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1.
Adv Exp Med Biol ; 1131: 985-1012, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646542

RESUMO

Calcium (Ca2+) ions are highly versatile intracellular signaling molecules and are universal second messenger for regulating a variety of cellular and physiological functions including synaptic plasticity. Ca2+ homeostasis in the central nervous system endures subtle dysregulation with advancing age. Research has provided abundant evidence that brain aging is associated with altered neuronal Ca2+ regulation and synaptic plasticity mechanisms. Much of the work has focused on the hippocampus, a brain region critically involved in learning and memory, which is particularly susceptible to dysfunction during aging. The current chapter takes a specific perspective, assessing various Ca2+ sources and the influence of aging on Ca2+ sources and synaptic plasticity in the hippocampus. Integrating the knowledge of the complexity of age-related alterations in neuronal Ca2+ signaling and synaptic plasticity mechanisms will positively shape the development of highly effective therapeutics to treat brain disorders including cognitive impairment associated with aging and neurodegenerative disease.


Assuntos
Envelhecimento , Encéfalo , Sinalização do Cálcio , Doenças Neurodegenerativas , Plasticidade Neuronal , Encéfalo/fisiopatologia , Hipocampo/fisiopatologia , Humanos , Plasticidade Neuronal/fisiologia
2.
J Surg Res ; 245: 321-329, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421380

RESUMO

In the adult rodents' brain, CD24 expression is restricted to immature neurons located in the neurogenesis areas. Our previous studies have confirmed that CD24 expression could be markedly elevated in the cerebral cortex after traumatic brain injury (TBI) both in humans and in mice. Although there is a close relationship between CD24 and neurogenesis, it remains unknown about the specific role of CD24 in neurogenesis areas after TBI. Here, the expression of CD24 was detected in the ipsilateral hippocampus by the Western blotting and real-time quantitative polymerase chain reaction. RNA interference was applied to investigate the effects of CD24 on post-traumatic neurogenesis. Brain sections were labeled with CD24 and doublecortin (DCX) via immunofluorescence. The Morris water maze test was used to assess cognitive functions. The results indicated that both mRNA and protein levels of CD24 were markedly elevated in the hippocampus after TBI. Meanwhile, TBI could cause a decrease of DCX-positive cells in the dentate gyrus of the hippocampus. Downregulation of CD24 significantly inhibited the phosphorylation of Src homology region 2-containing protein tyrosine phosphatase 2 in the ipsilateral hippocampus. Meanwhile, inhibition of CD24 could reduce the number of DCX-positive cells in the dentate gyrus area and impair cognitive functions of the TBI mice. These data suggested that hippocampal expression of CD24 might positively regulate neurogenesis and improve cognitive functions after TBI.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Antígeno CD24/metabolismo , Cognição/fisiologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Antígeno CD24/genética , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Neurônios/fisiologia , RNA Interferente Pequeno/metabolismo , Recuperação de Função Fisiológica , Regulação para Cima
3.
Adv Neurobiol ; 23: 363-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667816

RESUMO

Cognitive dysfunction is one of the comorbidities of diabetes mellitus, but hippocampus-dependent learning and memory, a component of cognitive function, shows particular decline in type 2 diabetes, suggesting an increased risk for dementia and Alzheimer's disease. Cognitive function is related to dysregulated glucose metabolism, which is the typical cause of type 2 diabetes; however, hippocampal glycogen and its metabolite lactate are also crucial for hippocampus-dependent memory function. Type 2 diabetes induced hippocampus-dependent learning and memory dysfunction can be improved by chronic exercise and this improvement may possibly mediate through an adaptation of the astrocyte-neuron lactate shuttle (ANLS). This chapter focuses on the dysregulation of hippocampal glycometabolism in type 2 diabetes examining both existing evidence as well as the potential underlying pathophysiological mechanism responsible for memory dysfunction in type 2 diabetes, and showing for the first time that chronic exercise could be an effective therapy for type-2-diabetes-induced hippocampal memory decline.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício/fisiologia , Glicogênio/metabolismo , Hipocampo/metabolismo , Memória Espacial , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Terapia por Exercício , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Ácido Láctico/metabolismo , Neurônios/metabolismo
4.
Nat Commun ; 10(1): 4900, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653847

