RESUMO
Investigations indicated that sn-2 palmitate have positive effects on brain development, although its mechanism remains largely unexamined. This research delved into how a diet abundant in sn-2 palmitate influenced the cognitive behavior of mice and elucidated the associated mechanisms using metabolomics and lipidomics. The study demonstrated that dietary sn-2 palmitate led to improved working memory and cognition in mice, as well as an increase in brain BDNF concentration when compared to those fed blend vegetable oil (BVO). This was because sn-2 palmitate feeding promoted the synthesis of very long-chain fatty acids (VLCPUFAs) for the lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) in the liver. This led to more efficient delivery of VLCPUFAs to the brain, as indicated by elevated concentration of LPC/LPE-VLCPUFAs in the liver and heightened expression of the major facilitator superfamily domain containing 2a (MFSD2A). In essence, this paper offered a potential mechanism by which sn-2 palmitate enhanced mouse neurodevelopment.
Assuntos
Encéfalo , Cognição , Fígado , Lisofosfatidilcolinas , Palmitatos , Animais , Lisofosfatidilcolinas/metabolismo , Camundongos , Fígado/metabolismo , Encéfalo/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/efeitos dos fármacos , Masculino , Palmitatos/metabolismo , Cognição/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ácidos Graxos/metabolismo , Ácidos Graxos/química , HumanosRESUMO
Alcoholic beverages flavour is complex and unique with different alcohol content, and the application of flavour perception could improve the objectivity of flavour evaluation. This study utilized electroencephalogram (EEG) to assess brain reactions to alcohol percentages (5 %-53 %) and Baijiu's complex flavours. The findings demonstrate the brain's proficiency in discerning between alcohol concentrations, evidenced by increasing physiological signal strength in tandem with alcohol content. When contrasted with alcohol solutions of equivalent concentrations, Baijiu prompts a more significant activation of brain signals, underscoring EEG's capability to detect subtleties due to flavour complexity. Additionally, the study reveals notable correlations, with δ and α wave intensities escalating in response to alcohol stimulation, coupled with substantial activation in the frontal, parietal, and right temporal regions. These insights verify the efficacy of EEG in charting the brain's engagement with alcoholic flavours, setting the stage for more detailed exploration into the neural encoding of these sensory experiences.
Assuntos
Bebidas Alcoólicas , Encéfalo , Eletroencefalografia , Etanol , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Encéfalo/metabolismo , Adulto , Bebidas Alcoólicas/análise , Masculino , Adulto Jovem , Feminino , Etanol/análise , Paladar , Aromatizantes/química , Percepção GustatóriaRESUMO
Introduction: Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy. Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aß1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level. Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-ß deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation. Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Cério , Curcumina , Estresse Oxidativo , Zircônio , Animais , Doença de Alzheimer/tratamento farmacológico , Células PC12 , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Zircônio/química , Zircônio/farmacocinética , Camundongos , Ratos , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Curcumina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Cério/química , Cério/farmacocinética , Cério/farmacologia , Cério/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Distribuição Tecidual , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Modelos Animais de Doenças , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacocinética , Estruturas Metalorgânicas/farmacologia , Masculino , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Hormonal contraceptives (HCs) are one of the most highly prescribed classes of drugs in the world used for both contraceptive and noncontraceptive purposes. Despite their prevalent use, the impact of HCs on the brain remains inadequately explored. This review synthesizes recent findings on the neuroscience of HCs, with a focus on human structural neuroimaging as well as translational, nonhuman animal studies investigating the cellular, molecular, and behavioral effects of HCs. Additionally, we consider data linking HCs to mood disorders and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress response as a potential mediator. The review also addresses the unique sensitivity of the adolescent brain to HCs, noting significant changes in brain structure and function when HCs are used during this developmental period. Finally, we discuss potential effects of HCs in combination with smoking-derived nicotine on outcomes of ischemic brain damage. Methodological challenges, such as the variability in HC formulations and user-specific factors, are acknowledged, emphasizing the need for precise and individualized research approaches. Overall, this review underscores the necessity for continued interdisciplinary research to elucidate the neurobiological mechanisms of HCs, aiming to optimize their use and improve women's health.
