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1.
Endocr Regul ; 53(2): 59-64, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517628

RESUMO

OBJECTIVE: Enkephalins are neuropeptides involved in functions such as pain modulation and/ or cognitive processes. It has been reported that dietary fat modifies enkephalins in the brain. Since enkephalins are hydrolyzed by enkephalinases, the study of the influence of dietary fats, differing in their degree of saturation, on brain fatty acids content and enkephalinase activity is important to understand its regulatory role on neuropeptides under different type of diets. METHODS: We analyzed enkephalinase activity, assayed with alanine-ß-naphthylamide as sub-strate, in frontal cortex of adult male rats fed diets supplemented with fish oil, olive oil or coconut oil, which markedly differed in the saturation of their fatty acids. RESULTS: Rats fed a diet enriched with coconut oil had lower soluble enkephalinase activity than the group fed olive oil (p<0.01) and fish oil (p<0.05) whereas rats fed a diet enriched with fish oil had lower membrane-bound enkephalinase activity than the group fed with olive (p<0.001) or coconut oil (p<0.05). Significant negative correlations were observed between certain fatty acids and enkephalinase activities in the groups fed with olive and coconut oils. No correlations were observed in the group fed with fish oil. CONCLUSIONS: Dietary fat modifies enkephalinase activity in the frontal cortex depending on the degree of saturation of the used oil. It is postulated that the functions, in which enkephalins are involved, such as pain modulation or cognitive functions, may also be affected according to the type of oil used in the diet.


Assuntos
Gorduras na Dieta/farmacologia , Ácidos Graxos/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Neprilisina/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Óleo de Coco/farmacologia , Dieta , Óleos de Peixe/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Neprilisina/efeitos dos fármacos , Azeite de Oliva/farmacologia , Ratos , Ratos Wistar
2.
Dev Cogn Neurosci ; 39: 100679, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31437736

RESUMO

Children born preterm are at higher risk to develop language deficits. Auditory speech discrimination deficits may be early signs for language developmental problems. The present study used functional near-infrared spectroscopy to investigate neural speech discrimination in 15 preterm infants at term-equivalent age compared to 15 full term neonates. The full term group revealed a significantly greater hemodynamic response to forward compared to backward speech within the left hemisphere extending from superior temporal to inferior parietal and middle and inferior frontal areas. In contrast, the preterm group did not show differences in their hemodynamic responses during forward versus backward speech, thus, they did not discriminate speech from non-speech. Groups differed significantly in their responses to forward speech, whereas they did not differ in their responses to backward speech. The significant differences between groups point to an altered development of the functional network underlying language acquisition in preterm infants as early as in term-equivalent age.


Assuntos
Lobo Frontal/crescimento & desenvolvimento , Recém-Nascido Prematuro/fisiologia , Desenvolvimento da Linguagem , Lobo Parietal/crescimento & desenvolvimento , Percepção da Fala/fisiologia , Nascimento a Termo/fisiologia , Fatores Etários , Feminino , Lobo Frontal/metabolismo , Hemodinâmica/fisiologia , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/psicologia , Masculino , Lobo Parietal/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/tendências , Nascimento a Termo/psicologia
3.
Dev Cogn Neurosci ; 38: 100676, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31299480

RESUMO

How and when a concept of the 'self' emerges has been the topic of much interest in developmental psychology. Self-awareness has been proposed to emerge at around 18 months, when toddlers start to show evidence of physical self-recognition. However, to what extent physical self-recognition is a valid indicator of being able to think about oneself, is debated. Research in adult cognitive neuroscience has suggested that a common network of brain regions called Default Mode Network (DMN), including the temporo-parietal junction (TPJ) and the medial prefrontal cortex (mPFC), is recruited when we are reflecting on the self. We hypothesized that if mirror self-recognition involves self-awareness, toddlers who exhibit mirror self-recognition might show increased functional connectivity between frontal and temporoparietal regions of the brain, relative to those toddlers who do not yet show mirror self-recognition. Using fNIRS, we collected resting-state data from 18 Recognizers and 22 Non-Recognizers at 18 months of age. We found significantly stronger fronto-temporoparietal connectivity in Recognizers compared to Non-Recognizers, a finding which might support the hypothesized relationship between mirror-self recognition and self-awareness in infancy.


Assuntos
Lobo Frontal/metabolismo , Rede Nervosa/metabolismo , Lobo Parietal/metabolismo , Percepção/fisiologia , Lobo Temporal/metabolismo , Mapeamento Encefálico/métodos , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Espectroscopia de Luz Próxima ao Infravermelho/métodos
4.
Neurology ; 93(8): e758-e765, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31315971

RESUMO

OBJECTIVE: To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. METHODS: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. RESULTS: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. CONCLUSION: Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.


