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1.
PLoS One ; 15(2): e0229288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078638

RESUMO

The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.


Assuntos
Ansiedade/patologia , Depressão/patologia , Medo , Glutamato Desidrogenase/fisiologia , Relações Interpessoais , Transtornos da Memória/patologia , Transtornos do Comportamento Social/patologia , Animais , Ansiedade/etiologia , Comportamento Animal , Depressão/etiologia , Masculino , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Transtornos do Comportamento Social/etiologia
2.
Science ; 367(6473)2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31896692

RESUMO

In 1904, Richard Semon introduced the term "engram" to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory retrieval. Although Semon's contributions were largely ignored in his lifetime, new technologies that allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated engram research. We review recent progress in studying engrams, including an evaluation of evidence for the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory.


Assuntos
Química Encefálica , Encéfalo/citologia , Encéfalo/fisiologia , Rememoração Mental/fisiologia , Animais , Humanos , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Neurônios/química , Neurônios/fisiologia
3.
Psychiatry Res Neuroimaging ; 296: 111021, 2020 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-31887712

RESUMO

Alzheimer's disease (AD) is characterised by episodic memory impairment, but people also experience memory distortions, including false memories, which can impact on safety and reduce functioning. Understanding the neural networks that underpin false memories could help to predict the need for intervention and guide development of cognitive strategies to reduce memory errors. However, there is a relative absence of research into how the neuropathology of AD contributes to false memory generation. This paper systematically reviews the methodology and outcomes of studies investigating the neuroimaging correlates of false memory in AD. Four studies using structural imaging and three studies using functional imaging were identified. Studies were heterogenous in methodology and received mostly 'weak' quality assessment ratings. Combined, and consistent with neuroimaging findings in non-AD populations, results from identified studies provide preliminary support for the hypothesis that medial temporal lobe and prefrontal cortex dysfunction may lead to generation of false memories in AD. However, the small number of studies and significant heterogeneity within them means further study is necessary to assess replicability of results.


Assuntos
Doença de Alzheimer/patologia , Transtornos da Memória/patologia , Doença de Alzheimer/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/etiologia , Memória Episódica , Neuroimagem , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/fisiopatologia
4.
BMC Neurosci ; 20(1): 60, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852437

RESUMO

BACKGROUND: Ketamine has been reported to cause neonatal neurotoxicity in a variety of developing animal models. Various studies have been conducted to study the mechanism of neurotoxicity for general anesthetic use during the neonatal period. Previous experiments have suggested that developmentally generated granule neurons in the hippocampus dentate gyrus (DG) supported hippocampus-dependent memory. Therefore, this study aimed to investigate whether ketamine affects the functional integration of developmentally generated granule neurons in the DG. For this purpose,the postnatal day 7 (PND-7) Sprague-Dawley (SD) rats were divided into the control group and the ketamine group (rats who received 4 injections of 40 mg/kg ketamine at 1 h intervals). To label dividing cells, BrdU was administered for three consecutive days after the ketamine exposure; NeuN+/BrdU+cells were observed by using immunofluorescence. To evaluate the developmentally generated granule neurons that support hippocampus-dependent memory, spatial reference memory was tested by using Morris Water Maze at 3 months old, after which the immunofluorescence was used to detect c-Fos expression in the NeuN+/BrdU+ cells. The expression of caspase-3 was measured by western blot to detect the apoptosis in the hippocampal DG. RESULTS: The present results showed that the neonatal ketamine exposure did not influence the survival rate of developmentally generated granule neurons at 2 and 3 months old, but ketamine interfered with the integration of these neurons into the hippocampal DG neural circuits and caused a deficit in hippocampal-dependent spatial reference memory tasks. CONCLUSIONS: In summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.


