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1.
Life Sci ; 265: 118844, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33278389

RESUMO

AIMS: Methamphetamine (METH) has become a major public health problem because of its abuse and profound neurotoxic effects, causing alterations in brain structure and function, and impairing cognitive functions, including attention, decision making, emotional memory, and working memory. This study aimed to determine whether melatonin (MEL), the circadian-control hormone, which has roles beyond circadian rhythm regulation, could restore METH-induced cognitive and neuronal impairment. MAIN METHODS: Mice were treated with either METH (1 mg/kg) or saline for 7 days, followed by MEL (10 mg/kg) or saline for another 14 days. The Morris water maze (MWM) test was performed one day after the last saline or MEL injection. The hippocampal neuronal density, synaptic density, and receptors involved in learning and memory, along with downstream signaling molecules (NMDA receptor subunits GluN2A, GluN2B, and CaMKII) were investigated by immunoblotting. KEY FINDINGS: METH administration significantly extended escape latency in learning phase and reduced the number of target crossings in memory test-phase as well as decreased the expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin, and synaptophysin. MEL treatment significantly ameliorated METH-induced increased escape latency, decreased the number of target crossings and decreased expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin and synaptophysin. SIGNIFICANCE: METH administration impairs learning and memory in mice, and MEL administration restores METH-induced neuronal impairments which is probably through the changes in BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin and synaptophysin. Therefore, MEL is potentially an innovative and promising treatment for learning and memory impairment of humans.


Assuntos
Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Metanfetamina/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Cognição/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/patologia
2.
Sci Rep ; 10(1): 16424, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009465

RESUMO

Trigonelline (TGN; 1-methylpyridin-1-ium-3-carboxylate) is a widely distributed alkaloid derived from plants. Since we previously found a neurite outgrowth effect of TGN, we hypothesised that TGN might help to improve memory deficits. Here, the efficacy of TGN in restoring amyloid ß (Aß)-induced axonal degeneration and in improving memory function was investigated in Alzheimer's disease 5XFAD model mice that overexpress mutated APP and PS1 genes. Exposure of Aß25-35 for 3 days induced atrophy of axons and dendrites. Post treatment of TGN recovered the lengths of axons and dendrites. Following oral administration of TGN in mice, TGN itself was detected in the plasma and cerebral cortex. Oral administration of TGN to 5XFAD mice for 14 days showed significant improvement in object recognition memory (P < 0.001) and object location memory (P < 0.01). TGN administration also normalised neurofilament light levels in the cerebral cortex (P < 0.05), which is an axonal damage-associated biomarker. Analysis of target proteins of TGN in neurons by a drug affinity responsive target stability (DARTS) method identified that creatine kinase B-type (CKB) is a direct binding protein of TGN. Treatment with a CKB inhibitor cancelled the TGN-induced axonal and dendritic growth. In conclusion, we found for the first time that TGN penetrates the brain and may activate CKB, leading to axonal formation. This study shows the potential of TGN as a new drug candidate, and a new target molecule, CKB, in memory recovery signalling.


Assuntos
Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Córtex Cerebral/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Alcaloides/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Atrofia/tratamento farmacológico , Atrofia/metabolismo , Axônios/efeitos dos fármacos , Axônios/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo
3.
J Food Sci ; 85(11): 4009-4017, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33051874

RESUMO

The antioxidant-mediated neuroprotective effect of Allium cepa outer scale extract (ACE) in mice with cerebral ischemia-reperfusion (I-R) injury was demonstrated in our earlier work. The current investigation aimed at establishing the bioactive component(s) responsible for this activity. Thus ACE was fractionated into ethyl acetate (EF) and aqueous (AF) fractions. These fractions were evaluated against cerebral I-R injury in mice. I-R injury in mice was induced by bilateral common carotid artery occlusion followed by 24 hr reperfusion. Memory, sensorimotor functions, cerebral infarct size, and oxidative stress were measured to address the neuroprotective mechanism of test substances. EF showed marked improvement of memory and sensorimotor functions by reducing brain oxidative stress and infarct size in mice after I-R injury. The bioactive EF was subjected to chromatographic (HPLC-PDA, HPLC-MS, preparative HPLC) and spectroscopic studies to isolate and identify the neuroprotective compounds. This lead to separation of three components, namely quercetin, quercetin 4'-O-glucoside, and the remaining fraction, from EF. The separated components were biologically evaluated. These components showed improvement in mice with I-R injury. But, EF displayed more marked neuroprotective effects as compared to the isolated components. The distinct neuroprotective outcome of EF may be credited to the synergistic action of compounds present in EF. Further studies such as evaluation of neurotoxic effects and other possible neuroprotective mechanisms are required to develop EF as a neuroprotective drug.