Assuntos
Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Demência/metabolismo , Lobo Frontal/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Inositol/metabolismo , Proteínas tau/metabolismo , Adulto , Ácido Aspártico/metabolismo , Doenças Assintomáticas , Biomarcadores/metabolismo , Estudos de Casos e Controles , Demência/complicações , Demência/genética , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/diagnóstico , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem , Proteínas tau/genética
5.
Arch Pharm Res ; 42(8): 722-731, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31350730

RESUMO

Isoorientin (ISO) is considered one of the most important flavonoids with various pharmacological effects such as antioxidant, anti-inflammatory, and anti-cancer activities. Despite these beneficial activities, the effects of ISO on learning and memory have not been investigated so far. The current study evaluated the memory-enhancing effects of ISO in a scopolamine-treated mouse model by using the Y-maze and passive avoidance tests. The results showed that ISO (5 and 10 mg/kg, p.o.) treatment significantly improved the cognitive impairments caused by scopolamine. Additionally, ISO significantly decreased scopolamine-induced acetylcholinesterase and thiobarbituric acid reactive substance activities in both the hippocampus and frontal cortex of mice. In addition, ISO significantly increased the levels of total superoxide dismutase induced by scopolamine in the hippocampus and frontal cortex. Moreover, Western blot results indicated that ISO reversed the decreases in expression of phosphorylated cAMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex of scopolamine-treated mice. Thus, our results provide initial evidence that ISO ameliorates scopolamine-induced memory and cognitive impairments partly by restoring the cholinergic system, antioxidant defense, and p-CREB/BDNF signaling pathway, thereby exhibiting memory-enhancing activities.


Assuntos
Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colinérgicos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Luteolina/farmacologia , Animais , Colinérgicos/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Luteolina/química , Masculino , Memória/efeitos dos fármacos , Camundongos , Estrutura Molecular , Escopolamina , Transdução de Sinais/efeitos dos fármacos
6.
J Agric Food Chem ; 67(29): 8160-8167, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31241932

RESUMO

An increase in the aging population has spurred recent efforts to identify diet and lifestyle changes that help prevent cognitive decline. Several epidemiological investigations and clinical studies have indicated that consuming fermented dairy products prevents cognitive decline. Some peptides from whey including ß-lactolin improve memory impairment; the intake of Camembert cheese has been shown to prevent Alzheimer's in mouse models. To elucidate the molecular mechanisms underlying these preventive effects, we screened peptides from digested casein protein for their ability to improve spatial memory in a scopolamine-induced amnesia mouse model. Administration of KEMPFPKYPVEP peptide from ß-casein at 0.5 mg/kg (54.8 ± 2.5) and 2 mg/kg (57.9 ± 3.7) improved memory impairment in the amnesia mice in comparison with control (44.9 ± 3.4; p = 0.031 and p = 0.042, respectively) and increased dopamine (5.9 ± 3.8 [control] and 12.4 ± 6.2 [KEMPFPKYPVEP peptide]) and norepinephrine (7.7 ± 0.8 [control] and 9.9 ± 2.0 [KEMPFPKYPVEP peptide]) levels in the frontal cortex (p = 0.039 and p = 0.031, respectively). Collectively, our findings suggest that peptides in fermented dairy products prevent cognitive decline and support previously reported observations.


Assuntos
Amnésia/tratamento farmacológico , Caseínas/química , Peptídeos/administração & dosagem , Amnésia/metabolismo , Amnésia/psicologia , Animais , Produtos Fermentados do Leite/análise , Modelos Animais de Doenças , Dopamina/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Norepinefrina/metabolismo , Peptídeos/química , Escopolamina/efeitos adversos , Navegação Espacial/efeitos dos fármacos
7.
Neuron ; 103(2): 203-216.e8, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31174959

RESUMO

The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology.


Assuntos
Lobo Frontal , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Lobo Frontal/embriologia , Lobo Frontal/crescimento & desenvolvimento , Lobo Frontal/metabolismo , Ontologia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Neurosci Lett ; 706: 207-210, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31108129

RESUMO

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy (1H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using 1H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (ß = -0.44, t = -3.09, p = 0.004) and glycine (ß = -0.68, t = -5.72, p < 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (ß = -0.11, t = -0.81, p = 0.42) whereas the effect of glycine remained significant (ß = -0.62, t = -4.38, p < 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.


