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1.
J Chem Neuroanat ; 119: 102043, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34808256

RESUMO

The purpose of this study was to highlight the possible effects on the hippocampus of the electromagnetic field (EMF) emitted by mobile phones, and to investigate whether these potential effects can be reduced using various antioxidant substances. Twenty-seven female Wistar albino rats were divided into nine equal groups, each containing three pregnant rats aged 8-10 weeks and weighing 200-250 gr. The EMF groups were exposed to 900 Megahertz (MHz) EMF for 1 h (hr) a day for 21 days. No EMF exposure was applied to the Cont and also the groups given only Garcinia kola (GK), Momordica charantia (MC), and thymoquinone (TQ). The Sham group was kept in the polycarbonate EMF exposure system, but was not exposed to EMF. Four weeks after birth, rat pups were subjected to behavioural tests. Brain tissue samples were evaluated using histological, stereological, functional, and immunohistochemical methods. The numbers of pyramidal neurons in the rat cornu ammonis (CA) were determined using the optical fractionator method. Superoxide dismutase (SOD) and catalase (CAT) enzyme activities in the blood samples were also evaluated. The analysis data indicated that total pyramidal neuron numbers were decreased significantly in the CA of the EMF (1 hr) group (p < 0.01). Our results also showed that the protective effect of MC was more potent than that of the other antioxidant substances (p < 0.01). A 900 MHz EMF can cause deleterious changes in the brain. It can also be suggested that GK, MC and TQ are capable of reducing these adverse effects.


Assuntos
Telefone Celular , Campos Eletromagnéticos , Animais , Campos Eletromagnéticos/efeitos adversos , Feminino , Hipocampo/patologia , Gravidez , Células Piramidais , Ratos , Ratos Wistar
2.
Comput Intell Neurosci ; 2022: 9325302, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685133

RESUMO

Gradual cognition decline and mitochondrial dysfunction are two notable changes closely associated with aging. Enhancing mitochondrial function has been assumed to be antiaging. However, most current mitochondria-promoting agents usually target 1-2 aspects of mitochondrial function. In the present study, we transplanted mitochondria isolated from young mice into the hippocampus of aged mice, which presumably boost mitochondrial function more thoroughly, examined the effects on cognition, and explored the possible underlying mechanism. Our data showed that exogenous mitochondria were efficiently internalized by nestin-positive neural progenitors in the hippocampus. Mitochondrial transplantation quickly increased ATP levels, enhanced the activity of mitochondrial complexes I, II, and IV, and decreased Tom20 expression in the hippocampus. In regard of cognitive function, mitochondria-treated mice displayed a remarkable improvement of novel object recognition and spatial memory. Utilizing the Wnt signaling reporting mouse line, TOPGAL mice, we detected activated canonical Wnt signaling in the neural progenitors of the mitochondria-treated hippocampus. Further, BrdU labeling showed that exogenous mitochondria significantly stimulated neural progenitor neurogenesis and proliferation. Taken together, our data demonstrated that exogenous mitochondria from young mice might be a novel way of rejuvenating the function of hippocampal neural progenitors to exert antiaging effects.


Assuntos
Disfunção Cognitiva , Via de Sinalização Wnt , Animais , Hipocampo , Camundongos , Mitocôndrias/metabolismo , Neurogênese
3.
Mol Brain ; 15(1): 50, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672792

RESUMO

Theta is one of the most prominent extracellular synchronous oscillations in the mammalian brain. Hippocampal theta relies on an intact medial septum (MS) and has been consistently recorded during the training phase of some learning paradigms, suggesting that it may be implicated in hippocampus-dependent long-term memory processing. Object recognition memory (ORM) allows animals to identify familiar items and is essential for remembering facts and events. In rodents, long-term ORM formation requires a functional hippocampus but the involvement of the MS in this process remains controversial. We found that training adult male Wistar rats in a long-term ORM-inducing learning task involving exposure to two different, but behaviorally equivalent novel stimuli objects increased hippocampal theta power, and that suppressing theta via optogenetic MS inactivation caused amnesia. Importantly, the amnesia was specific to the object the animals were exploring when the MS was inactivated. Taken together, our results indicate that the MS is necessary for long-term ORM formation and suggest that hippocampal theta activity is causally linked to this process.