Assuntos
Giro Denteado/efeitos dos fármacos , Giro Denteado/crescimento & desenvolvimento , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ketamina/efeitos adversos , Neurônios/efeitos dos fármacos , Animais , Antígenos Nucleares/metabolismo , Bromodesoxiuridina , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
5.
Life Sci ; 238: 116898, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610193

RESUMO

AIMS: Learning and memory impairment is a common symptom in the early stages of various types of dementia. It is likely to reduce the incidence of dementia with correct intervention. α-Asarone is the main bioactive substance isolated from Acorus tatarinowii Schott and has been proven to improve memory dysfunction; however, at present, the specific underlying mechanism is poorly understood. The aim of the present study was to investigate the effect of α-asarone on ethanol-impaired cognitive ability and explore the underlying mechanism in mice. MAIN METHODS: A mouse model of impaired learning and memory was created by ethanol (2.0 g/kg, i.g.). α-Asarone (7.5, 15 or 30 mg/kg, i.p.) was delivered 10 min prior to ethanol administration. The behavioral effect of α-asarone was evaluated using the novel object recognition test. Glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the hippocampus were determined by ELISA, and the protein expression levels of hippocampal GluR2, NMDAR2B, SYNΙ, GLT-1 and CaMKⅡ were detected by western blotting. KEY FINDINGS: Pretreatment with α-asarone significantly improved the behavioral performance, regulated the imbalance of Glu and GABA in the hippocampus and the abnormal expression of related proteins. A possible underlying mechanism is regulation of the calcium signaling cascade to correct functioning of related proteins, and thus, maintain the level of Glu. SIGNIFICANCE: Our results show that the improvement in learning and memory elicited by α-asarone may providing a possible novel candidate for the prevention of learning and memory impairment in the early stages of dementia.


Assuntos
Anisóis/farmacologia , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Fibrinolíticos/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo
6.
Biol Pharm Bull ; 42(8): 1384-1393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366873

RESUMO

We previously demonstrated that Bacopa monnier (L.) WETTST. extract (BME) ameliorated cognitive dysfunction in animal models of dementia by enhancing synaptic plasticity-related signaling in the hippocampus and protecting cholinergic neurons in the medial septum. To further clarify the pharmacological features and availability of BME as a novel anti-dementia agent, we investigated whether BME affects neuronal repair using a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampus. Mice pretreated with TMT (2.8 mg/kg, intraperitoneally (i.p.)) on day 0 were given BME (50 mg/kg, per os (p.o.)) once daily for 15-30 d. Cognitive performance of the animals was elucidated twice by the object location test and modified Y maze test on days 17-20 (Phase I) and days 32-35 (Phase II) or by the passive avoidance test on Phase II. TMT impaired hippocampus-dependent spatial working memory and amygdala-dependent fear-motivated memory. The administration of BME significantly prevented TMT-induced cognitive deficits. The protective effects of BME on the spatial memory deficits were confirmed by Nissl staining of hippocampal tissues and propidium iodide staining of organotypic hippocampal slice cultures. Immunohistochemical studies conducted on days 17 and 32 revealed that thirty days of treatment with BME increased the number of 5-bromo-2'-deoxyuridine (BrdU)-immunopositive cells in the dentate gyrus region of TMT-treated mice, whereas fifteen days of treatment with BME had no effect. These results suggest that BME ameliorates TMT-induced cognition dysfunction mainly via protecting the hippocampal neurons from TMT-induced hippocampal lesions and partly via promoting neuroregeneration in the dentate gyrus regions.