RESUMO

The tau protein aggregates in aging and Alzheimer disease and may lead to memory loss through disruption of medial temporal lobe (MTL)-dependent memory systems. Here, we investigated tau-mediated mechanisms of hippocampal dysfunction that underlie the expression of episodic memory decline using fMRI measures of hippocampal local coherence (regional homogeneity; ReHo), distant functional connectivity and tau-PET. We show that age and tau pathology are related to higher hippocampal ReHo. Functional disconnection between the hippocampus and other components of the MTL memory system, particularly an anterior-temporal network specialized for object memory, is also associated with higher hippocampal ReHo and greater tau burden in anterior-temporal regions. These associations are not observed in the posteromedial network, specialized for context/spatial information. Higher hippocampal ReHo predicts worse memory performance. These findings suggest that tau pathology plays a role in disconnecting the hippocampus from specific MTL memory systems leading to increased local coherence and memory decline.


Assuntos
Envelhecimento/metabolismo , Córtex Entorrinal/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Emaranhados Neurofibrilares/metabolismo , Lobo Temporal/diagnóstico por imagem , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Envelhecimento/psicologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Carbolinas , Envelhecimento Cognitivo/fisiologia , Envelhecimento Cognitivo/psicologia , Meios de Contraste , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiopatologia , Função Executiva , Feminino , Neuroimagem Funcional , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Memória Episódica , Memória de Curto Prazo , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Tomografia por Emissão de Pósitrons , Lobo Temporal/metabolismo , Lobo Temporal/fisiologia , Tiazóis , Adulto Jovem
5.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581684

RESUMO

Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell-cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory-inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Modelos Biológicos , Animais , Hipocampo/embriologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Células-Tronco Neurais/metabolismo , Neurogênese
6.
Acta Neurobiol Exp (Wars) ; 79(3): 232-237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587015

RESUMO

Emotional stress is considered a serious pathogenetic factor of depression. In this study an ultrasound model of emotional stress developed in our laboratory was applied. It is characterized by the use of ultrasound as the stressor agent. Animals are triggered not by any organic or physical disturbances but by the perception of adverse information. This type of stress can induce depressive-like behavioral changes in rodents, manifested by decreased sucrose preference and increased time of immobility in a forced swim test. Ultrasound stress also increased the levels of oxidative stress markers. This is important, as stress has an established association with increased oxidative processes in the central nervous system. Total glutathione and carbonyl protein content were selected as relevant brain markers, as glutathione plays a critical role in cellular defensive mechanisms during oxidative stress and the level of protein carbonyls can be a measure of global protein oxidation. We demonstrated that two weeks of chronic exposure to ultrasound was enough to cause depressive-like behavioral changes in rats. Increased levels of oxidative stress markers in the hippocampus and prefrontal cortex were also observed after two weeks of such stress. The current study has two goals: the first is to study the relationship of depression and oxidative stress; the second is an additional validation of our approach to modeling stress­induced depressive-like states in rats. The present data further support the validity of the ultrasound model by expanding information related to the influence of ultrasound stress on behavioral and physiological parameters, which are of great importance in the development of stress-induced depression. A time correlation between the onset of symptoms and a change in the level of oxidative stress markers in the brain is also demonstrated.


Assuntos
Comportamento Animal/fisiologia , Depressão/fisiopatologia , Estresse Oxidativo/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Depressão/metabolismo , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Glutationa/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Córtex Pré-Frontal/fisiopatologia , Ratos
7.
Nat Commun ; 10(1): 4799, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641124

RESUMO

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Aprendizagem/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Epigênese Genética , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Histona Desacetilase 2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Sirtuína 2/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética
8.
Depress Anxiety ; 36(12): 1143-1153, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31600020

RESUMO

BACKGROUND: Social anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD. METHODS: Participants (n = 110; age, 9.2 - 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated. RESULTS: Our data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate - to-moderately high heritability in the right hippocampus. CONCLUSION: The present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD.


Assuntos
Endofenótipos , Expressão Facial , Família , Predisposição Genética para Doença , Habituação Psicofisiológica , Fobia Social/genética , Fobia Social/fisiopatologia , Adolescente , Adulto , Tonsila do Cerebelo/fisiopatologia , Criança , Feminino , Hipocampo/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Molecules ; 24(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561643

RESUMO

Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinical studies. In this study, the synthesis of these KYNA derivatives and their evaluation with divergent molecular characteristics are presented together with their most typical effects on the monosynaptic transmission in CA1 region of the hippocampus of the rat. Their effects on the basic neuronal activity (on the field excitatory postsynaptic potentials: fEPSP) were studied in in vitro hippocampal slices in 1 and 200 µM concentrations. KYNA and its derivative 4 in both 1 and 200 µM concentrations proved to be inhibitory, while derivative 8 only in 200 µM decreased the amplitudes of fEPSPs. Derivative 5 facilitated the fEPSPs in 200 µM concentration. This is the first comparative study which evaluates the structural and functional differences of formerly and newly developed KYNA analogs. Considerations on possible relations between molecular structures and their physiological effects are presented.