Assuntos
Alcoolismo/metabolismo , Bebedeira/metabolismo , Lobo Frontal/metabolismo , Glicina/metabolismo , Adulto , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem
9.
Neurochem Res ; 44(7): 1764-1772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093904

RESUMO

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5-2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.


Assuntos
Etanol/farmacologia , Histamina/metabolismo , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Lobo Frontal/metabolismo , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Histamínicos H1/genética
10.
Brain Dev ; 41(7): 567-576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30954358

RESUMO

BACKGROUNDS: Metabotropic glutamate receptors, besides ionotropic receptors, mediate the complicated effect of glutamate on neurogenesis. Previous studies showed that metabotropic glutamate receptor 4 (mGluR4) regulated the proliferation and differentiation of neural stem/progenitor cells in vitro. However, little is known about the expression pattern of mGluR4 on prenatal central nervous system in vivo, especially the human being. METHODS: The normal brain tissues of human fetus were collected and divided into 4 groups according to the gestational age: 9-11 W, 14-16 W, 22-24 W and 32-36 W. Then the expression of mGluR4 was evaluated at mRNA and protein levels by means of PCR or immunohistochemistry method, respectively. The type of cell expressing mGluR4 was further investigated using double-labeling immunofluorescence. RESULTS: RT-PCR showed that the mRNA of mGluR4 could be detected in frontal lobe from 9 W to 32 W and real-time PCR quantificationally demonstrated the mRNA increased with development. Similarly, immnoreactivity was found in all layers of frontal lobe, VZ/SVZ. The intensity scores analysis showed that the staining became stronger and the range extended gradually with development. The double-labeling immunofluorescence showed that mGluR4 was present in neural stem/progenitor cells (nestin-positive cells after 9 W), young neurons (DCX-positive cells after 9 W), mature neurons (NeuN-positive cells in cortex after 32 W), as well as typical astrocytes (GFAP-positive cells in medulla after 32 W). CONCLUSION: These results supply an important evidence that mGluR4 is expressed in prenatal human cerebrum, and main kinds of cells related to neurogenesis are involved in its expression.


Assuntos
Encéfalo/embriologia , Lobo Frontal/embriologia , Receptores de Glutamato Metabotrópico/metabolismo , Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Feminino , Desenvolvimento Fetal/genética , Lobo Frontal/citologia , Lobo Frontal/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Gravidez , Receptores de Glutamato Metabotrópico/genética
11.
Neurotox Res ; 36(1): 39-48, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006828

RESUMO

Benzophenones, frequently used as UV chemical filters, are absorbed through the skin and can exert systemic adverse effects. So far, most of the data are related to their action on sex hormone receptors whereas potential neurotoxic effect is expected mainly on the basis of in vitro studies. The aim of the present study was to determine concentrations of BP-2, oxidative stress and apoptosis markers in the rat brain after topical administration of this compound. Male Wistar rats were treated dermally with BP-2 (100 mg/kg, 4 weeks), and next, blood and tissue BP-2 concentrations and oxidative stress and apoptotic markers in the frontal cortex and hippocampus were determined. After dermal BP-2 administration, blood level of this compound was about 300 ng/ml while in the liver and adipose tissue 1354 and 823 ng/g wt tissue, respectively. In the studied brain structures, the levels of the test compound were from 5 to 19 ng/g tissue. In the hippocampus, where BP-2 level was about 3.5-fold lower than in the frontal cortex, no significant changes in either oxidative stress and apoptosis markers were observed. There was also no change in apoptosis markers in the frontal cortex but unexpectedly the oxidative stress markers were reduced. The research showed that BP-2 passes through the blood-brain barrier but its concentration in the brain structures are much lower than in the blood. This compound did not exacerbate oxidative stress and apoptosis markers in the hippocampus and frontal cortex, and even lowered oxidative stress in the frontal cortex.


Assuntos
Apoptose/efeitos dos fármacos , Benzofenonas/análise , Benzofenonas/toxicidade , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Lobo Frontal/química , Lobo Frontal/metabolismo , Hipocampo/química , Hipocampo/metabolismo , Masculino , Ratos Wistar
12.
PLoS One ; 14(4): e0215210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30995237