Assuntos
Bacopa , Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Transtornos da Memória/patologia , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Compostos de Trimetilestanho
7.
Nat Commun ; 10(1): 3756, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434897

RESUMO

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however, the underlying mechanisms that enable memory flexibility are still poorly understood. Here, we identify transcriptional repressor Wilm's Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 is activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhances CA1 neuronal excitability, LTP and long-term memory whereas its overexpression weakens memory retention. Moreover, forebrain WT1-deficient mice show deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experiences.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Proteínas Repressoras/metabolismo , Animais , Comportamento Animal/fisiologia , Região CA1 Hipocampal/metabolismo , Medo/fisiologia , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/patologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética
8.
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
9.
Food Chem Toxicol ; 132: 110698, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348966

RESUMO

The misfolding and aggregation of amyloid ß (Aß) peptide is a common histopathologic characteristic in patients with Alzheimer's disease, so is considered to play an critical role. In the present study, we examined the effect of rubrofusarin, an ingredient of Cassiae semen, on Aß aggregation and memory loss in an AD mouse model. Rubrofusarin inhibited Aß aggregation in a concentration-dependent manner. Moreover, rubrofusarin dis-aggregated preformed Aß fibrils in a concentration-dependent manner. Although aggregated Aß induced memory loss, Aß pre-incubated with rubrofusarin failed to induce memory loss. Moreover, rubrofusarin administration ameliorated Aß aggregates-induced memory loss. Finally, rubrofusarin reduced glial fibrillary acidic protein or Iba-1-positive area, markers of neuroinflammation, in the hippocampus of Aß-treated mice. These results suggest that rubrofusarin can decrease Aß fibril formation and ameliorate memory loss in the AD mouse model.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Transtornos da Memória/patologia , Fragmentos de Peptídeos/antagonistas & inibidores , Pironas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fragmentos de Peptídeos/metabolismo
10.
Biofactors ; 45(5): 725-739, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301192

RESUMO

Lipoproteins are the complexes of different lipids and proteins, which are devoted to the transport and clearance of lipids or lipid-related molecules in the circulation. Lipoproteins have been found to play a crucial role in brain function and may influence myelination process. Among lipoproteins, high-density lipoproteins (HDLs) and their major protein component, apoA-I, are directly involved in cholesterol efflux in the brain. It has been suggested that inadequate or dysfunctional brain HDLs may contribute to cerebrovascular dysfunctions, neurodegeneration, or neurovascular instability. HDL deficiency could also promote cognitive decline through impacting on atherosclerotic risk. The focus of this review is to discuss knowledge on HDL dysregulation in neurological disorders. A better understanding on how changes in cellular HDL and apolipoprotein homeostasis affect central nervous system function may provide promising novel avenues for the treatment of specific HDL-related neurological disorders.


Assuntos
Doença de Alzheimer/metabolismo , Aterosclerose/metabolismo , Demência/metabolismo , Doença de Huntington/metabolismo , Lipoproteínas HDL/metabolismo , Transtornos da Memória/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína A-I/metabolismo , Aterosclerose/patologia , Transporte Biológico , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Demência/patologia , Humanos , Doença de Huntington/patologia , Transtornos da Memória/patologia , Doença de Parkinson/patologia
11.
Life Sci ; 233: 116695, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351082

RESUMO

Alzheimer's disease (AD) is neurodegenerative disorder that is associated with memory and cognitive decline in the older adults. Scopolamine is commonly used as a behavioral model in studying cognitive disorders including AD. Many studies have also concurrently examined the neurochemical mechanisms underlying the behavioral modifications by scopolamine treatment. Nonetheless, the scopolamine model has not become a standard tool in the early assessment of drugs. Furthermore, the use of scopolamine as a pharmacological model to study AD remains debatable. This report reviews the scopolamine-induced cellular and molecular changes and discusses how these changes relate to AD pathogenesis.


Assuntos
Doença de Alzheimer/fisiopatologia , Biomarcadores/metabolismo , Antagonistas Colinérgicos/efeitos adversos , Transtornos da Memória/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Escopolamina/efeitos adversos , Doença de Alzheimer/tratamento farmacológico , Animais , Humanos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo
12.
Cancer Radiother ; 23(5): 370-377, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331843

RESUMO

PUPOSE: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern. PATIENTS AND METHODS: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College. RESULTS: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively. CONCLUSION: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment.


