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1.
Chem Biol Interact ; 326: 109113, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360496

RESUMO

Apple polyphenols (AP) have attracted much attention due to their various bioactivities. In this study, the protective effect of AP against chronic ethanol exposure-induced neural injury as well as the possible mechanisms were investigated. Body weight, daily average food intake and daily average fluid intake were measured and daily average ethanol consumption was calculated. The influences of AP on motor behavior and memory were detected by locomotor activity test, rotarod test, beam walking test, and Y maze test and novel object recognition test, respectively. The changes of blood ethanol concentration and the oxidative stress were also measured. AP improved chronic ethanol exposure-induced the inhibition of body weight and the decrease of daily average food intake, but did not influence the daily average fluid intake and the daily average ethanol intake, indicating that the improve effect of AP did not result from the decrease of ethanol intake. Motor activity and motor coordination were not influenced after chronic ethanol exposure though the blood ethanol concentration was higher than that in control group. AP improved significantly chronic ethanol-induced the memory impairment and the hippocampal CA1 neurons damage. Further studies found that AP decreased the contents of NO and MDA and increased the levels of T-AOC and GSH in the hippocampus of rats. These results suggest that AP exerts a protective effect against chronic ethanol-induced memory impairment through improving the oxidative stress in the hippocampus.


Assuntos
Etanol/efeitos adversos , Neurônios/efeitos dos fármacos , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Animais , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Malus , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Artigo em Inglês | MEDLINE | ID: mdl-32161213

RESUMO

Memory retrieval is not a passive process. When a memory is retrieved, the retrieved memory is destabilized, similar to short-term memory just after learning, and requires memory reconsolidation to re-stabilize the memory. Recent studies characterizing destabilization and reconsolidation showed that a retrieved memory is not always destabilized and that there are boundary conditions that determine the induction of destabilization and reconsolidation according to certain parameters, such as the duration of retrieval and the memory strength and age. Moreover, the reconsolidation of contextual fear memory is not independent of memory extinction; rather, these memory processes interact with each other. There is an increasing number of findings suggesting that destabilization following retrieval facilitates the modification, weakening, or strengthening of the original memory, and the resultant updated memory is stabilized through reconsolidation. Reconsolidation could be targeted therapeutically to improve emotional disorders such as post-traumatic stress disorder and phobia. Thus, this review summarizes recent findings to understand the mechanisms and function of reconsolidation.


Assuntos
Extinção Psicológica/fisiologia , Consolidação da Memória/fisiologia , Animais , Encéfalo , Medo , Humanos , Transtornos da Memória/metabolismo , Transtornos Mentais/metabolismo , Transtornos Fóbicos/metabolismo , Transdução de Sinais , Transtornos de Estresse Traumático/metabolismo
3.
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
4.
Oxid Med Cell Longev ; 2019: 7860650, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827700

RESUMO

Curcumin is a natural polyphenolic compound widely known to have antioxidant, anti-inflammatory, and antiapoptotic properties. In the present study, we explored the neuroprotective effect of curcumin against lipopolysaccharide- (LPS-) induced reactive oxygen species- (ROS-) mediated neuroinflammation, neurodegeneration, and memory deficits in the adult rat hippocampus via regulation of the JNK/NF-κB/Akt signaling pathway. Adult rats were treated intraperitoneally with LPS at a dose of 250 µg/kg for 7 days and curcumin at a dose of 300 mg/kg for 14 days. After 14 days, the rats were sacrificed, and western blotting and ROS and lipid peroxidation assays were performed. For immunohistochemistry and confocal microscopy, the rats were perfused transcardially with 4% paraformaldehyde. In order to verify the JNK-dependent neuroprotective effect of curcumin and to confirm the in vivo results, HT-22 neuronal and BV2 microglial cells were exposed to LPS at a dose of 1 µg/ml, curcumin 100 µg/ml, and SP600125 (a specific JNK inhibitor) 20 µM. Our immunohistochemical, immunofluorescence, and biochemical results revealed that curcumin inhibited LPS-induced oxidative stress by reducing malondialdehyde and 2,7-dichlorofluorescein levels and ameliorating neuroinflammation and neuronal cell death via regulation of the JNK/NF-κB/Akt signaling pathway both in vivo (adult rat hippocampus) and in vitro (HT-22/BV2 cell lines). Moreover, curcumin markedly improved LPS-induced memory impairment in the Morris water maze and Y-maze tasks. Taken together, our results suggest that curcumin may be a potential preventive and therapeutic candidate for LPS-induced ROS-mediated neurotoxicity and memory deficits in an adult rat model.