Assuntos
Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Cebolas/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/isolamento & purificação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/psicologia
4.
Chemosphere ; 254: 126608, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957262

RESUMO

Al2O3 Nanoparticles (Al2O3-NPs) have been widely used because of their unique physical and chemical properties, and Al2O3-NPs can be released into the environment directly or indirectly. Our previous research found that 13 nm Al2O3-NPs can induce neural cell death and autophagy in primarily cultured neural cells in vitro. The aim of this study was to determine where Al2O3-NPs at 13 nm particle size can cause neural cells in vivo and assess related behavioural changes and involved potential mechanisms. Zebrafish from embryo to adult were selected as animal models. Learning and memory as functional indicators of neural cells in zebrafish were measured during the development from embryo to adult. Our results indicate that Al2O3-NPs treatment in zebrafish embryos stages can cause the accumulation of aluminium content in zebrafish brain tissue, leading to progressive impaired neurodevelopmental behaviours and latent learning and memory performance. Additionally, oxidative stress and disruption of dopaminergic transmission in zebrafish brain tissues are correlated with the dose-dependent and age-dependent accumulation of aluminium content. Moreover, the number of neural cells in the telencephalon tissue treated with Al2O3-NPs significantly declined, and the ultramicroscopic morphology indicated profound autophagy alternations. The results suggest that Al2O3-NPs has dose-dependent and time-dependent progressive damage on learning and memory performance in adult zebrafish when treated in embryos. This is the first study of the effects of Al2O3-NPs on learning and memory during the development of zebrafish from embryo to adult.


Assuntos
Óxido de Alumínio/toxicidade , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Nanopartículas/toxicidade , Alumínio/farmacologia , Óxido de Alumínio/química , Animais , Embrião não Mamífero , Nanopartículas Metálicas , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Peixe-Zebra/embriologia
5.
Sci Rep ; 10(1): 15957, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994439

RESUMO

Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.


Assuntos
/administração & dosagem , Memória/efeitos dos fármacos , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Quercetina/administração & dosagem , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Expressão Gênica , Glutationa Peroxidase/metabolismo , Masculino , Memória/fisiologia , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quercetina/química , Ratos , Ratos Wistar , Superóxido Dismutase-1/metabolismo
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 235-239, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981278

RESUMO

Objective: To investigate the effects of exogenous NaHS on myelin basic protein (MBP) and learning and memory of hippocampal neurons in mice with spinocerebellar ataxia type 3 (SCA3) and its therapeutic significance.Methods: Twelve male normal mice were randomly selected as normal control group (NC Group), and 48 SCA3 mice were randomly selected as SCA3 model group (M Group), low dose group (NL Group, 10 µmol/kg), medium dose group (NM Group, 50µmol/kg) and high dose group (NH Group, 100 µmol/kg), 12 rats in each group. The drug treated groups were injected with NaHS intraperitoneally once a day for 4 weeks. The changes of learning and memory ability of SCA3 mice before and after the intervention of different doses of NaHS were determined by Morris water maze, the content of hydrogen sulfide (H2S) in hippocampus was measured by spectrophotometry, the expression of MBP was detected by immunohistochemistry, and the morphological changes of neuron myelin sheath were observed by electron microscope. Results: Compared with the control group, the learning and memory ability of SCA3 mice was decreased significantly (P<0.05), and the content of H2S in hippocampus was decreased (P<0.05). After different doses of exogenous NaHS treatment, the learning and memory ability was improved in different degrees (P<0.05), and the contents of H2S and MBP in hippocampus of SCA3 mice were also improved in different degrees (P<0.05). Conclusion: Exogenous NaHS may increase the contents of H2S and MBP in the hippocampus of SCA3 mice, which may have a protective effect on the neurons, and then improve the learning and memory ability of SCA3 mice, and provide a new idea for the treatment of SCA3.