Assuntos
Ácido Cinurênico/química , Ácido Cinurênico/farmacologia , Desenho de Drogas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ácido Cinurênico/análogos & derivados , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Relação Estrutura-Atividade
10.
Int J Mol Sci ; 20(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480539

RESUMO

An olfactory bulbectomy (OBX) rodent is a widely-used model for depression (especially for agitated depression). The present study aims to investigate the hippocampus metabolic profile and autophagy-related pathways in OBX rats and to explore the modulatory roles of fluoxetine. OBX rats were given a 30-day fluoxetine treatment after post-surgery rehabilitation, and then behavioral changes were evaluated. Subsequently, the hippocampus was harvested for metabonomics analysis and Western blot detection. As a result, OBX rats exhibited a significantly increased hyperemotionality score and declined spatial memory ability. Fluoxetine reduced the hyperemotional response, but failed to restore the memory deficit in OBX rats. Sixteen metabolites were identified as potential biomarkers for the OBX model including six that were rectified by fluoxetine. Disturbed pathways were involved in amino acid metabolism, fatty acid metabolism, purine metabolism, and energy metabolism. In addition, autophagy was markedly inhibited in the hippocampus of OBX rats. Fluoxetine could promote autophagy by up-regulating the expression of LC3 II, beclin1, and p-AMPK/AMPK, and down-regulating the levels of p62, p-Akt/Akt, p-mTOR/mTOR, and p-ULK1/ULK1. Our findings indicated that OBX caused marked abnormalities in hippocampus metabolites and autophagy, and fluoxetine could partly redress the metabolic disturbance and enhance autophagy to reverse the depressive-like behavior, but not the memory deficits in OBX rats.


Assuntos
Autofagia , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo/metabolismo , Transtornos da Memória , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Redes e Vias Metabólicas , Bulbo Olfatório/cirurgia , Ratos , Ratos Sprague-Dawley
11.
EBioMedicine ; 47: 384-401, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31492565

RESUMO

INTRODUCTION: Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. METHODS: In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. FINDINGS: When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. INTERPRETATION: PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels. FUND: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: "Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities". M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant'Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Miocárdio/metabolismo , Estresse Psicológico , Animais , Apoptose , Comportamento Animal , Biomarcadores , Comorbidade , Dieta Hiperlipídica , Ecocardiografia , Fibrose , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , Neurogênese , Estresse Oxidativo , Proteínas Tirosina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
J Stroke Cerebrovasc Dis ; 28(11): 104288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395423

RESUMO

PURPOSE: The present study was to observe the therapeutic efficiency of Clematichinenoside (AR) on cerebral ischemic injury in rats, especially on neurological and motor function recovery and to explore the underlying mechanism. METHODS: Following middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, rats were treated orally with 32, 16, and 8 mg/kg AR respectively for 14 days during which cerebral injury was evaluated and proinflammatory factors tumor necrosis factor-α and interleukin-6 as well as neurotrophic factors brain-derived neurotrophic factor and Neurotrophin-3 levels were determined with ELISA kits. Immunohistochemical analysis on number of neurons and reactive astrocytes in the hippocampus was to demonstrate the effect of AR on neuronal survival. Motor, learning, and memory recovery were assessed by Morris water maze, passive avoidance experiment, and rotatory rod test. Neuroprotection and anti-inflammation-related Notch and nuclear factor-κB (NF-κB) signaling pathways were analyzed by PCR and Western blot techniques on mammalian achaete-scute homologs1, Notch-1, intracellular Notch receptor domain, Jagged-1, transcription factor hairy, enhancer of split1 (Hes1), as well as the nuclear import of NF-κB in hippocampus. RESULTS: AR administration reduced cerebral injury in rats exposed to MCAO/R and after treatment of AR for 14 days, proinflammatory reaction was inhibited, with neuronal survival rate raised and motor function recovery facilitated. PCR and WB analysis of Notch/NF-κB signaling pathway revealed the inhibitory effect of AR on pathway related components. CONCLUSIONS: AR is beneficial to recovery of neurological and motor function in rats after cerebral ischemic injury via inhibiting Notch/NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptor Notch1/metabolismo , Saponinas/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Masculino , Memória/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais
13.
Life Sci ; 234: 116739, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400352