Assuntos
Optogenética , Ritmo Teta , Amnésia , Animais , Hipocampo/fisiologia , Masculino , Mamíferos , Memória de Longo Prazo , Optogenética/métodos , Ratos , Ratos Wistar , Ritmo Teta/fisiologia
4.
Cells ; 11(11)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35681508

RESUMO

Hippocampus is one of the neurogenic zones where adult neurogenesis takes place. This process is quite complex and has a multicomponent regulation. A family of G protein-coupled trace amine-associated receptors (TAARs) was discovered only in 2001, and most of them (TAAR2-TAAR9) were primarily considered olfactory. Recent studies have shown, however, that they are also expressed in the mouse brain, particularly in limbic formations, and can play a role in the regulation of emotional behaviors. The observations in knockout mice indicate that at least two members of the family, TAAR2 and TAAR5, have an impact on the regulation of adult neurogenesis. In the present study, we analyzed the expression of TAARs in the murine and human hippocampus using public RNAseq datasets. Our results indicate a low but detectable level of certain TAARs expression in the hippocampal cells in selected high-quality transcriptomic datasets from both mouse and human samples. At the same time, we observed the difference between humans, where TAAR6 expression was the highest, and murine samples, where TAAR1, TAAR2, TAAR3, TAAR4 and TAAR5 are more pronouncedly expressed. These observations provide further support to the data gained in knockout mice, indicating a role of TAARs in the regulation of adult neurogenesis in the hippocampus.


Assuntos
Receptores Acoplados a Proteínas G , Transcriptoma , Aminas/metabolismo , Animais , Hipocampo/metabolismo , Humanos , Camundongos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transcriptoma/genética
5.
Int J Mol Sci ; 23(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35682647

RESUMO

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.


Assuntos
Antipsicóticos , Esquizofrenia , Animais , Antipsicóticos/efeitos adversos , Comportamento Animal , Modelos Animais de Doenças , Hipocampo , Humanos , Córtex Pré-Frontal , Esquizofrenia/tratamento farmacológico
6.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682713

RESUMO

We studied the effects of stimulation of the medial septal area on the gene expression in the dorsal and ventral hippocampus. Rats under urethane anesthesia were implanted with a recording electrode in the right hippocampus and stimulating electrode in the dorsal medial septum (dMS) or medial septal nucleus (MSN). After one-hour-long deep brain stimulation, we collected ipsi- and contralateral dorsal and ventral hippocampi. Quantitative PCR showed that deep brain stimulation did not cause any changes in the intact contralateral dorsal and ventral hippocampi. A comparison of ipsi- and contralateral hippocampi in the control unstimulated animals showed that electrode implantation in the ipsilateral dorsal hippocampus led to a dramatic increase in the expression of immediate early genes (c-fos, arc, egr1, npas4), neurotrophins (ngf, bdnf) and inflammatory cytokines (il1b and tnf, but not il6) not only in the area close to implantation site but also in the ventral hippocampus. Moreover, the stimulation of MSN but not dMS further increased the expression of c-fos, egr1, npas4, bdnf, and tnf in the ipsilateral ventral but not dorsal hippocampus. Our data suggest that the activation of medial septal nucleus can change the gene expression in ventral hippocampal cells after their priming by other stimuli.


Assuntos
Anestesia , Estimulação Encefálica Profunda , Núcleos Septais , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Expressão Gênica , Hipocampo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Septo do Cérebro/metabolismo , Uretana
7.
Int J Mol Sci ; 23(11)2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35682930

RESUMO

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer's disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background.


Assuntos
Doença de Alzheimer , Anestésicos Inalatórios , Síndromes Neurotóxicas , Doença de Alzheimer/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Anestésicos Inalatórios/efeitos adversos , Animais , Apoptose , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Camundongos , Síndromes Neurotóxicas/metabolismo , Sevoflurano/efeitos adversos
8.
Int J Mol Sci ; 23(11)2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35683023