Assuntos
Encéfalo , Humanos , Animais , Feminino , Encéfalo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Contraceptivos Hormonais/farmacologia , Neurociências/métodos , Anticoncepcionais Orais Hormonais/farmacologiaRESUMO
Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the "monoamine hypothesis", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K+ channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K+ channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K+ channels, such as Kv, Kir and K2P, meaning the functioning of these drug via a "multi-target" manner. On the other hand, the scenario of antidepressants impinging K+ channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a "druggable target" to develop novel therapeutic compound to antagonize this psychiatry.
Assuntos
Antidepressivos , Canais de Potássio , Humanos , Antidepressivos/farmacologia , Canais de Potássio/metabolismo , Canais de Potássio/efeitos dos fármacos , Animais , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
This study aims to compare the efficacy of 5-alpha-reductase inhibitors (5ARIs) on anxiety and depression between long-term and short-term treatment followed by withdrawal in d-galactose (Dgal)-induced senescent male rats. Thirty-two, 8-week-old, male Wistar rats were divided into two groups: control rats and Dgal-treated rats (150 mg/kg/day; subcutaneously) for 18 weeks. At week 13, Dgal-treated rats were subdivided into three subgroups: (1) vehicle (DgV), (2) long-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 6 weeks (DgF), (3) short-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 2 weeks followed by a 4-week withdrawal period (DgW). Anxiety and depression were assessed using the elevated-plus maze (EPM) and splash test (ST). Blood was collected for biochemical analysis. After euthanasia, the brains were removed to examine brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and brain senescent markers. We found that DgV rats exhibited metabolic disturbance with a reduced preference index of the EPM, and grooming duration in ST. Increased brain neurotoxic metabolites, along with increased brain inflammation/oxidative stress, and reduced microglia complexity were observed in the DgV rats. Both therapeutic approaches improved metabolic parameters and preference index in the open arm of EPM in Dgal-treated rats, while grooming duration and microglia complexity were increased only in DgF rats. Our results indicate that Fin reduces depression-like and anxiety-like behaviors by reducing brain inflammation, oxidative stress, and brain senescent. In conclusion, long-term treatment with 5ARIs is more effective in alleviating depression than short-term treatment followed by withdrawal in Dgal-induced early senescent male rats.
Assuntos
Inibidores de 5-alfa Redutase , Envelhecimento , Ansiedade , Depressão , Finasterida , Ratos Wistar , Animais , Masculino , Finasterida/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Ratos , Inibidores de 5-alfa Redutase/farmacologia , Envelhecimento/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/toxicidade , Comportamento Animal/efeitos dos fármacosRESUMO
Long-term use of opioid drugs such as morphine can induce addiction in the central nervous system through dysregulation of the reward system of the brain. Deep brain stimulation (DBS) is a non-pharmacological technique capable of attenuating behavioral responses associated with opioid drug consumption and possesses the capability to selectively activate and target localized brain regions with a high spatial resolution. However, long-term implantation of electrodes in brain tissue may limit the effectiveness of DBS due to changes in impedance, position, and shape of the tip of the stimulation electrode and the risk of infection of nerve tissue around the implanted electrode. The main objective of the current study is to evaluate the effect of temporal interference (TI) brain stimulation on addictive behaviors of morphine-induced conditioned place preference (CPP) in rats. TI stimulation is a non-invasive technique used transcranially to modulate neural activity within targeted brain regions. It involves applying two high-frequency currents with slightly different frequencies, resulting in interference and targeted stimulation of different brain areas with the desired spatial resolution. The results indicated that TI stimulation with the amplitude of I 1 = I 2 = 0.5 mA, carrier frequency of 2 kHz, frequency difference of 25 Hz, ON-OFF stimulation frequency of 0.25 Hz, and total duration of 10 min in three consecutive days resulted in a significant reduction of morphine preference in the morphine-stimulation group in comparison with the morphine group (p < 0.001). These findings highlight the potential of TI stimulation as a modulatory intervention in mitigating the addictive properties of morphine and provide valuable insights into the therapeutic implications of this stimulation paradigm for treatment of opioid drugs in human subjects.