RESUMO

AIM: This study aimed to investigate the effect of icariin (referred as ICA) on Alzheimer's disease (AD) model through endoplasmic reticulum (ER) stress pathway. MAIN METHODS: Nine months male APP/PS1 and wild-type (WT) mice were randomly divided into four groups: APP/PS1 control, APP/PS1 + ICA, WT control and WT + ICA groups. The treated mice were given ICA 60 mg/kg/d and control mice were received the same volume distilled water for consecutive 3 months. The Morris water maze and Novel object recognition were used to detect animals' behavior. Nissl staining was used to observe the neuronal morphology in hippocampus area. Aß deposition in hippocampal region was observed by immunofluorescence staining. TUNEL staining was used to observe apoptosis. Detection of expression of ER stress related factors by Western blot and real time RT-PCR. KEY FINDINGS: Chronically administrated with ICA compared with APP/PS1 control mice significantly improved the behavior performance, reduced neuronal apoptosis, as well as suppressing the ER stress signaling pathway, including that decreased the level of glucose-regulated protein 78, phosphorylated ER-regulated kinase and phosphorylated eukaryotic initiation factor α, as well activating transcription factor-4, C/EBP homologous protein, DNA damage inducible protein 34 and tribbles homologous protein 3. SIGNIFICANCE: Our data indicated that ICA suppressed the ER stress signaling to protect against AD animal model, these findings suggest that a potential point for researching the effect of ICA on neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Cognição/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonoides/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Camundongos
14.
Arch Oral Biol ; 107: 104516, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31408810

RESUMO

OBJECTIVE: To provide a systematic review of the effects of the bite-raised condition in animal models, a widespread technique in modern orthodontics. DESIGN: A systematic review of the literature was conducted. Original articles were searched through Pubmed, Cochrane Central database and Embase until December 2018. RESULTS: 242 articles were identified through database searching. After removing the duplicates, 198 articles were screened by reviewing the abstracts. 27 full text articles were assessed for eligibility and, after 7 exclusions, 20 articles were included in the review process. Studies selected by the review process concerned animal models. Histological, molecular, biochemical and electromyographical studies were evaluated. The results, with a high level of agreement in different animals, showed that the bite-raised condition is a source of stress, inducing increased plasma corticosterone, urinary cortisol and HPA axis alterations; it predisposes the organism to react to subsequent stressful stimulation with a significantly greater incretion of glucocorticoids, thus inducing hypersensitivity to novel forms of stress; it affects the structure of the hippocampus, reducing the number of neurons, increasing the number of glial cells and worsening memory and spatial orientation; it alters the electromyographical activity of masticatory muscles. CONCLUSIONS: The results of research conducted on animal models do not necessarily apply directly to human beings. More clinical research, with special attention to adolescent patients, is necessary to clarify whether, in humans, the bite-raised condition is accompanied by adverse effects comparable to those observed in animals.


Assuntos
Oclusão Dentária , Sistema Hipotálamo-Hipofisário , Modelos Animais , Sistema Hipófise-Suprarrenal , Animais , Glucocorticoides/fisiologia , Hipocampo/fisiopatologia , Humanos , Neuroglia , Neurônios
15.
Mol Med Rep ; 20(4): 3363-3370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432127

RESUMO

The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid ß protein alloform 1­40 (Aß1­40) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aß1­40 co­injection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by co­injection of APOE4 + Aß1­40. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcription­quantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubule­associated protein tau and glycogen synthase kinase 3ß (GSK3ß). APOE4 and Aß1­40 co­aggregation decreased the short­term spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aß1­40 co­aggregation­induced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aß1­40 co­aggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3ß protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3ß phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aß1­40 co­aggregation in model rats.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Lesões Encefálicas/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Desacetilase 6 de Histona/biossíntese , Inibidores de Histona Desacetilases/farmacologia , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Colina O-Acetiltransferase/biossíntese , Hipocampo/patologia , Hipocampo/fisiopatologia , Desacetilase 6 de Histona/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/fisiopatologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
16.
Mol Med Rep ; 20(4): 3448-3455, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432129