RESUMO

As aging and cognitive decline progresses, the impact of a sedentary lifestyle on the appearance of environment-dependent cellular morphologies in the brain becomes more apparent. Sedentary living is also associated with poor oral health, which is known to correlate with the rate of cognitive decline. Here, we will review the evidence for the interplay between mastication and environmental enrichment and assess the impact of each on the structure of the brain. In previous studies, we explored the relationship between behavior and the morphological features of dentate gyrus glial fibrillary acidic protein (GFAP)-positive astrocytes during aging in contrasting environments and in the context of induced masticatory dysfunction. Hierarchical cluster and discriminant analysis of GFAP-positive astrocytes from the dentate gyrus molecular layer revealed that the proportion of AST1 (astrocyte arbors with greater complexity phenotype) and AST2 (lower complexity) are differentially affected by environment, aging and masticatory dysfunction, but the relationship is not straightforward. Here we re-evaluated our previous reconstructions by comparing dorsal and ventral astrocyte morphologies in the dentate gyrus, and we found that morphological complexity was the variable that contributed most to cluster formation across the experimental groups. In general, reducing masticatory activity increases astrocyte morphological complexity, and the effect is most marked in the ventral dentate gyrus, whereas the effect of environment was more marked in the dorsal dentate gyrus. All morphotypes retained their basic structural organization in intact tissue, suggesting that they are subtypes with a non-proliferative astrocyte profile. In summary, the increased complexity of astrocytes in situations where neuronal loss and behavioral deficits are present is counterintuitive, but highlights the need to better understand the role of the astrocyte in these conditions.


Assuntos
Astrócitos , Disfunção Cognitiva , Envelhecimento , Astrócitos/metabolismo , Disfunção Cognitiva/metabolismo , Giro Denteado/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Humanos , Comportamento Sedentário
9.
Neuropharmacology ; 214: 109153, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35661657

RESUMO

(2R,6R)-hydroxynorketamine (HNK) is a metabolite of ketamine that exerts rapid and sustained antidepressant-like effects in preclinical studies. We hypothesize that the rapid antidepressant actions of (2R,6R)-HNK involve an acute increase in glutamate release at Schaffer collateral synapses. Here, we used an optogenetic approach to assess whether (2R,6R)-HNK promotes glutamate release at CA1-projecting Schaffer collateral terminals in response to select optical excitation of CA3 afferents. The red-shifted channelrhodopsin, ChrimsonR, was expressed in dorsal CA3 neurons of adult male Sprague Dawley rats. Transverse slices were collected four weeks later to determine ChrimsonR expression and to assess the acute synaptic effects of an antidepressant-relevant concentration of (2R,6R)-HNK (10 µM). (2R,6R)-HNK led to a rapid potentiation of CA1 field excitatory postsynaptic potentials evoked by recurrent optical stimulation of ChrimsonR-expressing CA3 afferents. This potentiation is mediated in part by an increase in glutamate release probability, as (2R,6R)-HNK suppressed paired-pulse facilitation at CA3 projections, an effect that correlated with the magnitude of the (2R,6R)-HNK-induced potentiation of CA1 activity. These results demonstrate that (2R,6R)-HNK increases the probability of glutamate release at CA1-projecting Schaffer collateral afferents, which may be involved in the antidepressant-relevant behavioral adaptations conferred by (2R,6R)-HNK in vivo. The current study also establishes proof-of-principle that genetically-encoded light-sensitive proteins can be used to investigate the synaptic plasticity induced by novel antidepressant compounds in neuronal subcircuits.


Assuntos
Antidepressivos , Hipocampo , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Ácido Glutâmico/metabolismo , Ketamina/análogos & derivados , Masculino , Ratos , Ratos Sprague-Dawley
10.
Nat Commun ; 13(1): 3236, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688821

RESUMO

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.


Assuntos
Síndrome do Cromossomo X Frágil , Receptores de Glutamato Metabotrópico , Animais , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glutamato Metabotrópico/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
11.
Transl Psychiatry ; 12(1): 245, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688836

RESUMO

It is well known that neuroinflammation is closely related to the pathophysiology of depression. Due to individual differences in clinical research, the reduction of hippocampal volume in patients with depression is still controversial. In this experiment, we studied a typical kind of tricyclic antidepressant, clomipramine. We designed a series of experiments to find its role in depressive-like behavior, hippocampal neuroinflammation as well as hippocampal volume changes induced by chronic unpredictable mild stress (CMS). Rats exhibited defective behavior and hippocampal neuroinflammation after 12 weeks of CMS, which included elevated expression of cleaved interleukin-1ß (IL-1ß) and NLRP3 inflammasome together with the activation of microglia. Rats exposed to CMS showed weakened behavioral defects, reduced expression of IL-18, IL-6, and IL-1ß along with reversed activation of microglia after clomipramine treatment. This indicates that the antidepressant effect of clomipramine may be related to the reduced expression of NLRP3 inflammasome and cleaved IL-1ß. Moreover, we found an increased hippocampal volume in rats exposed to CMS after clomipramine treatment while CMS failed to affect hippocampal volume. All these results indicate that the NLRP3 inflammasome of microglia in the hippocampus is related to the antidepressant effects of clomipramine and CMS-induced depressive-like behavior in rats.