Assuntos
Sulfeto de Hidrogênio , Aprendizagem , Memória , Ataxias Espinocerebelares , Sulfetos , Animais , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Proteína Básica da Mielina , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ataxias Espinocerebelares/tratamento farmacológico , Sulfetos/farmacologia , Sulfetos/uso terapêutico
7.
J Neuroimmunol ; 348: 577390, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32956951

RESUMO

Gut-Brain-Axis imbalance due to gut dysbiosis by antibiotics may lead to neurobehavioral changes. Here we determine neuroprotective effect of probiotic against gut dysbiosis associated decline in learning and memory. Oral Ampicillin was used to induce gut dysbiosis while probiotic was administered along with antibiotic as treatment in Swiss albino mice. Antibiotic decreased Lactobacillus, Bifidobacterium, Firmicutes and Clostridium level. This was followed by reduced cognition, hippocampal neuronal density, intestinal crypt depth, villus length and increased corticohippocampal acetylcholinesterase, myeloperoxidase activity and oxidative stress which were partially reversed by probiotic treatment. Probiotic protected hippocampal neurons from gut dysbiosis associated inflammatory and oxidative damage in mice.


Assuntos
Disbiose/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Probióticos/farmacologia , Ampicilina/toxicidade , Animais , Antibacterianos/toxicidade , Disbiose/complicações , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos
8.
Toxicol Lett ; 335: 11-27, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949623

RESUMO

Lead is a toxin of great public health concern affecting the young and aging population. Several factors such as age, gender, lifestyle, dose, and genetic makeup result in interindividual variations to lead toxicity mainly due to variations in metabolic consequences. Hence, the present study aimed to examine dose-dependent lead-induced systemic changes in metabolism using rat model by administering specific doses of lead such as 10 (low lead; L-Pb), 50 (moderate lead; M-Pb), and 100 mg/kg (high lead; H-Pb) body weight for a period of one month. Biochemical and haematological analysis revealed that H-Pb was associated with low body weight and feed efficiency, low total protein levels (p ≤ 0.05), high blood lead (Pb-B) levels (p ≤ 0.001), low ALAD (δ-aminolevulinate dehydratase) activity (p ≤ 0.0001), high creatinine (p ≤ 0.0001) and blood urea nitrogen (BUN) (p ≤ 0.01) levels, elevated RBC and WBC counts, reduced haemoglobin and blood cell indices compared to control. Spatial learning and memory test revealed that H-Pb exposed animals presented high latency to the target quadrant and escape platform compared to other groups indicating H-Pb alters cognition function in rats. Histopathological changes were observed in liver and kidney as they are the main target organs of lead toxicity. LC-MS analysis further revealed that Butyryl-L-carnitine (p ≤ 0.01) and Ganglioside GD2 (d18:0/20:0) (p ≤ 0.05) levels were significantly reduced in H-Pb group compared to all groups. Further, pathway enrichment analysis revealed abundance and significantly modulated metabolites associated with oxidative stress pathways. The present study is the first in vivo model of dose-dependent lead exposure for serum metabolite profiling.