Assuntos
Neoplasias Cerebelares/radioterapia , Irradiação Craniana/efeitos adversos , Meduloblastoma/radioterapia , Transtornos Neurocognitivos/etiologia , Fatores Etários , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Terapia Combinada , Seguimentos , Substância Cinzenta/lesões , Substância Cinzenta/patologia , Hipocampo/lesões , Hipocampo/patologia , Humanos , Meduloblastoma/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Transtornos Neurocognitivos/patologia , Tamanho do Órgão , Modelos de Riscos Proporcionais , Escalas de Wechsler , Substância Branca/lesões , Substância Branca/patologia
13.
Molecules ; 24(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174251

RESUMO

Ginseng has been used to alleviate age-related dementia and memory deterioration for thousands of years. This study investigated the protective effect of red ginseng saponins against scopolamine-induced cerebral injury. Meanwhile, pharmacokinetics of ginsenosides in normal and scopolamine-treated rats were compared. After scopolamine injection, glutathione, catalase and superoxide dismutase levels were significantly decreased when compared with control group. Compared with SA group, pretreatment of rats with red ginseng saponins could increase glutathione, catalase and superoxide dismutase level. Treatment with red ginseng saponins significantly decreased malondialdehyde level. In the pharmacokinetic analysis, a pattern recognition analysis method was used to investigate the pharmacokinetics of the absorbed compounds in blood. The pharmacokinetic parameters of Rg1, Rg2, Rh3, Rg5 and Rk1 in model group had higher area under the curve (AUC), mean residence time (MRT) and peak plasma concentration (Cmax) values; area under the curve (AUC) values and peak plasma concentration (Cmax) of model group was significantly different from that of normal group (p < 0.05). The Cmax value of Rk3, Rh1, Rh2 and Rh4 in model group was higher than normal group, but their AUC values were not significantly different. There was no significantly difference in time at Cmax (Tmax), AUC and Cmax values of Rb1, Rb2 Re, Rc, Rd and Rf between the model and normal group. 16 ginsenosides were grouped into three separate clusters according to principal component analysis (PCA) score plot based on pharmacokinetic data. The results suggested red ginseng saponins have significant protective effect against scopolamine-induced memory deficit and scopolamine-induced rats could lead to the changes of pharmacokinetic behaviors of ginsenosides.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Panax/química , Saponinas/farmacologia , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/patologia , Humanos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Fármacos Neuroprotetores/farmacocinética , Ratos , Ratos Sprague-Dawley , Saponinas/química , Saponinas/farmacocinética , Escopolamina/toxicidade
14.
J Nat Med ; 73(4): 717-726, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31190266

RESUMO

Tau oligomers are the etiologic molecules of Alzheimer's disease, and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside (CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203X (WM/GFX, 200 µM each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When orally administered with CIG at 60 and 120 mg/kg/day for 14 days, CIG decreased the escape latency in the Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95 (PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3ß (wtGSK-3ß). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.


Assuntos
Doença de Alzheimer/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicosídeos Iridoides/farmacologia , Transtornos da Memória/patologia , Proteínas tau/toxicidade , Animais , Autofagia/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Proteína 4 Homóloga a Disks-Large/metabolismo , Indóis/toxicidade , Masculino , Maleimidas/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fosforilação , Substâncias Protetoras , Ratos , Ratos Wistar , Sinapsinas/metabolismo , Sinaptofisina/metabolismo , Wortmanina/toxicidade
15.
Oxid Med Cell Longev ; 2019: 4032428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049134

