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1.
Gene ; 806: 145920, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455026

RESUMO

Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.


Assuntos
Antidepressivos/farmacologia , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Proteínas do Tecido Nervoso/genética , Derrota Social , Estresse Psicológico/tratamento farmacológico , Administração Oral , Animais , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Japão , Masculino , Medicina Kampo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Milnaciprano/farmacologia , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
2.
ACS Chem Neurosci ; 12(18): 3387-3396, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469122

RESUMO

Quercitrin (Qc) is a well-known flavonoid compound that exerts anti-inflammation effects on various diseases. The present study aimed to investigate the antidepressant-like response of Qc and its underlying mechanisms concerning neuroinflammation and neuroplasticity in mice with lipopolysaccharide (LPS)-induced depression-like behaviors. The results showed a single dose of Qc (10 mg/kg) produced an antidepressant-like effect at 2 h postadministration and lasted for at least 3 days. The expressions of neuroplasticity signaling molecules of pCREB/BDNF/PSD95/Synapsin1 were upregulated at 2 h, and ERK signaling was upregulated for 3 days in the hippocampus after a single administration of Oc or ketamine. A 5-day treatment of LPS led to depression-like behaviors, including reduced sucrose preference and increased immobility in the tail suspension test or forced swim test, which were all reversed by a single dose of Qc. In LPS-treated mice, Qc reduced the levels of inflammation-related factors including IL-10, IL-1ß, and TNF-α in serum, as well as the activations of PI3K/AKT/NF-κB and MEK/ERK pathways in the hippocampus. Moreover, Qc restored the expressions of pCREB/BDNF/PSD95/Synapsin1 signaling in the hippocampus that were impaired by LPS. LY294002, a PI3K inhibitor, but not PD98059, a MEK inhibitor, produced effects similar to Qc. LY294002 also restored the expressions of pCREB/BDNF/PSD95/Synapsin1 signaling in the hippocampus impaired by LPS. Additionally, subeffective doses of Qc and LY294002 induced behavioral and molecular synergism. Together, the depression-like behaviors in LPS-treated mice were alleviated by a single dose of Qc likely via inhibition of the activations PI3K/AKT/NF-κB inflammation signaling and subsequent improvement of neuroplasticity.


Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Hipocampo/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/análogos & derivados
3.
FASEB J ; 35(9): e21827, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383980

RESUMO

Neuron-derived orphan receptor 1, NR4A3 (Nor1)/NR4A3 is an orphan nuclear receptor involved in the transcriptional control of developmental and neurological functions. Oxidative stress-induced conditions are primarily associated with neurological defects in humans, yet the impact on Nor1-mediated transcription of neuronal genes remains with unknown mechanism. Here, we demonstrate that Nor1 is a non-conventional target of SUMO2/3 conjugation at Lys-137 contained in an atypic ψKxSP motif referred to as the pSuM. Nor1 pSuM SUMOylation differs from the canonical process with the obligate phosphorylation of Ser-139 by Ras signaling to create the required negatively charged interface for SUMOylation. Additional phosphorylation at sites flanking the pSuM is also mediated by the coordinated action of protein kinase casein kinase 2 to function as a small ubiquitin-like modifier enhancer, regulating Nor1-mediated transcription and proteasomal degradation. Nor1 responsive genes involved in cell proliferation and metabolism, such as activating transcription factor 3, cyclin D1, CASP8 and FADD-like apoptosis regulator, and enolase 3 were upregulated in response to pSuM disruption in mouse HT-22 hippocampal neuronal cells and human neuroblastoma SH-SY5Y cells. We also identified critical antioxidant genes, such as catalase, superoxide dismutase 1, and microsomal glutathione S-transferase 2, as responsive targets of Nor1 under pSuM regulation. Nor1 SUMOylation impaired gene transcription through less effective Nor1 chromatin binding and reduced enrichment of histone H3K27ac marks to gene promoters. These effects resulted in decreased neuronal cell growth, increased apoptosis, and reduced survival to oxidative stress damage, underlying the role of pSuM-modified Nor1 in redox homeostasis. Our findings uncover a hierarchical post-translational mechanism that dictates Nor1 non-canonical SUMOylation, disrupting Nor1 transcriptional competence, and neuroprotective redox sensitivity.