Assuntos
Rim/efeitos dos fármacos , Intoxicação por Chumbo/metabolismo , Chumbo/toxicidade , Fígado/efeitos dos fármacos , Nitratos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Rim/metabolismo , Rim/patologia , Chumbo/sangue , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metabolômica , Nitratos/sangue , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
9.
PLoS One ; 15(9): e0239270, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936829

RESUMO

In a between-subject comparison of two memantine administration schedules we observed that treatment with the NMDA receptor antagonist memantine before testing sessions reduced ingestion of a 10% sucrose solution in rats, due to reduced licking burst size, thus suggesting a blunted hedonic response. Conversely, daily post-session administration reduced burst number, indicating a reduced level of behavioural activation, likely due to the development of conditioned taste aversion (CTA). In this study, the effect of pre-session and post-session memantine administration was investigated within-subjects. Memantine was administered in daily intraperitoneal injections for 13 days, on alternate days, either 1-h before-"before testing" sessions-or immediately after a 30-min session-"after testing" sessions. The effects on the microstructure of licking for a 10% sucrose solution were examined in the course of treatment and for 21 days after treatment discontinuation. The results show reduced burst size in the "before testing" sessions, without effects on the intra-burst lick rate, an index of motoric effects. Moreover, burst number was reduced since the third session of both administration conditions until the end of treatment. Interestingly, the effect of memantine of reducing the activation of ingestive behaviour was less pronounced in this study with respect to that observed with the previous study post-session administration schedule, in spite of the longer treatment. This apparent paradox might be explained if one considers these effects as instances of a memory-related effect, such as the development of CTA. In the framework of this hypothesis, the "before testing" sessions, not being followed by memantine administration, can be considered as extinction sessions performed every other day. Moreover, the animals treated with memantine at the highest dose failed to recover to pre-treatment ingestion levels 21 days after treatment discontinuation, while the animals treated after testing sessions in the previously published study showed a complete recovery well before the 15th day test. Within the same interpretative framework, this might depend by the reduced number and frequency of the extinction trials-i.e. the number of the sessions run after treatment discontinuation-in the present study. These results provide further support to the conclusion that memantine administration before sessions reduce burst size, an effect which is likely due to blockade of NMDA receptors occurring during behavioural testing. The observation that this effect can be obtained even in absence of a reduced intra-burst lick rate, which rules out the involvement of motor impairment, provides an important piece of evidence in support to the interpretation of this effect as a blunted hedonic response. Moreover, these results provide further evidence that burst number reduction is due to a memory-related effect induced by memantine administration after sessions.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Memantina/farmacologia , Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Ingestão de Alimentos , Humanos , Memantina/efeitos adversos , Memória/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/genética
10.
Phytomedicine ; 79: 153324, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920292

RESUMO

BACKGROUND: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs. PURPOSE: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aß1-42) peptide-infused AD rat hippocampus. STUDY DESIGN: A micro-osmotic pump containing aggregated Aß1-42 was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days. METHODS: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively. RESULTS: Administration of TQ enhanced the memory performance of Aß1-42 infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aß1-42-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aß1-42-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aß, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3ß or MAPK signaling pathways which were affected due to Aß1-42 infusion. CONCLUSION: TQ has the capacity to recover the neuropathology by removing Aß plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzoquinonas/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley
11.
Sci Rep ; 10(1): 15070, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934245

RESUMO

Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) have an ameliorative effect on diabetes-induced memory impairment. The current study aimed to compare the effect of quercetin (QC) and QCSPIONs on inflammation-related microRNAs and NF-κB signaling pathways in the hippocampus of diabetic rats. The expression levels of miR-146a, miR-9, NF-κB, and NF-κB-related downstream genes, including TNF-α, BACE1, AßPP, Bax, and Bcl-2 were measured using quantitative real-time PCR. To determine the NF-κB activity, immunohistochemical expression of NF-κB/p65 phosphorylation was employed. Computer simulated docking analysis also performed to find the QC target proteins involved in the NF-κB pathway. Results indicate that diabetes significantly upregulated the expression levels of miR-146a, miR-9, TNF-α, NF-κB, and subsequently AßPP, BACE1, and Bax. Expression analysis shows that QCSPIONs are more effective than pure QC in reducing the expression of miR-9. Interestingly, QCSPIONs reduce the pathological activity of NF-κB and subsequently normalize BACE1, AßPP, and the ratio of Bax/Bcl-2 expression better than pure QC. Comparative docking analyses also show the stronger binding affinity of QC to IKK and BACE1 proteins compared to specific inhibitors of each protein. In conclusion, our study suggests the potent efficacy of QCSPIONs as a promising drug delivery system in memory improvement through targeting the NF-κB pathway.