RESUMO

The aim of the present study was to evaluate the neuroprotective effect of Citrus aurantium extract (CAE) and nobiletin against amyloid ß 1­42 (Aß 1­42)­induced spatial learning and memory impairment in mice. After injecting Aß 1­42 (5 µl/2.5 min, intracerebroventricular injection), amnesic mice were orally administered CAE and nobiletin for 28 days. Memory, spatial and cognitive ability were measured using passive avoidance and a Morris water maze task. Acetylcholinesterase (AchE) activity was investigated in the hippocampus and cortex using commercial kits and the analysis of Bax, Bcl­2, and cleaved caspase­3 protein expression by western blot assays was used to confirm the anti­apoptotic mechanism of CAE and nobiletin. The present study confirmed impairments in learning and memory in the Aß­induced neurodegenerative mice with increased AchE activity in the brain. However, the daily administration of CAE and nobiletin reduced the spatial learning deficits and increased the AchE activity in the cortex and hippocampus. Furthermore, CAE and nobiletin significantly downregulated the Bax and cleaved caspase­3 protein expression and upregulated the Bcl­2 and Bcl­2/Bax expression in the cortex and hippocampus of Aß­treated mice. These results suggest that CAE and nobiletin exert a neuroprotective effect by regulating anti­apoptotic mechanisms, including reduced AchE activity in the cortex and hippocampus of the cognitive deficit mouse model.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Citrus/química , Flavonas/farmacologia , Transtornos da Memória/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Extratos Vegetais/farmacologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Extratos Vegetais/química
17.
Mol Med Rep ; 20(4): 3395-3405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432130

RESUMO

Cerebral ischemic injury is a major cause of death and long­term disability worldwide that leads to neurological and behavioral deficits, and for which successful treatments are still lacking. Ras homolog family member A (RhoA) and Rho­associated coiled­coil containing protein kinase (ROCK) are associated with the growth of neurons and the movement of neuronal growth cones. RhoA/ROCK inhibitors have been demonstrated to promote the recovery of motor function following nerve injury, but the underlying mechanism requires further investigation. The present study aimed to investigate the effects of the ROCK inhibitor Y­27632 on middle cerebral artery occlusion (MCAO)­induced cerebral ischemic injury. Rats were randomly assigned to the Control, Y­27632, MCAO + Vehicle or MCAO + Y­27632 group. Firstly, infarct volume, cognitive ability and cerebral injury were assessed. Secondly, indicators of cerebral inflammation, oxidative stress and apoptosis were evaluated. Finally, the expression of recombinant glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (AIF1) in the brain were measured to assess the activation of astrocytes and microglia, respectively. The results showed that Y­27632 effectively increased the survival rate and behavioral performance of rats, and attenuated the cerebral injury, oxidative stress and cerebral inflammation levels following MCAO. The disturbance in hippocampal neurons caused by MCAO was also alleviated following treatment with Y­27632. Neuronal apoptosis was also decreased following Y­27632 treatment, as demonstrated by the TUNEL assay and the expression levels of Caspases­3, 8 and 9 and Bax/Bcl­2 ratio. The levels of GFAP and AIF1 were increased by MCAO and further promoted by Y­27632, indicating the activation of astrocytes and microglia. In conclusion, the present study offered evidence of a protective effect of Y­27632 administration on cerebral ischemia/reperfusion induced behavioral and hippocampal damage by activating astrocytes and microglia.


Assuntos
Amidas/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas , Piridinas/farmacologia , Traumatismo por Reperfusão , Quinases Associadas a rho/antagonistas & inibidores , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
18.
BMC Neurosci ; 20(1): 37, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366391