Assuntos
Curcumina/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Transtornos da Memória/prevenção & controle , Síndromes Neurotóxicas/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Suplementos Nutricionais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
5.
Cogn Behav Neurol ; 32(4): 278-283, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31800488

RESUMO

Aspects of cognitive flexibility are modulated by the noradrenergic system, which is important in arousal and attention. Acetylcholine also modulates arousal and attention, as well as working memory. Effects of muscarinic and nicotinic antagonism on memory are well established. Our purpose was to test whether muscarinic and nicotinic antagonism affect aspects of cognitive flexibility, specifically verbal problem-solving, as well as memory, given acetylcholine's role in attention and arousal. Eighteen participants attended three testing sessions. Two hours before testing, participants received either 0.6 mg scopolamine, 10 mg mecamylamine, or placebo. Then, participants were tested on three memory tasks (Buschke Selective Reminding Test [BSRT], California Verbal Learning Test [CVLT], Rey Complex Figure Test), two verbal problem-solving/cognitive flexibility tasks (Compound Remote Associates Test, a timed anagram test), and a spatial inductive reasoning task (Raven's Progressive Matrices). Task order and drug order were counterbalanced. Memory impairment was seen on one BSRT measure and multiple CVLT measures with scopolamine, and with one BSRT measure with mecamylamine. There were no effects of either drug on any of the tasks involving cognitive flexibility, including verbal problem-solving. Specific memory impairments were detected using muscarinic, and to a marginal extent, nicotinic antagonists, as expected, but no effect was seen on cognitive flexibility. Therefore, although both the noradrenergic and cholinergic systems play important roles in arousal and cortical signal-to-noise processing, the cholinergic system does not appear to have the same effect as the noradrenergic system on cognitive flexibility, including verbal problem-solving.


Assuntos
Transtornos da Memória/metabolismo , Memória de Curto Prazo/fisiologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Nicotínicos/efeitos adversos , Adulto , Animais , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Adulto Jovem
6.
Proc Natl Acad Sci U S A ; 116(51): 25982-25990, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31792184

RESUMO

Retrotransposons compose a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created from exogenous retroviral infection. ERVs make up 8 to 10% of human and mouse genomes and range from evolutionarily ancient sequences to recent acquisitions. Studies in Drosophila have provided a causal link between genomic retroviral elements and cognitive decline; however, in mammals, the role of ERVs in learning and memory remains unclear. Here we studied 2 independent murine models for ERV activation: muMT strain (lacking B cells and antibody production) and intracerebroventricular injection of streptozotocin (ICVI-STZ). We conducted behavioral assessments (contextual fear memory and spatial learning), as well as gene and protein analysis (RNA sequencing, PCR, immunohistochemistry, and western blot assays). Mice lacking mitochondrial antiviral-signaling protein (MAVS) and mice lacking stimulator of IFN genes protein (STING), 2 downstream sensors of ERV activation, provided confirmation of ERV impact. We found that muMT mice and ICVI-STZ mice induced hippocampal ERV activation, as shown by increased gene and protein expression of the Gag sequence of the transposable element intracisternal A-particle. ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, the deficiency of the MAVS pathway was protective against ICVI-STZ-induced cognitive pathology. Overall, our results demonstrate that ERV activation is associated with cognitive impairment in mice. Moreover, they provide a molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders.