Assuntos
Sistemas de Liberação de Medicamentos , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , MicroRNAs , NF-kappa B , Quercetina , Transdução de Sinais/efeitos dos fármacos , Animais , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Quercetina/química , Quercetina/farmacologia , Ratos , Ratos Wistar
12.
Sci Rep ; 10(1): 13485, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778662

RESUMO

Chronic social defeat (CSD) in mice has been suggested as a model for studying post-traumatic stress disorder (PTSD). Our previous work indicated that exposure to Lactobacillus rhamnosus JB-1 (JB-1) during CSD can attenuate subsequent behavioural and immune disruption, suggesting a potential for microbe based therapeutic approaches in PTSD. In the current study, we assessed the ability of JB-1 to mitigate the behavioral consequences of CSD when treatment is instigated in the early post-stress period and compared the probiotic effects with those of the selective serotonin reuptake inhibitor (SSRI), sertraline. JB-1 or sertraline were administered orally 48 h following 10-days of CSD in male C57BL/6 mice. Contrary to our hypothesis of a beneficial effect, 30 days of treatment with either JB-1 or sertraline increased the persistence of both aggressor avoidance and reduced sociability in defeated mice. This was accompanied by lower hippocampal mRNA expression for genes related to fear memory. Defeated mice treated with either JB-1 or sertraline also exhibited systemic immune changes, with a decrease in Th1 cells, activated monocytes, and the monocyte chemoattractant CCL2. This study identifies potentially detrimental effects of both JB-1 and sertraline if administered in the early post-trauma period and suggests caution should be applied when considering psychobiotic or SSRI based approaches for early intervention in trauma related psychiatric disorders.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Oligopeptídeos/farmacologia , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Lactobacillus rhamnosus/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Captação de Serotonina/farmacologia , Sertralina/farmacologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/complicações
13.
Psychopharmacology (Berl) ; 237(10): 3057-3065, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772146

RESUMO

RATIONALE: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. OBJECTIVE: This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. RESULTS: Neither MCAM (0.32 mg/kg) nor morphine (1-5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01-0.056 mg/kg) and phencyclidine (0.1-0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. CONCLUSIONS: MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.


Assuntos
Cinamatos/farmacologia , Memória/efeitos dos fármacos , Derivados da Morfina/farmacologia , Morfina/antagonistas & inibidores , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Relação Dose-Resposta a Droga , Feminino , Macaca mulatta , Masculino , Memória/fisiologia , Receptores Opioides mu/fisiologia , Reforço Psicológico , Autoadministração
14.
BMC Womens Health ; 20(1): 177, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795281

RESUMO

BACKGROUND: There may be changes in cognitive function in women going through the menopause. The current evidence remains unclear, however, whether these changes occur over and above those of general ageing. We aimed to evaluate the potential impact of the menopause (assessed by reproductive age and hormone levels) on cognitive function in women in mid-life accounting for the underlying effects of ageing. METHODS: The study was based on the follow up of women originally enrolled in pregnancy in a birth cohort when resident in the South West of England, UK between 1991 and 1992. Using up to three repeated measurements in 2411 women (mean age 51 at first assessment), we modelled changes in six cognitive function domains: immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence and verbal fluency. The exposures of interest were reproductive age measured as years relative to the final menstrual period (FMP), chronological age and reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)). RESULTS: Processing speed (- 0.21 (95% CI - 0.36 to - 0.06) standard deviation (SD) difference per 10 years since FMP), immediate verbal episodic memory (- 0.15 (95% CI - 0.35 to 0.06)) and delayed verbal episodic memory (- 0.17 (95% CI - 0.37 to 0.03)) declined with reproductive age. Reproductive hormones were not robustly associated with processing speed, but FSH and LH were both negatively associated with immediate (- 0.08 (95% CI - 0.13 to - 0.02) SD difference per SD difference in hormone level) and delayed verbal episodic memory (- 0.08 (95% CI - 0.13 to - 0.03)). There was little consistent evidence of cognitive function declining with menopause in other cognitive domains. CONCLUSIONS: Of the cognitive domains tested only verbal episodic memory declined both in relation to age since the menopause and in conjunction with the reproductive hormones that reflect the menopause. This decline was independent of normal ageing and suggests that the menopause is associated with a mild impact on this specific domain of cognitive function.