RESUMO

Tolfenamic acid is a nonsteroidal anti-inflammatory drug with neuroprotective properties, and it alleviates learning and memory deficits in the APP transgenic mouse model of Alzheimer's disease. However, whether tolfenamic acid can prevent motor and memory dysfunction in transgenic animal models of Huntington's disease (HD) remains unclear. To this end, tolfenamic acid was orally administered to transgenic R6/1 mice from 10 to 20 weeks of age, followed by several behavioral tests to evaluate motor and memory function. Tolfenamic acid improved motor coordination in R6/1 mice as tested by rotarod, grip strength, and locomotor behavior tests and attenuated memory dysfunction as analyzed using the novel object recognition test and passive avoidance test. Tolfenamic acid decreased the expression of mutant huntingtin in the striatum of 20-week-old R6/1 mice by inhibiting specificity protein 1 expression and enhancing autophagic function. Furthermore, tolfenamic acid exhibited antioxidant effects in both R6/1 mice and PC12 cell models. Collectively, these results suggest that tolfenamic acid has a good therapeutic effect on R6/1 mice, and may be a potentially useful agent in the treatment of HD.


Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Doença de Huntington , Transtornos da Memória , Desempenho Psicomotor/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/prevenção & controle , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Transgênicos , Mutação , Células PC12 , Ratos
16.
Mol Med Rep ; 20(1): 332-340, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115535

RESUMO

Saikosaponin­D (SSD), which is the main bioactive component in the traditional Chinese medicine Chai Hu (Bupleurum falcatum L), possesses estrogen­like properties and is widely used in treating estrogen­related neurological disorders. The current study aimed to investigate the protective effects of SSD on the fear memory deficit in ovariectomized (OVX) rats and the potential underlying mechanism. SSD treatment significantly prolonged freezing time in OVX rats in a manner similar to that of estradiol (E2), whereas this effect was markedly suppressed by co­administration of ICI182780, a non­selective estrogen receptor (ER) inhibitor. The expression of ERα in the hippocampus of OVX rats was significantly elevated by SSD; however, Erß expression and E2 synthesis were not markedly affected by SSD treatment. Collectively, this study demonstrated that SSD­mediated fear memory improvement in OVX rats may be attributed not to E2 levels or ERß activity, but to ERα activation in the hippocampus.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Medo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Bupleurum/química , Estradiol/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/antagonistas & inibidores , Medo/fisiologia , Feminino , Fulvestranto/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Medicina Tradicional Chinesa , Transtornos da Memória/genética , Transtornos da Memória/patologia , Ácido Oleanólico/farmacologia , Ovariectomia , Ratos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia
17.
Int J Dev Neurosci ; 75: 19-26, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959098

RESUMO

Exposure to sevoflurane and other inhalational anesthetics can induce neurodegeneration in the developing brain. Although dexmedetomidine (DEX) has provided neuroprotection against hypoxic ischemic injury, relatively little is known about whether it has the neuroprotective effects against anesthetic-induced neurodegeneration. This study examined whether DEX improves the long-term cognitive dysfunction observed after exposure of neonatal rats to 3% sevoflurane. Seven-day-old rats received intraperitoneal saline (DEX 0) or DEX (6.6, 12.5, 25 µg/kg) 30 min before exposure to 3% sevoflurane with 21% oxygen for 4 h (n = 10 per group). The pups in the control group received only DEX 25 µg/kg without anesthesia. The escape latency in the Morris water maze was significantly increased in the DEX 0 group compared with the sham and control group, and the escape latency, but not the swimming path length, was significantly shorter at post-natal day 47 in the DEX 25 than in the DEX 0 group. The percent time spent in the quadrant was significantly decreased in the DEX 0 group compared with the sham and control group, and the percent time spent in the quadrant was significantly increased in the DEX 25 group compared with the DEX 0 groups. The freezing times of the DEX 0 and 6.6 groups were significantly decreased compared with those in the sham, control and DEX 25 groups. The number of NeuN-positive cells in the CA1 region was significantly decreased in the DEX 0 and 6.6 groups compared with the sham, control and DEX 25 groups. These findings indicate pre-treatment with DEX may improve long-term cognitive function and ameliorate the neuronal degeneration induced by sevoflurane exposure in neonatal rats.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Dexmedetomidina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sevoflurano/efeitos adversos , Animais , Animais Recém-Nascidos , Cognição/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Dexmedetomidina/farmacologia , Medo , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
18.
Magn Reson Imaging ; 60: 52-67, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30940494