Assuntos
Sobrevivência Celular/genética , Proteínas de Ligação a DNA/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Sumoilação/genética , Animais , Apoptose/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase do Ponto de Checagem 2/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Hipocampo/metabolismo , Homeostase/genética , Humanos , Camundongos , Neuroblastoma/genética , Neurônios/metabolismo , Oxirredução , Estresse Oxidativo/genética , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Regulação para Cima/genética
4.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
5.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360983

RESUMO

Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain.


Assuntos
Hipocampo/fisiopatologia , Potenciação de Longa Duração , Animais , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões Febris/metabolismo , Convulsões Febris/fisiopatologia , Potenciais Sinápticos
6.
Neuroscience ; 472: 157-166, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400247

RESUMO

Status epilepticus (SE) is a life-threatening neurological disorder that causes neuronal death and glial activation. Studies have explained the clinical side effects and lack of effectiveness of neurological disorder treatments based on sex-related differences in brain structure and function. However, the sex-specific outcomes of seizure disorders and the underlying mechanisms remain unknown. We compared SE-induced behavioral and pathophysiological changes in male and female mice. The time taken to reach stage 6 seizure following pilocarpine injection was shorter in male mice than in female mice, and the prevalence of SE was higher in male mice than in female mice. Fluoro-Jade B staining revealed more extensive SE-induced hippocampal neuronal death in male mice than in female mice. Glial cells were more activated in male mice than in female mice. In contrast, astrocyte-derived γ-aminobutyric acid (GABA)-immunostaining was less expressed in male mice than in female mice. Moreover, the mRNA levels of inflammatory cytokines released from activated glial cells were higher in male mice than in female mice. Notably, the mRNA level of astrocytic γ-aminobutyric acid transporter (GAT-3) involved in extracellular GABA uptake was lower in female mice than in male mice, while the mRNA levels of glutamate/aspartate transporter (GLAST (EAAT1)) and glutamate transporter (GLT-1 (EAAT2)) involved in extracellular glutamate uptake were higher in female mice. Our findings suggest that male mice are more vulnerable to SE than female mice, resulting in more extensive neuronal cell death and glial activation in male mice, partly due to increased GAT-3 expression that subsequently leads to reduced glial fibrillary acidic protein (GFAP)-positive GABA content assessed with anti-GABA antibodies.


Assuntos
Pilocarpina , Estado Epiléptico , Animais , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Pilocarpina/toxicidade , Estado Epiléptico/induzido quimicamente , Ácido gama-Aminobutírico
7.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445509

RESUMO

Ischemia-like conditions reflect almost the entire spectrum of events that occur during cerebral ischemia, including the induction of oxidative stress, Ca2+ overload, glutamate excitotoxicity, and activation of necrosis and apoptosis in brain cells. Mechanisms for the protective effects of the antioxidant enzyme peroxiredoxin-6 (Prx-6) on hippocampal cells during oxygen-glucose deprivation/reoxygenation (OGD/R) were investigated. Using the methods of fluorescence microscopy, inhibitory analysis, vitality tests and PCR, it was shown that 24-h incubation of mixed hippocampal cell cultures with Prx-6 does not affect the generation of a reversible phase of a OGD-induced rise in Ca2+ ions in cytosol ([Ca2+]i), but inhibits a global increase in [Ca2+]i in astrocytes completely and in neurons by 70%. In addition, after 40 min of OGD, cell necrosis is suppressed, especially in the astrocyte population. This effect is associated with the complex action of Prx-6 on neuroglial networks. As an antioxidant, Prx-6 has a more pronounced and astrocyte-directed effect, compared to the exogenous antioxidant vitamin E (Vit E). Prx-6 inhibits ROS production in mitochondria by increasing the antioxidant capacity of cells and altering the expression of genes encoding redox status proteins. Due to the close bond between [Ca2+]i and intracellular ROS, this effect of Prx-6 is one of its protective mechanisms. Moreover, Prx-6 effectively suppresses not only necrosis, but also apoptosis during OGD and reoxygenation. Incubation with Prx-6 leads to activation of the basic expression of genes encoding protective kinases-PI3K, CaMKII, PKC, anti-apoptotic proteins-Stat3 and Bcl-2, while inhibiting the expression of signaling kinases and factors involved in apoptosis activation-Ikk, Src, NF-κb, Caspase-3, p53, Fas, etc. This effect on the basic expression of the genome leads to the cell preconditions, which is expressed in the inhibition of caspase-3 during OGD/reoxygenation. A significant effect of Prx-6 is directed on suppression of the level of pro-inflammatory cytokine IL-1ß and factor TNFα, as well as genes encoding NMDA- and kainate receptor subunits, which was established for the first time for this antioxidant enzyme. The protective effect of Prx-6 is due to its antioxidant properties, since mutant Prx-6 (mutPrx-6, Prx6-C47S) leads to polar opposite effects, contributing to oxidative stress, activation of apoptosis and cell death through receptor action on TLR4.


