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1.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445210

RESUMO

Ischemic episodes are a leading cause of death worldwide with limited therapeutic interventions. The current study explored mitochondrial phosphate-activated glutaminase (GLS1) activity modulation by PKCßII through GC-MS untargeted metabolomics approach. Mitochondria were used to elucidate the endogenous resistance of hippocampal CA2-4 and dentate gyrus (DG) to transient ischemia and reperfusion in a model of ischemic episode in gerbils. In the present investigation, male gerbils were subjected to bilateral carotids occlusion for 5 min followed by reperfusion (IR). Gerbils were randomly divided into three groups as vehicle-treated sham control, vehicle-treated IR and PKCßII specific inhibitor peptide ßIIV5-3-treated IR. Vehicle or ßIIV5-3 (3 mg/kg, i.v.) were administered at the moment of reperfusion. The gerbils hippocampal tissue were isolated at various time of reperfusion and cell lysates or mitochondria were isolated from CA1 and CA2-4,DG hippocampal regions. Recombinant proteins PKCßII and GLS1 were used in in vitro phosphorylation reaction and organotypic hippocampal cultures (OHC) transiently exposed to NMDA (25 µM) to evaluate the inhibition of GLS1 on neuronal viability. PKCßII co-precipitates with GAC (GLS1 isoform) in CA2-4,DG mitochondria and phosphorylates GLS1 in vitro. Cell death was dose dependently increased when GLS1 was inhibited by BPTA while inhibition of mitochondrial pyruvate carrier (MPC) attenuated cell death in NMDA-challenged OHC. Fumarate and malate were increased after IR 1h in CA2-4,DG and this was reversed by ßIIV5-3 what correlated with GLS1 activity increases and earlier showed elevation of neuronal death (Krupska et al., 2017). The present study illustrates that CA2-4,DG resistance to ischemic episode at least partially rely on glutamine and glutamate utilization in mitochondria as a source of carbon to tricarboxylic acid cycle. This phenomenon depends on modulation of GLS1 activity by PKCßII and remodeling of MPC: all these do not occur in ischemia-vulnerable CA1.


Assuntos
Transtornos Cerebrovasculares/enzimologia , Glutaminase/metabolismo , Hipocampo/enzimologia , Mitocôndrias/enzimologia , Proteína Quinase C beta/metabolismo , Traumatismo por Reperfusão/enzimologia , Animais , Transtornos Cerebrovasculares/patologia , Gerbillinae , Hipocampo/patologia , Mitocôndrias/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia
2.
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
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360865

RESUMO

Traumatic brain injury (TBI) affects over 69 million people annually worldwide, and those with pre-existing depression have worse recovery. The molecular mechanisms that may contribute to poor recovery after TBI with co-morbid depression have not been established. TBI and depression have many commonalities including volume changes, myelin disruption, changes in proliferation, and changes in glutamatergic signaling. We used a well-established animal model of depression, the Wistar Kyoto (WKY) rat, to elucidate changes after TBI that may influence the recovery trajectory. We compared the histological and molecular outcomes in the hippocampal dentate gyrus after experimental TBI using the lateral fluid percussion injury (LFPI) in the WKY and the parent Wistar (WIS) strain. We showed that WKY had exaggerated myelin loss after LFPI and baseline deficits in proliferation. In addition, we showed that while after LFPI WIS rats exhibited glutamate receptor subunit changes, namely increased GluN2B, the WKY rats failed to show such injury-related changes. These differential responses to LFPI helped to elucidate the molecular characteristics that influence poor recovery after TBI in those with pre-existing depression and may lead to targets for future therapeutic interventions.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Hipocampo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Proliferação de Células , Transtorno Depressivo Maior/metabolismo , Hipocampo/patologia , Ratos , Ratos Endogâmicos WKY , Ratos Wistar
4.
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
5.
Neuroimage Clin ; 31: 102765, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34339947

RESUMO

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.


Assuntos
Epilepsia do Lobo Temporal , Inteligência Artificial , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose/patologia , Máquina de Vetores de Suporte
6.
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
7.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360774

RESUMO

Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies.