RESUMO

BACKGROUND: Cardiovascular conditions contribute to brain volume loss, reduced cerebrovascular health, and increased dementia risk in aging adults. Altered hippocampal connectivity has also been observed in individuals with cardiovascular conditions, yet the functional consequences of these changes remain unclear. In the present study, we collected functional magnetic resonance imaging data during memory encoding and used a psychophysiological interaction analysis to examine whether cardiovascular burden, indexed using the Framingham risk score, was associated with encoding-related hippocampal connectivity and task performance in cognitively-intact older adults between 65 and 85 years of age. Our goal was to better understand the early functional consequences of vascular and metabolic dysfunction in those at risk for cognitive decline. RESULTS: High Framingham risk scores were associated with lower total brain volumes. In addition, those with high Framingham risk scores showed an altered relationship between left hippocampal-medial prefrontal coupling and task performance compared to those with low Framingham risk scores. Specifically, we found a significant interaction of Framingham risk and learning on connectivity between the left hippocampus and primarily left midline prefrontal regions comprising the left ventral anterior cingulate cortex and medial prefrontal cortex. Those with lower Framingham risk scores showed a pattern of weaker connectivity between left hippocampal and medial prefrontal regions associated with better task performance. Those with higher Framingham risk scores showed the opposite pattern; stronger connectivity was associated with better performance. CONCLUSIONS: Findings from the current study show that amongst older adults with cardiovascular conditions, higher Framingham risk is associated with lower brain volume and altered left hippocampal-medial prefrontal coupling during task performance compared to those with lower Framingham risk scores. This may reflect a compensatory mechanism in support of memory function and suggests that older adults with elevated cardiovascular risk are vulnerable to early Alzheimer disease-like dysfunction within the episodic memory system.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Hipocampo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia , Vias Neurais/fisiologia , Fatores de Risco
19.
World Neurosurg ; 132: 314-320, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449994

RESUMO

BACKGROUND: Whereas transient, self-limiting seizures are an infrequent but known complication of deep brain stimulation (DBS) implantation surgery, stimulation itself has occasionally been reported to result in seizure activity at delayed time points. The neural circuitry implicated in stimulation-induced seizures is unknown. CASE DESCRIPTION: A 47-year-old woman underwent chronic subcallosal cingulate DBS for treatment of refractory anorexia nervosa and experienced seizure with stimulation onset. Supratherapeutic voltage caused a generalized seizure. The patient subsequently experienced a full recovery. We reviewed the literature for other cases of delayed postoperative DBS seizures associated with stimulation. We also investigated whether the higher voltage may have recruited networks implicated in epilepsy. The supratherapeutic voltage stimulated a larger area and engaged vulnerable networks, including bilateral hippocampi, cingulate gyrus, and temporal lobes. Literature review identified 20 studies reporting delayed seizure after DBS surgery, 13 of which demonstrated a robust association with mostly nonmotor DBS stimulation. CONCLUSIONS: Nonmotor DBS targets, particularly in patients with epilepsy, may be more vulnerable to stimulation-induced seizures; as such, extra caution should be used when programming stimulation parameters at these DBS targets.


Assuntos
Anorexia Nervosa/terapia , Encéfalo/fisiopatologia , Estimulação Encefálica Profunda/efeitos adversos , Convulsões/etiologia , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologia , Humanos , Lamotrigina/uso terapêutico , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Convulsões/diagnóstico por imagem , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia
20.
Life Sci ; 234: 116775, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425697

RESUMO

AIMS: The activation of the angiotensin (Ang) II after acute kidney injury (AKI) triggers oxidative stress and inflammatory cascade which involved not only the kidneys but also the brain. Ang II through the Ang II type 1 receptor (AT1R) may have deleterious effects on hippocampal synaptic transmission and cognitive functions under uremic encephalopathy. The present study was conducted to examine the effects of AT1R antagonist on AKI-induced cognitive and synaptic plasticity impairment. MAIN METHODS: Here, we investigated the effect of AKI and possible pathophysiological roles of AT1R with the selective AT1R antagonist losartan (10 mg/kg/day for consecutive 9 days) on cognitive performance using passive avoidance and Morris water maze tests. In order to understand the synaptic transmission, in vivo short and long-term plasticity were evaluated at the Schaffer collateral-CA1 synapse. Biochemical analysis was also performed to detect possible hippocampal nitric oxide and oxidative stress mechanisms. KEY FINDINGS: Our data provide evidence of hippocampal complication following AKI with increased level of nitrite (P < 0.01 vs. sham) as well as oxidative stress (P < 0.01 vs. sham) that may be responsible for behavioral dysfunction under uremia (spatial memory, P < 0.001; passive avoidance P < 0.01 vs. sham). Losartan treatment effectively protects against cognitive (spatial memory, P < 0.01; passive avoidance P < 0.05 vs. AKI-veh) and synaptic plasticity impairments induced by AKI possibly via modulation of oxidative stress in the hippocampus (P < 0.01 vs. AKI-veh). SIGNIFICANCE: The present study conclusively demonstrated a protective role of AT1R antagonist losartan in hippocampal complication and neurocognitive dysfunction after AKI via modulating oxidative stress.


Assuntos
Lesão Renal Aguda/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Losartan/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo
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