Assuntos
Astrócitos/citologia , Hipocampo/citologia , Peroxirredoxina VI/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cálcio/metabolismo , Células Cultivadas , Citosol/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Microscopia de Fluorescência , Peroxirredoxina VI/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445402

RESUMO

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein "apoptosis-associated speck-like protein containing a caspase recruitment domain" (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aß) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAß plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aß plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/genética , Animais , Grânulos Citoplasmáticos/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos
9.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445628

RESUMO

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.


Assuntos
Modelos Animais de Doenças , Hipocampo/patologia , Interneurônios/patologia , Doença de Parkinson/complicações , Parvalbuminas/metabolismo , Transtornos do Sono-Vigília/patologia , Sinapses/patologia , Animais , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropatologia , Ratos , Ratos Wistar , Formação Reticular/metabolismo , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/metabolismo , Sinapses/metabolismo , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
10.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360892

RESUMO

The explosive development of next-generation sequencing-based technologies has allowed us to take an unprecedented look at many molecular signatures of the non-coding genome. In particular, the ChIP-seq (Chromatin ImmunoPrecipitation followed by sequencing) technique is now very commonly used to assess the proteins associated with different non-coding DNA regions genome-wide. While the analysis of such data related to transcription factor binding is relatively straightforward, many modified histone variants, such as H3K27me3, are very important for the process of gene regulation but are very difficult to interpret. We propose a novel method, called HERON (HiddEn MaRkov mOdel based peak calliNg), for genome-wide data analysis that is able to detect DNA regions enriched for a certain feature, even in difficult settings of weakly enriched long DNA domains. We demonstrate the performance of our method both on simulated and experimental data.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação/métodos , DNA/genética , DNA/metabolismo , Genoma Humano , Histonas/genética , Histonas/metabolismo , Adulto , Algoritmos , Expressão Gênica , Regulação da Expressão Gênica , Hipocampo/embriologia , Hipocampo/metabolismo , Código das Histonas/genética , Humanos , Fígado/metabolismo , Metilação , Distribuição Normal , Ligação Proteica
11.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
Nutrients ; 13(8)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34444704

RESUMO

γ-Aminobutyric acid (GABA) is a potent bioactive amino acid, and several studies have shown that oral administration of GABA induces relaxation, improves sleep, and reduces psychological stress and fatigue. In a recent study, we reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain-gut interactions. Therefore, the purpose of this study was to verify the functionality of GABA-derived exosomes and to examine the possibility of improving memory function following GABA administration. The results showed that exosomes derived from GABA-treated intestinal cells (Caco-2) activated neuronal cells (SH-SY5Y) by regulating genes related to neuronal cell functions. Furthermore, we found that exosomes derived from the serum of GABA-treated mice also activated SH-SY5Y cells, indicating that exosomes, which are capable of activating neuronal cells, circulate in the blood of mice orally administered GABA. Finally, we performed a microarray analysis of mRNA isolated from the hippocampus of mice that were orally administered GABA. The results revealed changes in the expression of genes related to brain function. Gene Set Enrichment Analysis (GSEA) showed that oral administration of GABA affected the expression of genes related to memory function in the hippocampus.


Assuntos
Exossomos/metabolismo , Memória/efeitos dos fármacos , Neurônios/metabolismo , Ácido gama-Aminobutírico/administração & dosagem , Administração Oral , Animais , Células CACO-2/metabolismo , Hipocampo/metabolismo , Humanos , Camundongos , MicroRNAs/metabolismo , Modelos Animais
13.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445137

RESUMO

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment.