Assuntos
Metilação de DNA/efeitos dos fármacos , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Compostos de Trimetilestanho/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Caracteres Sexuais
8.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371875

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) have been recognized to cause neurobehavioral dysfunctions and disorder of cognition and behavioral patterns in childhood. Momordica charantia L. (MC) has been widely known for its nutraceutical and health-promoting properties. To date, the effect of MC for the prevention and handling of PAHs-induced neurotoxicity has not been reported. In the current study, the neuroprotective effects of MC and its underlying mechanisms were investigated in mouse hippocampal neuronal cell line (HT22); moreover, in silico analysis was performed with the phytochemicals MC to decipher their potential function as neuroprotectants. MC was demonstrated to possess neuroprotective effect by reducing reactive oxygen species' (ROS') production and down-regulating cyclin D1, p53, and p38 mitogen-activated protein kinase (MAPK) protein expressions, resulting in the inhibition of cell apoptosis and the normalization of cell cycle progression. Additionally, 28 phytochemicals of MC and their competence on inhibiting cytochrome P450 (CYP: CYP1A1, CYP1A2, and CYP1B1) functions were resolved. In silico analysis of vitamin E and stigmasterol revealed that their binding to either CYP1A1 or CYP1A2 was more efficient than the binding of each positive control (alizarin or purpurin). Together, MC is potentially an interesting neuroprotectant including vitamin E and stigmasterol as probable active components for the prevention for PAHs-induced neurotoxicity.


Assuntos
Hipocampo/efeitos dos fármacos , Momordica charantia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Estigmasterol/farmacologia , Vitamina E/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Momordica charantia/química , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Estigmasterol/isolamento & purificação , Vitamina E/isolamento & purificação
9.
Life Sci ; 283: 119842, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34298038

RESUMO

AIMS: Ischemic stroke occurs when there is a sudden blockage of cerebral blood flow. This condition is a major cause of mortality, especially in low-income countries, and its incidence is dramatically increasing. Therapeutic strategies against stroke are therefore required. The present study explored the effects of dihydrocapsaicin on neuronal loss, brain infarct volume, and antioxidants in a rat model of permanent occlusion of the right middle cerebral artery (Rt.MCAO). MAIN METHODS: Male Wistar rats received dihydrocapsaicin intraperitoneally for 7 days after permanent occlusion of their right middle cerebral artery (Rt.MCAO). Then, the brain infarct volume, neuronal density, and antioxidant and anti-apoptotic activities in the cortex and hippocampus were determined at the end of the study. KEY FINDING: Dihydrocapsaicin treatment was found to significantly improve neuronal density, decrease infarct volume, reduce MDA elevation, improve CAT and SOD activities, decrease the density ratio of Bax and caspase-3, and increase the density ratio of Bcl-XL to ß-actin in the cerebral cortex and hippocampus. SIGNIFICANCE: The present study suggests that dihydrocapsaicin effectively mitigates cerebral ischemia-induced pathological changes in vivo, partly via antioxidant and anti-apoptotic pathways.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Isquemia Encefálica , Capsaicina/análogos & derivados , Hipocampo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Capsaicina/farmacologia , Caspase 3/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
10.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279415

RESUMO

Neurodegeneration is the consequence of harmful events affecting the nervous system that lead to neuronal death. Toxic substances, including air pollutants, are capable of inducing neurodegeneration. Ozone (O3) is the most oxidative toxic pollutant. O3 reacts with cellular components and forms reactive oxygen and nitrogen species, triggering nitro-oxidative damage during short-term exposure. Curcumin (CUR) is a natural phenolic molecule bearing well-documented antioxidant and anti-inflammatory biological activities in diverse experimental models. The aim of this work was to evaluate the effect of preventive dietary administration of CUR against hippocampal neurodegeneration and nitro-oxidative damage caused by short-term exposure to O3. Eighty Wistar male rats were distributed into four experimental groups, twenty rats each: intact control; CUR dietary supplementation without O3 exposure; exposure to 0.7 ppm of O3; and exposed to O3 with CUR dietary supplementation. Five rats from each group were sacrificed at 1, 2, 4, and 8 h of exposure. The CUR dose was 5.6 mg/kg and adjusted according to food consumption. CUR significantly decreased oxidative damage to plasma lipids and proteins, as well as neurodegeneration in CA1 and CA3 hippocampal regions. Concluding, CUR proved effective protection in decreasing neurodegeneration in the hippocampus and prevented systemic oxidative damage.


Assuntos
Proteínas Sanguíneas/metabolismo , Curcumina/farmacologia , Hipocampo/efeitos dos fármacos , Lipídeos/análise , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Ozônio/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
11.
Molecules ; 26(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34299412