RESUMO

PURPOSE: The principal excitatory neurotransmitter glutamate plays an important role in many central nervous system disorders. Because glutamate resides predominantly in glutamatergic neurons, its relaxation properties reflect the intracellular environment of glutamatergic neurons. This study developed an improved echo time-independent technique for measuring transverse relaxation time and demonstrated that this radio frequency (RF)-driven longitudinal steady state technique can reliably measure glutamate transverse relaxation in the frontal cortex, where structural and functional abnormalities have been associated with psychiatric symptoms. METHOD: Bloch and Monte Carlo simulations were performed to improve and optimize the RF-driven, longitudinal, steady-state (MARzss) technique to significantly shorten scan time and increase measurement precision. Optimized four-flip angle measurements at 0°,12°, 24°, and 36° with matched repetition time were used in nine human subjects (6F, 3M; 27-49 years old) at 7 Tesla. Longitudinal and transverse relaxation rates for glutamate were measured from a 2 x 2 x 2 cm3 voxel placed in three different brain regions: gray matter-dominated medial prefrontal lobe, white matter-dominated left frontal lobe, and gray matter-dominated occipital lobe. RESULTS: Compared to the original MARzss technique, the scan time per voxel for measuring glutamate transverse relaxation was shortened by more than 50%. In the medial frontal, left frontal, and occipital voxels, the glutamate T2 was found to be 117.5±12.9 ms (mean ± standard deviation, n = 9), 107.3±12.1 (n = 9), and 124.4±16.6 ms (n = 8), respectively. CONCLUSIONS: The improvements described in this study make the MARZSS technique a viable tool for reliably measuring glutamate relaxation from human subjects in a typical clinical setting. It is expected that this improved technique can be applied to characterize the intracellular environment of glutamatergic neurons in a variety of brain disorders.


Assuntos
Lobo Frontal , Ácido Glutâmico/metabolismo , Imagem por Ressonância Magnética , Substância Branca , Adulto , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo
13.
Recent Pat Biotechnol ; 13(2): 137-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973107

RESUMO

BACKGROUND: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. OBJECTIVE: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. METHOD: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. RESULTS: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. CONCLUSION: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.


Assuntos
Analgésicos Opioides/farmacologia , Antioxidantes/farmacologia , Tolerância a Medicamentos/genética , Genes fos , Morfina/farmacologia , Dor/tratamento farmacológico , alfa-Tocoferol/farmacologia , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Dor/genética , Dor/metabolismo , Dor/fisiopatologia , Patentes como Assunto , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
14.
Neurotox Res ; 36(1): 91-100, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30989482

RESUMO

NBOMes are N-benzylmethoxy derivatives of the 2C family hallucinogens. 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is one of the commonly used illicit drugs. It exhibits high binding affinity for 5-HT2A/C and 5-HT1A serotonin receptors. Activation of 5-HT2A receptor induces head-twitch response (HTR) in rodents, a behavioral marker of hallucinogen effect in humans. There is not much data on neurochemical properties of NBOMes. Therefore, we aimed to investigate the effect of 25I-NBOMe on extracellular level of dopamine (DA), serotonin (5-HT), and glutamate (GLU) in the rat frontal cortex, tissue contents of monoamines, and hallucinogenic activity in rats. The extracellular levels of DA, 5-HT, and GLU were studied using microdialysis in freely moving animals. The tissue contents of DA, 5-HT and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the rat frontal cortex. We also tested a drug-elicited HTR. 25I-NBOMe at doses 1, 3, and 10 mg/kg (sc) increased extracellular DA, 5-HT, and GLU levels, enhanced tissue content of 5-HT and 5-HIAA, but did not affect tissue level of DA and its metabolites. The compound exhibited an inverted U-shaped dose-response curve with respect to the effect on extracellular DA and 5-HT levels, but a U-shaped dose-response curve was observed for its effect on GLU release and HTR. The data from our study suggest that hallucinogenic activity of 25I-NBOMe seems to be related with the increase in extracellular GLU level-mediated via cortical 5-HT2A receptors. The influence of 25I-NBOMe on 5-HT2C and 5-HT1A receptors may modulate its effect on neurotransmitters and HTR.


Assuntos
Drogas Desenhadas/farmacologia , Dimetoxifeniletilamina/análogos & derivados , Dopamina/metabolismo , Lobo Frontal/metabolismo , Ácido Glutâmico/metabolismo , Alucinógenos/farmacologia , Serotonina/metabolismo , Animais , Dimetoxifeniletilamina/farmacologia , Movimentos da Cabeça/efeitos dos fármacos , Masculino , Ratos Wistar
15.
Nature ; 568(7752): 420-423, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30894745

RESUMO

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the ß-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.


Assuntos
Encefalopatia Traumática Crônica , Microscopia Crioeletrônica , Interações Hidrofóbicas e Hidrofílicas , Dobramento de Proteína , Proteínas tau/química , Proteínas tau/ultraestrutura , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encefalopatia Traumática Crônica/metabolismo , Encefalopatia Traumática Crônica/patologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Humanos , Masculino , Modelos Moleculares
16.
Brain Behav ; 9(3): e01239, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30788911

RESUMO

INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.