Assuntos
Retrovirus Endógenos/genética , Hipocampo/virologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/virologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Comportamento Animal , Encéfalo/patologia , Disfunção Cognitiva , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Retrovirus Endógenos/fisiologia , Regulação da Expressão Gênica , Produtos do Gene gag , Hipocampo/efeitos dos fármacos , Aprendizagem , Masculino , Proteínas de Membrana/metabolismo , Memória , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estreptozocina/farmacologia
7.
Elife ; 82019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860442

RESUMO

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.


Assuntos
Transtorno Autístico/metabolismo , Região CA1 Hipocampal/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos da Memória/genética , Células Piramidais/metabolismo , Animais , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Região CA1 Hipocampal/citologia , Cerebelo/citologia , Cerebelo/metabolismo , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Regulação da Expressão Gênica , Humanos , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo
8.
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
9.
J Pharmacol Sci ; 141(3): 111-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31708401

RESUMO

Post-weaning social isolation of laboratory animals is known to induce many behavioural and neurochemical abnormalities, which resemble neuropsychiatric disorders such as depression and anxiety. Therefore, they can help provide a suitable animal model to investigate the pathophysiology of neuropsychiatric symptoms and explore potential drugs for the treatment of neuropsychiatric diseases. Our recent studies have demonstrated that post-weaning social isolation of mice for no less than one week causes behaviour changes such as reduced attention, impaired social affiliation behaviour, and impaired conditional fear memories. Our neuropharmacological analyses have revealed that these behavioural features are modulated by different neuronal mechanisms, suggesting that post-weaning social isolation of mice can help provide an animal model with comorbid symptoms of patients with developmental disorders, including attention-deficit hyperactivity disorder, autism spectrum disorder, and specific learning disability. In this review, we discuss the neuropharmacological features of developmental disorder-like behaviour induced by post-weaning social isolation in mice to offer new insights into the pathophysiology of developmental disorders and possible therapeutic strategies.


Assuntos
Antagonistas Colinérgicos/farmacologia , Dopaminérgicos/farmacologia , Transtornos da Memória/tratamento farmacológico , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Isolamento Social/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Camundongos , Atividade Motora/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/psicologia , Neurogênese/efeitos dos fármacos , Comportamento Social
10.
Pak J Pharm Sci ; 32(4(Supplementary)): 1893-1900, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31680089

RESUMO

Unpredictable chronic mild stress (UCMS) model is the most established method to study neurobiological mechanisms of depression. This work was intended to explore the efficacy of curcumin to revert the UCMS-induced oxidative burden and associated depression as well as potential of curcumin as an acetyl cholinesterase (AchE) inhibitor. Animals were initially grouped into control and curcumin (200mg/kg, p.o) and further subdivided into unstressed and stressed groups. Depression and anxiety were evaluated by forced swim test (FST) and light/dark transition (LDT) while memory function was assessed by passive avoidance test (PAT). Effect of curcumin on oxidative stress following UCMS was determined by measuring peroxidation of lipid (LPO) and antioxidant enzyme activities. AchE activity was also determined. Findings showed that curcumin supplementation significantly attenuated the UCMS-induced depression and anxiety like symptoms, decreased the load of UCMS propagated oxidative stress by improving antioxidant enzymes activities. Curcumin also improved the memory function and exhibited inhibitory effect on AchE activity. In conclusion it can be suggested that supplementation of curcumin in daily life can help in combating the stress-induced depression and ever increasing load of oxidative stress. Study also highlights the anti-acetylcholinesterase potential of curcumin which may be responsible for improved memory function following UCMS.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Curcumina/farmacologia , Depressão/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Depressão/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Ratos Wistar , Estresse Psicológico/metabolismo
11.
Behav Neurol ; 2019: 9546761, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781295