RESUMO

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética , Doença de Alzheimer/patologia , Animais , Comportamento Animal , Biomarcadores , Encéfalo/patologia , Mapeamento Encefálico/métodos , Cognição , Disfunção Cognitiva/patologia , Meios de Contraste , Estudos Transversais , Progressão da Doença , Fórnice/patologia , Genótipo , Hipocampo/patologia , Magnetismo , Aprendizagem em Labirinto , Memória , Transtornos da Memória/patologia , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Neuroimagem , Memória Espacial
19.
Life Sci ; 224: 128-137, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905783

RESUMO

AIM: To evaluate the therapeutic potential of ligands of beta-adrenoceptors in cognitive disorders. Testosterone and adrenergic pathways are involved in hippocampal and emotional memory. Moreover, is strongly suggested that androgen diminishing in aging is involved in cognitive deficit, as well as beta-adrenoceptors, particularly beta2-adrenoceptor, participate in the adrenergic modulation of memory. In this regard, some animal models of memory disruption have shown improved performance after beta-drug administration. MATERIAL AND METHODS: In this work, we evaluated the effects of agonists (isoproterenol and salbutamol) and antagonists (propranolol and carvedilol) on beta-adrenoceptors in orchiectomized rats, as well as their effects in the performance on avoidance task and damage in hippocampal neurons by immunohistochemistry assays. KEY FINDINGS: Surprisingly, we found that both antagonists and salbutamol (but not isoproterenol) modulate the effects of hormone deprivation, improving memory and decreasing neuronal death and amyloid-beta related changes in some regions (particularly CA1-3 and dentate gyrus) of rat hippocampus. SIGNIFICANCE: Two ß-antagonists and one ß2-agonist modulated the effects of hormone deprivation on memory and damage in brain. The mechanisms of signaling of these drugs for beneficial effects remain unclear, even if used ß-ARs ligands share a weak activity on ß-arrestin/ERK-pathway activation which can be involved in these effects as we proposed in this manuscript. Our observations could be useful for understanding effects suggested of adrenergic drugs to modulate emotional memory. But also, our results could be related to other pathologies involving neuronal death and Aß accumulation.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Comportamento Animal/efeitos dos fármacos , Emoções/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Orquiectomia/efeitos adversos , Receptores Adrenérgicos beta/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Ratos Wistar
20.
J Rehabil Med ; 51(5): 343-351, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30815708

RESUMO

OBJECTIVES: Memory deficits are common after stroke, yet remain a high unmet need within the community. The aim of this phase II randomized controlled trial was to determine whether group compensatory or computerized cognitive training approaches were effective in rehabilitating memory following stroke. METHODS: A parallel, 3-group, single-blind, randomized controlled trial was used to compare the effectiveness of a compensatory memory skills group with restorative computerized training on functional goal attainment. Secondary outcomes explored change in neuropsychological measures of memory, subjective ratings of prospective and everyday memory failures and ratings of internal and external strategy use. RESULTS: A total of 65 community dwelling survivors of stroke were randomized (24: memory group, 22: computerized cognitive training, and 19: wait-list control). Participants allocated to the memory group reported significantly greater attainment of memory goals and internal strategy use at 6-week follow-up relative to participants in computerized training and wait-list control conditions. However, groups did not differ significantly on any subjective or objective secondary outcomes. CONCLUSION: Preliminary evidence shows that memory skills groups, but not computerized training, may facilitate achievement of functional memory goals for community dwelling survivors of stroke. These findings require further replication, given the modest sample size, subjective nature of the outcomes and the absence of objective eligibility for inclusion.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtornos da Memória/terapia , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Feminino , Humanos , Masculino , Transtornos da Memória/patologia , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Acidente Vascular Cerebral/fisiopatologia
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