Assuntos
Clomipramina , Inflamassomos , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Clomipramina/metabolismo , Clomipramina/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Estresse Psicológico/metabolismo
12.
Nat Commun ; 13(1): 3349, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688838

RESUMO

The ability to resolve an approach-avoidance conflict is critical to adaptive behavior. The ventral CA3 (vCA3) and CA1 (vCA1) subfields of the ventral hippocampus (vHPC) have been shown to facilitate avoidance and approach behavior, respectively, in the face of motivational conflict, but the neural circuits by which this subfield-specific regulation is implemented is unknown. We demonstrate that two distinct pathways from these subfields to lateral septum (LS) contribute to this divergent control. In Long-Evans rats, chemogenetic inhibition of the vCA3- LS caudodorsal (cd) pathway potentiated approach towards a learned conflict-eliciting stimulus, while inhibition of the vCA1-LS rostroventral (rv) pathway potentiated approach non-specifically. Additionally, vCA3-LScd inhibited animals were less hesitant to explore food during environmental uncertainty, while the vCA1- LSrv inhibited animals took longer to initiate food exploration. These findings suggest that the vHPC influences multiple behavioral systems via differential projections to the LS, which in turn send inhibitory projections to motivational centres of the brain.


Assuntos
Hipocampo , Inibição Psicológica , Animais , Hipocampo/fisiologia , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans
13.
J Neuroinflammation ; 19(1): 143, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690816

RESUMO

BACKGROUND: Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice. METHODS: CD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20. RESULTS: Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system. CONCLUSIONS: These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.


Assuntos
Fármacos Neuroprotetores , Compostos de Trimetilestanho , Animais , Hipocampo/metabolismo , Camundongos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Linfócitos T Reguladores , Compostos de Trimetilestanho/metabolismo , Compostos de Trimetilestanho/toxicidade
14.
Sci Rep ; 12(1): 9142, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35650390

RESUMO

In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromised in vivo. But although LTP in blind mice was chronically impaired throughout adulthood, a recovery of the early phase of LTP became apparent when the animals reached 12 months of age. These data show that cortical and hippocampal adaptation to early postnatal blindness progresses into advanced adulthood and is a process that compromises hippocampal function. A partial recovery of hippocampal synaptic plasticity emerges in advanced adulthood, however.


Assuntos
Hipocampo , Plasticidade Neuronal , Animais , Cegueira/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Plasticidade Neuronal/fisiologia , Neurotransmissores/metabolismo , Receptores de Neurotransmissores/metabolismo , Ácido gama-Aminobutírico/metabolismo
15.
Food Res Int ; 156: 111311, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35651069

RESUMO

This work aimed to explore the underlying mechanisms of memory improvement effects of a walnut derived peptide WNP-10. The morris water maze test, combined with ultrastructural observation, hematoxylin and eosin and Nissl staining showed that WNP-10 significantly improved the learning and memory capability of the scopolamine-injured mice. The four-dimensional label-free quantification proteomics analysis identified 88 differentially expressed proteins in the WNP-10-treated group compared with scopolamine-induced impairment group. Pathway enrichment analysis and western blotting demonstrated that the WNP-10 can regulate the phosphatidylinositol-3-phosphate 5-kinase, cathepsin L, N-acetylgalactosamine 6-sulfate sulfatase and AP-3 complex subunit mu-1 expression to affect inositol phosphate metabolism, thereby maintaining lysosome homeostasis in scopolamine-injured mice. Notably, the results of phosphoproteomics demonstrated that WNP-10 administration resulted in the increased phosphorylation of phosphatidylinositol-3-phosphate 5-kinase. These findings provide novel insights into the underlying mechanism of memory improvement of walnut peptides.