Assuntos
Ceftriaxona/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
14.
Ecotoxicol Environ Saf ; 223: 112617, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34385058

RESUMO

PM2.5 is recently identified as a kind of material possessing severe biohazard. It can enter human body and exerts pathological effects on lung, eyes, and the central nervous system (CNS). Maternal exposure to PM2.5 can affect neural development and cause cognitive decline in offspring, with the underlying mechanisms unclear, however. The inflammasome monitors and responds to biological stressors, with HMGB1-NLRP3 inflammatory axis as an essential pathophysiological player outside the brain. The present work is to investigate its role in cognitive impairment induced by gestational exposure to PM2.5 in mice offspring. We found that HMGB1-NLRP3 pathway was activated in the hippocampus of mice offspring by gestational exposure to PM2.5 in a dose-dependent manner, with protein levels of HMGB1, NLRP3, and cleaved caspase-1 as approximately three times as high as those of control. And down-regulating HMGB1 during pregnancy could alleviate the resultant impairment on learning and working memory as well as hippocampal neurons, up-regulate the synapse related proteins of SYP and PSD-95 and correct the increased expression of 5-HT2A to comparable levels to control, as well as inhibiting the activation of microglia and decreasing the expression of HMGB1 and Iba1/HMGB1 double positive cells in the hippocampus of mice offspring. Meanwhile, protein levels of NLRP3, cleaved caspase-1, IL-1ß and IL-18, as well as TLR4, phosphorylated NF-κB, and MAPKs, were almost down-regulated to those of control. Therefore, HMGB1 intervention inhibits the NLRP3 inflammasome mediated hippocampal inflammatory response through TLR4/MAPKs/NF-κB signaling pathway, alleviating PM2.5-induced cognitive dysfunction. Further in vitro results suggest that PM2.5 can activate microglia and HMGB1-NLRP3 inflammatory axis. Pretreatment with HMGB1 inhibitor significantly reduced the phosphorylation of MAPKs and NF-κB, and inhibited the inflammatory response mediated by NLRP3 inflammasome similarly to those in vivo. These results suggest that PM2.5 exposure promotes the inflammatory response in hippocampus mediated by HMGB1-NLRP3 inflammatory axis in microglia, resulting in cognitive dysfunction in offspring, which could be alleviated by simultaneous HMGB1 suppression. These findings provide a theoretical basis for preventing cognitive impairment in offspring caused by environmental pollution during pregnancy.


Assuntos
Disfunção Cognitiva , Proteína HMGB1 , Animais , Disfunção Cognitiva/induzido quimicamente , Feminino , Proteína HMGB1/metabolismo , Hipocampo/metabolismo , Humanos , Inflamação/induzido quimicamente , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Material Particulado/toxicidade , Gravidez
15.
Nat Commun ; 12(1): 4737, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362910

RESUMO

Glucocorticoid hormones (GCs) - acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) - are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.


Assuntos
Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Receptores de Esteroides/metabolismo , Animais , Regulação da Expressão Gênica , Genoma , Hipocampo/patologia , Humanos , Masculino , Ligação Proteica , RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Fatores de Transcrição
16.
J Biomed Nanotechnol ; 17(7): 1371-1379, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34446140

RESUMO

Occlusal trauma (OT), by causing periodontal tissue damage, can activate and enhance the activity of the peripheral and central nervous system (CNS) neuropeptides. The brain-derived neurotrophic factor (BDNF) gene is activity-dependent and exhibits marked alterations, characterized by protection against injury and repair. Our results show the possible molecular mechanism through which noxious environmental stimuli induce alterations in BDNF activity in the local periodontal tissue, the primary sensory neurons-Vc, and the hippocampus, suggesting systemic impairment. BDNF serves a more positive and enduring trauma protection and repair function in Vc compared to that in local dental tissue.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Oclusão Dentária Traumática , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Humanos , Periodonto/metabolismo , Núcleos do Trigêmeo/metabolismo
17.
Brain Behav ; 11(8): e02107, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34333859