RESUMO

Gintonin is a kind of ginseng-derived glycolipoprotein that acts as an exogenous LPA receptor ligand. Gintonin has in vitro and in vivo neuroprotective effects; however, little is known about the cellular mechanisms underlying the neuroprotection. In the present study, we aimed to clarify how gintonin attenuates iodoacetic acid (IAA)-induced oxidative stress. The mouse hippocampal cell line HT22 was used. Gintonin treatment significantly attenuated IAA-induced reactive oxygen species (ROS) overproduction, ATP depletion, and cell death. However, treatment with Ki16425, an LPA1/3 receptor antagonist, suppressed the neuroprotective effects of gintonin. Gintonin elicited [Ca2⁺]i transients in HT22 cells. Gintonin-mediated [Ca2⁺]i transients through the LPA1 receptor-PLC-IP3 signaling pathway were coupled to increase both the expression and release of BDNF. The released BDNF activated the TrkB receptor. Induction of TrkB phosphorylation was further linked to Akt activation. Phosphorylated Akt reduced IAA-induced oxidative stress and increased cell survival. Our results indicate that gintonin attenuated IAA-induced oxidative stress in neuronal cells by activating the LPA1 receptor-BDNF-TrkB-Akt signaling pathway. One of the gintonin-mediated neuroprotective effects may be achieved via anti-oxidative stress in nervous systems.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Sobrevivência Celular , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais
12.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299103

RESUMO

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Citalopram/farmacologia , Depressão/tratamento farmacológico , Proteína 2 de Ligação a Metil-CpG/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/complicações , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 3/genética , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ratos , Ratos Wistar
13.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207724

RESUMO

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.


Assuntos
Antidepressivos , Estimulantes do Sistema Nervoso Central , Hipocampo/metabolismo , Peptídeos , Hormônio Liberador de Tireotropina/antagonistas & inibidores , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/patologia , Masculino , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Hormônio Liberador de Tireotropina/metabolismo
14.
Commun Biol ; 4(1): 823, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193971

RESUMO

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal, and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.


Assuntos
Envelhecimento , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Fatores Etários , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cromatografia Líquida/métodos , Feminino , Hipocampo/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Proteoma/classificação , Espectrometria de Massas em Tandem/métodos
15.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209576

RESUMO

Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9-/- and corresponding C57BL/6 wild-type control mice were infected with Theiler's murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9-/- mice showed an increased loss of neuronal nuclear protein+ mature neurons and doublecortin+ neuronal precursor cells and an increase in ß-amyloid precursor protein+ damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8+ T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Suscetibilidade a Doenças , Encefalite Viral/etiologia , Hipocampo/virologia , Infecções por Picornaviridae/etiologia , Picornaviridae/fisiologia , Animais , Biomarcadores , Modelos Animais de Doenças , Encefalite Viral/patologia , Predisposição Genética para Doença , Hipocampo/metabolismo , Hipocampo/patologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imuno-Histoquímica , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Camundongos , Camundongos Knockout , Infecções por Picornaviridae/patologia , Carga Viral
16.
J Clin Neurosci ; 90: 124-131, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275535

RESUMO

INTRODUCTION: We measured the proportion of Lewy body pathology (LB), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA) among community-dwelling people with and without dementia. METHODS: We searched for community-based cohorts with postmortem brain autopsy until 1 January 2020. We calculated the summary risk difference and 95% confidence interval (95% CI) using a random-effects model in R. RESULTS: We found 12 articles, comprising 2197 demented and 2104 non-demented participants. LB, HS, CAA were prevalent lesions among community-dwelling elderly (15%, 10%, and 24%, respectively). These significantly increased the risk of dementia (LB: risk difference 38%, 95% CI 20-56%, HS: 34%, 24-44%, CAA: 19%, 3-34%). 20% of cases with neocortical LB, 17% with bilateral HS, and 42% with moderate/severe CAA pathology remained non-demented by death. DISCUSSION: LB or HS or CAA are common neuropathologies among community-dwelling elderly. Although these lesions independently are associated with dementia, many remain non-demented, by death.


Assuntos
Angiopatia Amiloide Cerebral/epidemiologia , Demência/patologia , Hipocampo/patologia , Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/patologia , Demência/etiologia , Feminino , Humanos , Vida Independente , Masculino , Prevalência , Esclerose/epidemiologia , Esclerose/patologia
17.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206649

RESUMO

Neurons inevitably rely on a proper repertoire and distribution of membrane-bound ion-conducting channels. Among these proteins, the family of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels possesses unique properties giving rise to the corresponding Ih-current that contributes to various aspects of neural signaling. In mammals, four genes (hcn1-4) encode subunits of HCN channels. These subunits can assemble as hetero- or homotetrameric ion-conducting channels. In order to elaborate on the specific role of the HCN2 subunit in shaping electrical properties of neurons, we applied an Adeno-associated virus (AAV)-mediated, RNAi-based knock-down strategy of hcn2 gene expression both in vitro and in vivo. Electrophysiological measurements showed that HCN2 subunit knock-down resulted in specific yet anticipated changes in Ih-current properties in primary hippocampal neurons and, in addition, corroborated that the HCN2 subunit participates in postsynaptic signal integration. To further address the role of the HCN2 subunit in vivo, we injected recombinant (r)AAVs into the dorsal hippocampus of young adult male mice. Behavioral and biochemical analyses were conducted to assess the contribution of HCN2-containing channels in shaping hippocampal network properties. Surprisingly, knock-down of hcn2 expression resulted in a severe degeneration of the CA1 pyramidal cell layer, which did not occur in mice injected with control rAAV constructs. This finding might pinpoint to a vital and yet unknown contribution of HCN2 channels in establishing or maintaining the proper function of CA1 pyramidal neurons of the dorsal hippocampus.