Assuntos
Juglans , Animais , Hipocampo , Juglans/química , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Fosfatos , Fosfatidilinositóis/metabolismo , Fosfatidilinositóis/farmacologia , Fosforilação , Proteoma/metabolismo , Escopolamina/efeitos adversos , Escopolamina/metabolismo
16.
Theranostics ; 12(8): 3656-3675, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664081

RESUMO

Background: Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Methods: Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Results: Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Conclusion: Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.


Assuntos
Ansiolíticos , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Fluoxetina/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo I/metabolismo
17.
Drug Des Devel Ther ; 16: 1573-1593, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35665194

RESUMO

Purpose: Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates. Methods: Mice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25-75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection. Results: Chronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels. Conclusion: It is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.


Assuntos
Disfunção Cognitiva , Etanol , Animais , Ácido Ascórbico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Donepezila , Dopamina , Flavonas , Hipocampo , Aprendizagem em Labirinto , Camundongos , Norepinefrina
18.
BMC Neurosci ; 23(1): 33, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668361

RESUMO

BACKGROUND: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. RESULTS: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage. CONCLUSIONS: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.


Assuntos
Disfunção Cognitiva , Doenças Neurodegenerativas , Animais , Atrofia , Cognição , Hipocampo/metabolismo , Camundongos , Sirtuína 1/metabolismo
19.
Pak J Pharm Sci ; 35(2(Special)): 671-678, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35668569

RESUMO

Cadmium is a potent neurotoxin and induces adverse impact on brain function. Protective effects of monoterpenes on the CNS have been reported previously. The present study was designed to investigate the beneficial effect of thymol on cadmium-induced neurotoxicity. Rats were initially divided into 2 groups, vehicle control and thymol. Thymol (40mg/kg) was given orally for 14 days. Each group was subdivided into two groups (Vehicle control and Cadmium, Thymol and Thymol+Cadmium). Cadmium Chloride (5mg/kg) was given for last 3 days only to the groups assigned as Cadmium and Thymol+Cadmium. Behavioral parameters were assessed after 24h of last dose of cadmium. Brain sample were collected and BDNF was measured in hippocampus. The present study suggests that pre-administration of thymol provides a protective therapy against cadmium-induced intoxication by enhancing the brain BDNF levels and plasticity. Results further suggest that thymol not only ameliorates cadmium-induced learning and memory impairment but also reduced anxiety, motor incoordination and depression assessed by various behavioral tests. The study may provide a better apprehension of the neuroprotective role of thymol and highlighting its significance in the diet for human health particularly in cadmium intoxication.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Timol , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cádmio/toxicidade , Cognição , Hipocampo , Ratos , Timol/farmacologia
20.
PLoS One ; 17(6): e0267682, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35657963

RESUMO

Evaluating novel compounds for neuroprotective effects in animal models of traumatic brain injury (TBI) is a protracted, labor-intensive and costly effort. However, the present lack of effective treatment options for TBI, despite decades of research, shows the critical need for alternative methods for screening new drug candidates with neuroprotective properties. Because natural products have been a leading source of new therapeutic agents for human diseases, we used an in vitro model of stretch injury to rapidly assess pro-survival effects of three bioactive compounds, two isolated from natural products (clovanemagnolol [CM], vinaxanthone [VX]) and the third, a dietary compound (pterostilbene [PT]) found in blueberries. The stretch injury experiments were not used to validate drug efficacy in a comprehensive manner but used primarily, as proof-of-principle, to demonstrate that the neuroprotective potential of each bioactive agent can be quickly assessed in an immortalized hippocampal cell line in lieu of comprehensive testing in animal models of TBI. To gain mechanistic insights into potential molecular mechanisms of neuroprotective effects, we performed a pathway-specific PCR array analysis of the effects of CM on the rat hippocampus and microRNA sequencing analysis of the effects of VX and PT on cultured hippocampal progenitor neurons. We show that the neuroprotective properties of these natural compounds are associated with altered expression of several genes or microRNAs that have functional roles in neurodegeneration or cell survival. Our approach could help in quickly assessing multiple natural products for neuroprotective properties and expedite the process of new drug discovery for TBI therapeutics.


Assuntos
Produtos Biológicos , Lesões Encefálicas Traumáticas , Fármacos Neuroprotetores , Animais , Produtos Biológicos/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Hipocampo/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ratos
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