JNK isoforms (JNK1/JNK2/JNK3) in adult-hippocampal neurogenesis. To achieve this goal, we used JNK-knockout mice (Jnk1-/-, Jnk2-/-, and Jnk3-/-), untreated and treated with intraperitoneal injections of kainic acid (KA), as an experimental model of epilepsy. In each condition, we identified cell subpopulations at different stages of neuronal maturation by immunohistochemical specific markers. In physiological conditions, we evidenced that JNK1 and JNK3 control the levels of one subtype of early progenitor cells (GFAP+/Sox2+) but not the GFAP+/Nestin+ cell subtype. Moreover, the absence of JNK1 induces an increase of immature neurons (Doublecortin+; PSA-NCAM+ cells) compared with wild-type (WT). On the other hand, Jnk1-/- and Jnk3-/- mice showed an increased capacity to maintain hippocampal homeostasis, since calbindin immunoreactivity is higher than in WT. An important fact is that, after KA injection, Jnk1-/- and Jnk3-/- mice show no increase in the different neurogenic cell subpopulation analyzed, in contrast to what occurs in WT and Jnk2-/- mice. All these data support that JNK isoforms are involved in the adult neurogenesis control.


Assuntos
Envelhecimento/metabolismo , Epilepsia do Lobo Temporal/enzimologia , Hipocampo/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neurogênese , Animais , Calbindinas/metabolismo , Contagem de Células , Giro Denteado/enzimologia , Giro Denteado/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/patologia , Isoenzimas/metabolismo , Ácido Caínico , Camundongos Endogâmicos C57BL , Nestina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/enzimologia , Neurônios/patologia , Fatores de Transcrição SOXB1/metabolismo , Ácidos Siálicos/metabolismo
17.
Neuroscience ; 400: 120-131, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30625332

RESUMO

Day-to-day life involves the perception of events that resemble one another. For the sufficient encoding and correct retrieval of similar information, the hippocampus provides two essential cognitive processes. Pattern separation refers to the differentiation of similar input information, whereas pattern completion reactivates memory representations based on noisy or degraded stimuli. It has been shown that pattern separation specifically relies on the hippocampal dentate gyrus (DG), whereas pattern completion is performed within CA3 networks. Lesions to these hippocampal networks emerging in the course of neurological disorders may thus affect both processes. In anti-leucine-rich, glioma-inactivated 1 (LGI1) encephalitis it has been shown in animal models and human imaging studies that hippocampal DG and CA3 are preferentially involved in the pathophysiology process. Thus, in order to elucidate the structure-function relationship and contribution of hippocampal subfields to pattern separation, we examined patients (n = 15, age range: 36-77 years) with the rare LGI1 encephalitis showing lesions to hippocampal subfields. Patients were tested 3.53 ±â€¯0.65 years after the acute phase of the disease. Structural sequelae were determined by hippocampal subfield volumetry for the DG, CA1, and CA2/3. Patients showed an overall memory deficit including a significant reduction in pattern separation performance (p = 0.016). In volumetry, we found a global hippocampal volume reduction. The deficits in pattern separation performance were best predicted by the DG (p = 0.029), whereas CA1 was highly predictive of recognition memory deficits (p < 0.001). These results corroborate the framework of a regional specialization of hippocampal functions involved in cognitive processing.


Assuntos
Giro Denteado/patologia , Encefalite/patologia , Encefalite/psicologia , Memória/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Proteínas/genética , Adulto , Idoso , Atrofia/complicações , Encefalite/complicações , Encefalite/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , /fisiologia
18.
Neuropharmacology ; 148: 272-283, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659841

RESUMO

Binge drinking is becoming increasingly common among American women and girls. We have previously shown significant cell loss, downregulation of neurotrophins and microgliosis in female rats after a single 4-day ethanol exposure. To determine whether recurrent binge exposure would produce similar effects, we administered ethanol (5 g/kg) or iso-caloric control diet once-weekly for 11 weeks to adult female rats. As we have previously shown exercise neuroprotection against binge-induced damage, half the rats were given access to exercise wheels. Blood ethanol concentration (BEC) did not differ between sedentary and exercised groups, nor did it change across time. Using stereology, we quantified the number and/or size of neurons in the medial prefrontal cortex (mPFC) and hippocampal dentate gyrus (DG), as well as the number and activation state of microglia. Binged sedentary rats had significant cell loss in the dentate gyrus, but exercise eliminated this effect. Compared to sedentary controls, sedentary binged rats and all exercised rats showed increased neurogenesis in the DG. Number and nuclear volume of neurons in the mPFC were not changed. In the hippocampus and mPFC, the number of microglia with morphology indicative of partial activation was increased by recurrent binge ethanol and decreased by exercise. In summary, we show significant binge-induced loss of DG granule neurons despite increased neurogenesis, suggesting an unsuccessful compensatory response. Although exercise eliminated cell loss, our results indicate that infrequent, but recurrent exposure to clinically relevant BEC is neurotoxic.


Assuntos
Bebedeira/patologia , Giro Denteado/patologia , Etanol/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Contagem de Células , Etanol/sangue , Feminino , Microglia/efeitos dos fármacos , Atividade Motora , Córtex Pré-Frontal/patologia , Ratos , Comportamento Sedentário
19.
Mol Neurobiol ; 56(1): 502-512, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29725905

RESUMO

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1ß levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.


Assuntos
Astrócitos/patologia , Benzodiazepinas/uso terapêutico , Infarto Encefálico/tratamento farmacológico , Encéfalo/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Neurônios/patologia , Niacina/análogos & derivados , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzodiazepinas/farmacologia , Infarto Encefálico/líquido cefalorraquidiano , Infarto Encefálico/patologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Infarto da Artéria Cerebral Média/líquido cefalorraquidiano , Interleucina-10/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Neurônios/efeitos dos fármacos , Niacina/farmacologia , Niacina/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Resultado do Tratamento , Ácido gama-Aminobutírico/líquido cefalorraquidiano
20.
Neurobiol Learn Mem ; 160: 83-90, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29588221

RESUMO

Sleep and sleep loss have a profound impact on hippocampal function, leading to memory impairments. Modifications in the strength of synaptic connections directly influences neuronal communication, which is vital for normal brain function, as well as the processing and storage of information. In a recently published study, we found that as little as five hours of sleep deprivation impaired hippocampus-dependent memory consolidation, which was accompanied by a reduction in dendritic spine numbers in hippocampal area CA1. Surprisingly, loss of sleep did not alter the spine density of CA3 neurons. Although sleep deprivation has been reported to affect the function of the dentate gyrus, it is unclear whether a brief period of sleep deprivation impacts spine density in this region. Here, we investigated the impact of a brief period of sleep deprivation on dendritic structure in the dentate gyrus of the dorsal hippocampus. We found that five hours of sleep loss reduces spine density in the dentate gyrus with a prominent effect on branched spines. Interestingly, the inferior blade of the dentate gyrus seems to be more vulnerable in terms of spine loss than the superior blade. This decrease in spine density predominantly in the inferior blade of the dentate gyrus may contribute to the memory deficits observed after sleep loss, as structural reorganization of synaptic networks in this subregion is fundamental for cognitive processes.


Assuntos
Espinhas Dendríticas/patologia , Giro Denteado/patologia , Privação do Sono/patologia , Animais , Contagem de Células , Giro Denteado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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