RESUMO

Cu-Zhi-Yi-Hao (CZYH), an empirical formula of traditional Chinese medicine (TCM), has been used for amnesia treatment in clinical practice. However, its underlying pharmacological mechanism has not been fully illuminated. The current study was designed to investigate the neuroprotective effect of CZYH on a ß-amyloid 25-35- (Aß 25-35-) induced learning and memory deficit rat model. CZYH (200, 400, or 800 mg/kg), donepezil (1.0 mg/kg), or distilled water was given to Aß 25-35-stimulated animals for 17 days consecutively. The Morris water maze test revealed that CZYH (400 or 800 mg/kg) administration improved the Aß 25-35-induced cognitive impairments in rats, and Nissl staining demonstrated that CZYH mitigated the Aß-caused neuron loss. In addition, CZYH treatment markedly inhibited the activation of microglia as evidenced by a decreased level of IBA-1 and increased YM-1/2 protein expression. The protein expression levels of TNF-α, IL-1ß, and COX-2 were also repressed by CZYH. Besides, CZYH treatment alleviated Aß-induced IκB-α degradation and NF-κB p65 phosphorylation, as well as reduced the JNK phosphorylation level. In conclusion, the present study suggests that CZYH could improve learning and memory abilities and relieve neuron loss in Aß 25-35-induced rats, at least partly through inhibition of the neuroinflammatory response via inhibiting the JNK-dependent NF-κB activation, indicating that CZYH might be a promising formula for the treatment of AD.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , China , Disfunção Cognitiva/metabolismo , Ciclo-Oxigenase 2/metabolismo , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa/métodos , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
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
13.
Bull Exp Biol Med ; 167(5): 641-644, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31625062

RESUMO

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.


Assuntos
Ansiolíticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Nootrópicos/farmacologia , Oligopeptídeos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Alcoolismo/tratamento farmacológico , Alcoolismo/etiologia , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Animais , Animais não Endogâmicos , Ansiolíticos/síntese química , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/síntese química , Oligopeptídeos/síntese química , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Tuftsina/química , Tuftsina/metabolismo
14.
J Pharm Pharmacol ; 71(11): 1695-1705, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31531878

RESUMO

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder with no cure. Limited treatment options available today do not offer solutions to slow or stop any of the suspected causes. The current medications used for the symptomatic treatment of AD include memantine and acetylcholine esterase inhibitors. Some studies suggest that melatonin could also be used in AD patients due to its sleep-improving properties. METHODS: In this study, we evaluated whether a combination of memantine with melatonin, administered for 32 days in drinking water, was more effective than either drug alone with respect to Aß aggregates, neuroinflammation and cognition in the double transgenic APP/PS1 (5xFAD) mouse model of AD. KEY FINDINGS: In this study, chronic administration of memantine with melatonin improved episodic memory in the object recognition test and reduced the number of amyloid aggregates and reactive microgliosis in the brains of 5xFAD mice. Although administration of memantine or melatonin alone also reduced the number of amyloid aggregates and inflammation in brain, this study shows a clear benefit of the drug combination, which had a significantly stronger effect in this amyloid-dominant mouse model of AD. CONCLUSION: Our data suggest considerable potential for the use of memantine with melatonin in patients with AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Melatonina/farmacologia , Memantina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurônios/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia
15.
Arq Neuropsiquiatr ; 77(9): 601-608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553389