RESUMO

INTRODUCTION: This study mainly investigated the role of miR-199a-5p in depression. METHODS: qRT-PCR and western blotting were employed to detect the expressions of miR-199a-5p, CREB and BDNF. Sucrose preference test, forced swimming test, and tail suspension test were performed to evaluate depression-related symptoms. MTT assays and flow cytometry were used to examine the cell reproduction and apoptotic cells of hippocampal neuron. RESULTS: The data demonstrated that the expression levels of miR-199a-5p in the cerebrospinal fluids and serums of depression patient and the hippocampus of chronic unpredictable mild stress (CUMS) mouse were significantly increased. However, the expressions of WNT2, p-CREB, and BDNF were inhibited. In addition, miR-199a-5p-inhibitor enhanced sucrose preferences of CUMS mouse and decreased immobile time in sucrose preference test and forced swimming test. Knockdown of WNT2 attenuated the effects of miR-199a-5p-inhibitor on cell reproduction and apoptotic cells of hippocampal neuron and the expression of WNT2, p-CREB, and BDNF. CONCLUSION: MiR-199a-5p can target WNT2 to enhance the development of depression through regulation of the CREB/BDNF signaling. TRIAL REGISTRATION: JNU-Hos-49284.


Assuntos
MicroRNAs , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/genética , Hipocampo/metabolismo , Humanos , Camundongos , MicroRNAs/genética , Neurônios/metabolismo , Proteína Wnt2/genética , Proteína Wnt2/metabolismo
18.
Brain Behav ; 11(8): e2300, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34333865

RESUMO

In this study, the antidepression effects of genistein were investigated in rats induced with chronic mild stress. Animals were designated into the following groups: normal control, control, 10 mg, and 100 mg. The dose was given for 45 consecutive days via the oral route. Sucrose preference analysis, forced swim, and open field tests were performed, and serum cortisol and monoamine levels in brain tissue were determined. The mRNA and protein expression of brain-derived neurotrophic factor (BDNF) was also examined. Supplementation with genistein significantly increased the sucrose preference ratio, locomotor activity, and monoamines and decreased serum cortisol levels. The mRNA expression of BDNF in the brain tissue was substantially reduced by 0.73% in control rats. However, supplementation with genistein significantly increased BDNF mRNA expression (by 107% and 229.6% in groups 10 mg and 100 mg, respectively). Similarly, the protein expression of BDNF increased by 82.3% and 141.2% in groups 10 mg and 100 mg, respectively. Taken together, these results suggest that supplementation with genistein may be effective against depression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Animais , Antidepressivos/farmacologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Genisteína/farmacologia , Hipocampo/metabolismo , Ratos , Estresse Psicológico/tratamento farmacológico
19.
Brain Behav Immun ; 97: 423-439, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34343616

RESUMO

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal's ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.


Assuntos
Microglia , Receptores de Glucocorticoides , Animais , Feminino , Hipocampo/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Microglia/metabolismo , Neurogênese , Neurônios/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores Imunológicos , Estresse Psicológico
20.
Brain Behav Immun ; 97: 383-393, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34343615

RESUMO

Toll-like receptors (TLRs) participate in the response to infection, stress, and injury by initiating an innate immune response. In addition, these receptors are expressed in many neural cell types and under physiological conditions are implicated in modulating cognitive function and neural plasticity in the adult and aged brain. Knockout of the Toll-like receptor 4 (TLR4) subtype enhances spatial memory and adult hippocampal neurogenesis through increasing proliferation and neuronal differentiation. Currently unknown is whether pharmacological inhibition of TLR4 produces similar enhancements in cognitive function and cell proliferation. The present study evaluated water maze performance, cytokine expression, and cell proliferation in the hippocampus of young and aged male and female C57BL6/J mice following treatment with the TLR4 antagonist, TAK-242. Further, alterations in the response to an acute stressor were evaluated in TAK-242-treated mice. Results showed that TAK-242 selectively enhanced spatial learning and memory in young females. Additionally, TAK-242 treatment reduced thigmotaxis in the water maze and lowered corticosterone levels following acute stress in females. TAK-242 decreased hippocampal interleukin (IL)-1ß expression but had no effect on IL-6 or tumor necrosis factor-α (TNFα). Aged mice showed decreased cell proliferation compared to young mice, but TAK-242 administration had minimal effects on estimated Ki67 positive cell numbers. Findings indicate that pharmacological inhibition of TLR4 improves cognitive function in young females likely through attenuating stress reactivity.


Assuntos
Memória Espacial , Receptor 4 Toll-Like , Animais , Proliferação de Células , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor 4 Toll-Like/metabolismo
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