Assuntos
Apoptose/genética , Região CA1 Hipocampal/metabolismo , Hipocampo/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/deficiência , Canais de Potássio/deficiência , Células Piramidais/metabolismo , Fatores Etários , Animais , Região CA1 Hipocampal/patologia , Técnicas de Silenciamento de Genes , Hipocampo/patologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Imuno-Histoquímica , Camundongos , Canais de Potássio/química , Canais de Potássio/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Células Piramidais/patologia , Interferência de RNA
18.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201038

RESUMO

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague-Dawley pups during early postnatal development (p5-p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42-p44, p60-p62) and in early adulthood (p90-p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/patologia , Glutationa/deficiência , Hipocampo/patologia , Transtornos do Neurodesenvolvimento/patologia , Esquizofrenia/patologia , Animais , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Ratos , Ratos Sprague-Dawley , Esquizofrenia/etiologia , Esquizofrenia/metabolismo
19.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201282

RESUMO

Aging is associated with a general decline of cognitive functions, and it is widely accepted that this decline results from changes in the expression of proteins involved in regulation of synaptic plasticity. However, several lines of evidence have accumulated that suggest that the impaired function of the aged brain may be related to significant alterations in the energy metabolism. In the current study, we employed the label-free "Total protein approach" (TPA) method to focus on the similarities and differences in energy metabolism proteomes of young (1-month-old) and aged (22-month-old) murine brains. We quantified over 7000 proteins in each of the following three analyzed brain structures: the hippocampus, the cerebral cortex and the cerebellum. To the best of our knowledge, this is the most extensive quantitative proteomic description of energy metabolism pathways during the physiological aging of mice. The analysis demonstrates that aging does not significantly affect the abundance of total proteins in the studied brain structures, however, the levels of proteins constituting energy metabolism pathways differ significantly between young and aged mice.


Assuntos
Envelhecimento/metabolismo , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Metabolismo Energético , Hipocampo/metabolismo , Proteoma/metabolismo , Envelhecimento/patologia , Animais , Cerebelo/patologia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/análise
20.
FASEB J ; 35(8): e21726, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34196433

RESUMO

Increasing evidence shows that astrocytes, by releasing and uptaking neuroactive molecules, regulate synaptic plasticity, considered the neurophysiological basis of memory. This study investigated the impact of l-α-aminoadipate (l-AA) on astrocytes which sense and respond to stimuli at the synaptic level and modulate hippocampal long-term potentiation (LTP) and memory. l-AA selectivity toward astrocytes was proposed in the early 70's and further tested in different systems. Although it has been used for impairing the astrocytic function, its effects appear to be variable in different brain regions. To test the effects of l-AA in the hippocampus of male C57Bl/6 mice we performed two different treatments (ex vivo and in vivo) and took advantage of other compounds that were reported to affect astrocytes. l-AA superfusion did not affect the basal synaptic transmission but decreased LTP magnitude. Likewise, trifluoroacetate and dihydrokainate decreased LTP magnitude and occluded the effect of l-AA on synaptic plasticity, confirming l-AA selectivity. l-AA superfusion altered astrocyte morphology, increasing the length and complexity of their processes. In vivo, l-AA intracerebroventricular injection not only reduced the astrocytic markers but also LTP magnitude and impaired hippocampal-dependent memory in mice. Interestingly, d-serine administration recovered hippocampal LTP reduction triggered by l-AA (2 h exposure in hippocampal slices), whereas in mice injected with l-AA, the superfusion of d-serine did not fully rescue LTP magnitude. Overall, these data show that both l-AA treatments affect astrocytes differently, astrocytic activation or loss, with similar negative outcomes on hippocampal LTP, implying that opposite astrocytic adaptive alterations are equally detrimental for synaptic plasticity.


Assuntos
Ácido 2-Aminoadípico/toxicidade , Astrócitos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Ácido 2-Aminoadípico/administração & dosagem , Ácido 2-Aminoadípico/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Técnicas In Vitro , Injeções Intraventriculares , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Serina/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
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