RESUMO

OBJECTIVE: Hypothalamic inflammation and glial fibrillary acidic protein (GFAP) overexpression in astrocytes are well described in obese animals, as are some cognitive and memory deficits. As the hippocampus plays important roles in the consolidation of information, this investigation aimed to observe the memory function and the astrocyte expression of GFAP in the hippocampus of rats that received either a hypercaloric or a normocaloric diet. METHODS: Adult male Wistar rats received a high-fat (cafeteria) or a standard diet for 60 days. On the 61st day, the rats were submitted to the novel object recognition (NOR) test at three and 24 hours after the first contact with objects, to assess short-term and long-term memory, respectively. Thereafter, the rats were euthanized and their brains were collected for GFAP immunohistochemical investigation in the hippocampus (CA1, CA2, CA3 areas) and hypothalamus (periventricular and arcuate nuclei). Astrocytic reactivity was assessed by morphometry. Different white adipose tissue depots and brown adipose tissue were weighed to calculate the adiposity index. RESULTS: The hypercaloric diet increased body weight gain, adiposity index, white adipose tissue weight (epididymal, subcutaneous and retroperitoneal) and brown adipose tissue weight. Rats fed with the hypercaloric diet showed short-term and long-term memory impairments in the NOR test, as well as increased GFAP expression in astrocytes from all analyzed hypothalamic and hippocampal areas. CONCLUSION: This astrogliosis suggests that the neuroinflammatory response also occurs in the hippocampus and may be involved in the memory losses observed in obese/overweight animals.


Assuntos
Astrócitos/química , Dieta Hiperlipídica/efeitos adversos , Proteína Glial Fibrilar Ácida/análise , Hipocampo/citologia , Transtornos da Memória/etiologia , Obesidade/complicações , Tecido Adiposo/metabolismo , Animais , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Masculino , Transtornos da Memória/metabolismo , Obesidade/metabolismo , Ratos Wistar , Valores de Referência , Fatores de Tempo
16.
PLoS One ; 14(9): e0217190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31498792

RESUMO

Neuropsychiatric systemic lupus erythematosus (NPSLE) is associated with learning and memory deficit. Murine model of lupus induced by pristane in BALB/c mice is an experimental model that resembles some clinical and immunological SLE pathogenesis. Nevertheless, there is no experimental evidence that relates this model to cognitive dysfunction associated with NR2A/2B relative expression. To evaluate cognitive impairment related to memory deficits in a murine model of lupus induced by pristane in BALB/c mice related to mRNA relative expression levels of NR2A/2B hippocampal subunits in short and long-term memory task at 7 and 12 weeks after LPS exposition in a behavioral test with the use of Barnes maze. A total of 54 female BALB/c mice 8-12 weeks old were included into 3 groups: 7 and 12 weeks using pristane alone (0.5 mL of pristane) by a single intraperitoneal (i.p.) injection. A control group (single i.p. injection of 0.5 mL NaCl 0.9%) and pristane plus LPS exposure using single i.p. pristane injection and LPS of E. coli O55:B5, in a dose of 3mg/kg diluted in NaCl 0.9% 16 weeks post-pristane administration. To determine cognitive dysfunction, mice were tested in a Barnes maze. Serum anti-Sm antibodies and relative expression of hippocampal NR2A/2B subunits (GAPDH as housekeeping gene) with SYBR green quantitative reverse transcription polymerase chain reaction and 2-ΔΔCT method were determined in the groups. Downregulation of hippocampal NR2A subunit was more evident than NR2B in pristane and pristane+LPS at 7 and 12 weeks of treatment and it is related to learning and memory disturbance assayed by Barnes maze. This is the first report using the murine model of lupus induced by pristane that analyzes the NMDA subunit receptors, finding a downregulation of NR2A subunit related to learning and memory disturbance being more evident when they were exposed to LPS.


Assuntos
Disfunção Cognitiva/genética , Hipocampo/metabolismo , Lúpus Eritematoso Sistêmico/genética , Transtornos da Memória/genética , Receptores de N-Metil-D-Aspartato/genética , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Expressão Gênica , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/administração & dosagem , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/fisiopatologia , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Receptores de N-Metil-D-Aspartato/metabolismo , Terpenos/administração & dosagem
17.
Life Sci ; 235: 116819, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473194