Assuntos
Dopamina/metabolismo , Jogo de Azar , Levodopa/administração & dosagem , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo , Adulto , Azidas/metabolismo , Benzodiazepinas/metabolismo , Dopaminérgicos/administração & dosagem , Método Duplo-Cego , Lobo Frontal/metabolismo , Jogo de Azar/metabolismo , Jogo de Azar/psicologia , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Autocontrole , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
17.
Brain Struct Funct ; 224(4): 1417-1428, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30747315

RESUMO

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.


Assuntos
Cocaína/administração & dosagem , Lobo Frontal/efeitos dos fármacos , Glucose/metabolismo , Microglia/efeitos dos fármacos , Substância Branca/efeitos dos fármacos , Animais , Comportamento de Procura de Droga , Lobo Frontal/metabolismo , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/metabolismo , Macaca mulatta , Masculino , Microglia/metabolismo , Esquema de Reforço , Substância Branca/metabolismo
18.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740518

RESUMO

Cognitive decline with aging is often due to altered levels of protein expression. The NMDA receptor (NMDAR) and the complex of proteins surrounding the receptor are susceptible to age-related changes in expression. In the frontal cortex of aged mice, there is a significant loss of expression of the GluN2B subunit of the NMDAR, an increase in Fyn expression, and no change in PSD-95. Studies have also found that, in the frontal cortex, phosphorylation of GluN2B subunits and palmitoylation of GluN2 subunits and NMDAR complex proteins are affected by age. In this study, we examined some of the factors that may lead to the differences in the palmitoylation levels of NMDAR complex proteins in the frontal cortex of aged animals. The Morris water maze was used to test spatial learning in 3- and 24-month-old mice. The acyl-biotinyl exchange method was used to precipitate palmitoylated proteins from the frontal cortices and hippocampi of the mice. Additionally, brain lysates from old and young mice were probed for the expression of fatty acid transporter proteins. An age-related increase of palmitoylated GluN2A, GluN2B, Fyn, PSD-95, and APT1 (acyl protein thioesterase 1) in the frontal cortex was associated with poorer reference memory and/or executive functions. These data suggest that there may be a perturbation in the palmitoylation cycle in the frontal cortex of aged mice that contributes to age-related cognitive declines.


Assuntos
Envelhecimento/metabolismo , Disfunção Cognitiva/metabolismo , Função Executiva/fisiologia , Lobo Frontal/metabolismo , Memória/fisiologia , Envelhecimento/psicologia , Animais , Lipoilação , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Nutrients ; 11(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736353

RESUMO

Tryptophan-tyrosine (WY)-related peptides including the ß-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, ß-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.


Assuntos
Amnésia/tratamento farmacológico , Dipeptídeos/farmacologia , Dopamina/metabolismo , Memória/efeitos dos fármacos , Triptofano/farmacologia , Tirosina/farmacologia , Amnésia/induzido quimicamente , Animais , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Escopolamina
20.
Psychiatry Res ; 271: 649-657, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30791338

RESUMO

The purpose of this study was to investigate the effects and mechanism of repeated oral administration of gamma-aminobutyric acid (GABA) on anxiety-like behaviors induced by emotional stress. Male Sprague-Dawley rats were randomly divided into five groups (8 rats each): control, emotional stress model, three emotional stress + GABA-treated groups (0.5, 1, 2 mg/kg). The rats were given empty water bottles after the training of drinking water to induce emotional stress. Each group was treated with saline or different doses of GABA respectively for 21 consecutive days. Then open field and elevated plus maze were used to assess anxiety-like behaviors. Both frontal cortex and plasma NO metabolites nitrate and nitrite (NOx) levels were determined spectrophotometrically. Results showed that oral administration of GABA significantly reversed the stress-induced anxiety-like negative responses dose-dependently. The frontal cortex NOx levels were lower in stressed rats than in control group (P < 0.05), but higher in 2 mg/kg GABA-treated group than stress model group (P < 0.05). On the other hand, NOx levels in plasma showed a gradual decline trend. Collectively, these results suggest that short repeated oral administration of GABA has an anxiolytic-like effect possibly via preventing NO reduction caused by stress and improving availability of NO in the frontal cortex.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Estresse Psicológico/complicações , Ácido gama-Aminobutírico/uso terapêutico , Administração Oral , Animais , Ansiolíticos/administração & dosagem , Ansiedade/etiologia , Ansiedade/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Ácido gama-Aminobutírico/administração & dosagem
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