Assuntos
Envelhecimento/fisiologia , Cognição/efeitos dos fármacos , Hormônios/fisiologia , Menopausa/efeitos dos fármacos , Inglaterra , Terapia de Reposição de Estrogênios , Feminino , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Humanos , Estudos Longitudinais , Memória/efeitos dos fármacos , Memória/fisiologia , Memória Episódica , Menopausa/fisiologia , Pessoa de Meia-Idade , Reino Unido
15.
Life Sci ; 257: 118046, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622948

RESUMO

Orexin-A is an endogenous peptide with receptors throughout the brain. According to some recent research, learning and memory are affected by the central administration of orexin; however, no study so far has investigated the long-term inhibition of the orexinergic system. The present study has evaluated the effect of pretraining administration of orexin 1 receptor (OXR1) antagonist, SB-334867, on the acquisition of memory. The Morris water maze (MWM) task was used for training and trial purposes in all groups. Memory performance was analyzed by measuring escape latency, traveled distance, and time spent in the target quadrant. Moreover, the effect of SB-334867 on phospholipase Cß3 (PLCß3) levels in the CA1 region of hippocampus slices was examined. Hippocampus slices were prepared using an immunohistochemistry (IHC) approach. SB-334867 (20 mg/kg) increased escape latency in SB-treated rats compared to SB-vehicle group (P < 0.01). SB-treated rats spent less time in the target quadrant compared to the SB-vehicle group (P < 0.001). Distance traveled in the target quadrant was significantly more in SB-treated rats compared to the SB-vehicle group (P < 0.001). Furthermore, SB-334867 decreased PLCß3 levels in the CA1 of the hippocampus (P < 0.01 and P < 0.05, respectively). Put together, our results suggest that the long-term inhibition of OXR1 plays a prominent role in spatial learning and memory, probably by attenuating PLCß3 in CA1 neurons.


Assuntos
Memória/efeitos dos fármacos , Memória/fisiologia , Fosfolipase C beta/metabolismo , Animais , Benzoxazóis/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Fosfolipase C beta/fisiologia , Ratos , Ratos Wistar , Ureia/análogos & derivados , Ureia/farmacologia
16.
Life Sci ; 257: 118049, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634430

RESUMO

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.


Assuntos
Concussão Encefálica/tratamento farmacológico , Cognição/efeitos dos fármacos , Silimarina/uso terapêutico , Animais , Animais não Endogâmicos , Concussão Encefálica/metabolismo , Lesões Encefálicas/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fatores Sexuais , Silimarina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
PLoS One ; 15(7): e0236251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692754

RESUMO

This study investigated the effects of kaempferol and zinc gluconate on neurobehavioural and oxidative stress changes in Wistar rats exposed to noise. Thirty (30) rats were randomly divided into five groups: Groups I and II were administered with deionized water (DW); Group III, kaempferol (K); Group IV, zinc gluconate (Zn); Group V, kaempferol + zinc gluconate. Groups II, III, IV, and V were subjected to noise stress (N) induced by exposing rats to 100 dB (4 h/day) for 15 days, from day 33 to day 48 after starting the drug treatments. Neuromuscular coordination, motor coordination, motor strength, sensorimotor reflex, and learning and memory, were evaluated using standard laboratory methods. Levels of nitric oxide (NO), malondialdehyde (MDA) and activities of glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were evaluated in the hippocampus. Exposure of rats to noise, induced significant neurobehavioural deficits and oxidative stress while the combined administration of kaempferol and zinc gluconate significantly (P < 0.05) improved open-field performance, motor coordination, motor strength, sensorimotor reflex, and learning and memory. Co-administration of kaempferol and zinc gluconate ameliorated noise-induced oxidative stress as demonstrated by the significantly increased activities of GPx, catalase, and SOD, and decreased levels of NO and MDA (P < 0.05 and P < 0.01 respectively), compared to the DW + N group. Our results suggest that oxidative stress, evidenced by increased NO and MDA concentration and decreased activities of GPx, catalase and SOD, were involved in the molecular mechanism underlying neurobehavioural impairment in Wistar rats, exposed to noise stress. Single treatment of kaempferol exerted a more potent mitigative effect than zinc gluconate, while their combination produced an improved outcome.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Gluconatos/farmacologia , Quempferóis/farmacologia , Ruído/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Reflexo/efeitos dos fármacos , Zinco/farmacologia
18.
Toxicology ; 442: 152532, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619457