RESUMO

AIMS: Traumatic brain injury (TBI) not only induces physiological disabilities but also leads to cognitive impairment. However, no effective therapeutic approach for TBI-related memory decline exists. In this study, we treated TBI mice with cinnamic acid (CNA) to detect whether CNA is able to rescue the memory deficits induced by TBI and to explore the potential mechanisms. MAIN METHODS: Mice were divided into the following groups: the sham group, the TBI group, the TBI + CNA group and the CNA group. Basic physiological parameters, neurological severity score and brain water content were analyzed. The Morris water maze and inhibitory avoidance step-down task were used to determine learning and memory. Golgi staining was used to measure alterations in dendritic spines. Western blot analysis and a commercial kit were used to detect the content and activity of HDAC2. qPCR was used to detect the relative level of miR-455. KEY FINDINGS: CNA did not affect physiological function but effectively restored neurological function and brain edema. CNA alleviated the memory impairments induced by TBI in both the Morris water maze and step-down task. CNA also recovered abnormalities in the synapses of TBI mice by suppressing the activity of HDAC2. Furthermore, CNA did not alter HDAC mRNA because it promoted the expression of miR-455-3p, a miRNA that regulates HDAC2 at the posttranscriptional level. SIGNIFICANCE: The application of CNA effectively treats TBI-induced memory deficits by increasing miR-455-3p and by inhibiting HDAC2.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Cinamatos/farmacologia , Histona Desacetilase 2/metabolismo , Transtornos da Memória/prevenção & controle , MicroRNAs/genética , Transmissão Sináptica/efeitos dos fármacos , Animais , Histona Desacetilase 2/genética , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
18.
Neurobiol Learn Mem ; 164: 107065, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400468

RESUMO

The aim of the present study was to assess thealterations of corticolimbic microRNAs and protein expressions in the effect of scopolamine with or without stress on passive-avoidance memory in male Wistar rats. The expressions of miR-1, miR-10 and miR-26 and also the levels of p-CREB, CREB, C-FOS and BDNF in the prefrontal cortex (PFC), the hippocampus and the amygdala were evaluated using RT-qPCR and Western blotting techniques. The data showed that the administration of a muscarinic receptor antagonist, scopolamine or the exposure to 30 min stress significantly induced memory loss. Interestingly, the injection of an ineffective dose of scopolamine (0.5 mg/kg) alongside with exposure to an ineffective time of stress (10 min) impaired memory formation, suggesting a potentiative effect of stress on scopolamine response. Our results showed that memory formation was associated with the down-regulated expression of miR-1, miR-10 and miR-26 in the PFC and the hippocampus, but not the amygdala. The relative expression increase of miR-1 and miR-10 in the PFC and the hippocampus was shown in memory loss induced by scopolamine administration or 30-min stress. The PFC level of miR-10 and also hippocampal level of miR-1 and miR-10 were significantly up-regulated, while amygdala miR-1 and miR-26 were down-regulated in scopolamine-induced memory loss under stress. Memory formation increased BDNF, C-FOS and p-CREB/CREB in the PFC, the hippocampus and the amygdala. In contrast, the PFC, hippocampal and amygdala protein expressions were significantly decreased in memory loss induced by scopolamine administration (2 mg/kg), stress exposure (for 30 min) or scopolamine (0.5 mg/kg) plus stress (10 min). One of the most significant findings to emerge from this study is that the stress exposure potentiated the amnesic effect of scopolamine may via affecting the expressions of miRs and proteins in the PFC, the hippocampus and the amygdala. It is possible to hypothesis that corticolimbic signaling pathways play a critical role in relationship between stress and Alzheimer's disease.


Assuntos
Sistema Límbico/metabolismo , Transtornos da Memória/metabolismo , MicroRNAs/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Límbico/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Antagonistas Muscarínicos/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Escopolamina/administração & dosagem , Estresse Psicológico/induzido quimicamente
19.
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
20.
Nutrients ; 11(8)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426549

RESUMO

The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-ß (Aß). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aß42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aß-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aß-related memory decline, the modifications of IRS1 may be a marker of early detection of Aß42 elevation prior to the onset of memory decline in AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Transtornos da Memória/metabolismo , Memória , Envelhecimento , Doença de Alzheimer/complicações , Animais , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Transtornos da Memória/etiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação , Serina/metabolismo , Transdução de Sinais
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