RESUMO

Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats.


Assuntos
Antioxidantes/uso terapêutico , Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Biogênese de Organelas , Resveratrol/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Gravidez , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
19.
Proc Natl Acad Sci U S A ; 117(30): 18029-18036, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665437

RESUMO

Memory reconsolidation occurs when a retrieving event destabilizes transiently a consolidated memory, triggering thereby a new process of restabilization that ensures memory persistence. Although this phenomenon has received wide attention, the effect of new information cooccurring with the reconsolidation process has been less explored. Here we demonstrate that a memory-retrieving event sets a neural tag, which enables the reconsolidation of memory after binding proteins provided by the original or a different contiguous experience. We characterized the specific temporal window during which this association is effective and identified the protein kinase A (PKA) and the extracellular signal-regulated kinase 1 and 2 (ERK 1/2) pathways as the mechanisms related to the setting of the reconsolidation tag and the synthesis of proteins. Our results show, therefore, that memory reconsolidation is mediated by a "behavioral tagging" process, which is common to different memory forms. They represent a significant advance in understanding the fate of memories reconsolidated while being adjacent to other events, and provide a tool for designing noninvasive strategies to attenuate (pathological/traumatic) or improve (education-related) memories.


Assuntos
Comportamento , Consolidação da Memória/fisiologia , Memória/fisiologia , Animais , Biomarcadores , Masculino , Memória/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Ratos
20.
Psychopharmacology (Berl) ; 237(10): 2959-2966, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700022

RESUMO

BACKGROUND: Ethanol use disorders are a serious medical and public health problem in the world today. Acute ethanol intoxication can lead to cognitive dysfunction such as learning and memory impairment. Gamma oscillations (γ, 30-80 Hz) are synchronized rhythmic activity generated by population of neurons within local network, and closely related to learning and memory function. The hippocampus is a critical anatomic structure that supports learning and memory. On the grounds of structure and function, hippocampus can be divided into the intermediate (IH), the dorsal (DH), and ventral hippocampus (VH). The current study is the first to investigate the effects of acute ethanol on γ oscillations in these sub-regions of rat hippocampal slices. METHODS: The sustained γ oscillations were induced by 200 nM kainate (KA) in the CA3c of IH, DH, and VH. When KA-induced γ oscillation reached the steady state, ethanol (50 mM or 100 mM) was applied and the effects of ethanol on γ oscillation power was measured in the slices sequentially sectioned from ventral to dorsal hippocampus of adult rats. RESULTS: In the intermediate hippocampal slices, compared with control (KA only), ethanol (50 mM) caused 36.1 ± 3.9% decrease in γ power (p < 0.05, n = 10), while ethanol (100 mM) caused 55.3 ± 5.5% decrease in γ power (p < 0.001, n = 14). In the dorsal hippocampus, only ethanol (100 mM) caused 18.1 ± 8.6% decrease in γ power (p < 0.05, n = 12). However, in the ventral hippocampus, neither 50 mM nor 100 mM ethanol affected γ oscillation. CONCLUSIONS: Our results demonstrate that ethanol may produce the differential suppression of γ oscillations in a dose-dependent manner in different sub-regions of hippocampus, suggesting that the modulation of ethanol on hippocampal γ oscillation is region-dependent.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Ritmo Gama/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Ritmo Gama/fisiologia , Hipocampo/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
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