Assuntos
Estimulação Encefálica Profunda , Morfina , Animais , Morfina/farmacologia , Ratos , Estimulação Encefálica Profunda/métodos , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Analgésicos Opioides/farmacologia , Ratos Sprague-DawleyRESUMO
BACKGROUND: Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. RESULTS: In this study, we examine the effect of ß-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis. CONCLUSIONS: This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.
Assuntos
Encéfalo , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Material Particulado , Animais , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Material Particulado/toxicidade , Camundongos , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/metabolismo , Suplementos Nutricionais , Poluentes Atmosféricos/toxicidade , LipidômicaRESUMO
INTRODUCTION: Mental fatigue (MF) significantly affects both cognitive and physical performance. However, the precise mechanisms, particularly concerning neurotransmission, require further investigation. An implication of the role of dopamine (DA) and noradrenaline (NA) is stated, but empirical evidence for this theory still needs to be provided. To address this gap, we aim to investigate the role of brain neurotransmission in elucidating if, and how prolonged cognitive activity induces MF and its subsequent impact on cognitive performance. METHODS: This study (registration number: G095422N) will adopt a randomized cross-over design with sixteen healthy participants aged 18-35 years. The sessions include a familiarization, two experimental (DA: 20mg Methylphenidate; NA: 8mg Reboxetine) conditions, and one placebo (lactose tablet: 10mg) condition. A 60-minute individualized Stroop task will be used to investigate whether, and how the onset of MF changes under the influence of reuptake inhibitors. Attention and response inhibition will be assessed before and after the MF-inducing task using a Go/NoGo task. The integration of physiological (electroencephalography, heart rate), behavioral (attention, response inhibition), and subjective indicators (scales and questionnaires) will be used to detect the underlying mechanisms holistically. Data analysis will involve linear mixed models with significance at p<0.05. DISCUSSION: The integration of diverse techniques and analyses offers a comprehensive perspective on the onset and impact of MF, introducing a novel approach. Future research plans involve extending this protocol to explore the connection between brain neurotransmission and physical fatigue. This protocol will further advance our understanding of the complex interplay between the brain and fatigue.
Assuntos
Encéfalo , Estudos Cross-Over , Fadiga Mental , Metilfenidato , Transmissão Sináptica , Humanos , Fadiga Mental/fisiopatologia , Adulto , Adolescente , Adulto Jovem , Encéfalo/fisiologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Metilfenidato/farmacologia , Masculino , Feminino , Reboxetina , Cognição/fisiologia , Norepinefrina/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Atenção/fisiologia , Atenção/efeitos dos fármacos , Eletroencefalografia , Dopamina/metabolismoRESUMO
Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.
Drinking excessive amounts of alcohol during pregnancy can cause foetal alcohol spectrum disorder and other conditions in children that affect their physical and mental development. Many countries advise women who are pregnant or trying to conceive to avoid drinking alcohol entirely. However, surveys of large groups of women in Western countries indicate that most women continue drinking low to moderate amounts of alcohol until they discover they are pregnant and then stop consuming alcohol for the rest of their pregnancy. It remains unclear how this common drinking pattern affects the foetus. The instructions needed to build and maintain a human body are stored within molecules of DNA. Some regions of DNA called genes contain the instructions to make proteins, which perform many tasks in the body. Other so-called 'non-coding' regions do not code for any proteins but instead have roles in regulating gene activity. One way cells control which genes are switched on or off is adding or removing tags known as methyl groups to certain locations on DNA. Previous studies indicate that alcohol may affect how children develop by changing the patterns of methyl tags on DNA. To investigate the effect of moderate drinking during the early stages of pregnancy, Bestry et al. exposed pregnant mice to alcohol and examined how this affected the patterns of methyl tags on DNA in their offspring. The experiments found moderate levels of alcohol were sufficient to alter the patterns of methyl tags in the brains and livers of the newborn mice. Most of the changes were observed in non-coding regions of DNA, suggesting alcohol may affect how large groups of genes are regulated. Fewer changes in the patterns of methyl tags were found in mice whose mothers had diets rich in two essential nutrients known as folate and choline. Further experiments found that some of the affected mouse genes were similar to genes linked to foetal alcohol spectrum disorder and other related conditions in humans. These findings highlight the potential risks of consuming even moderate levels of alcohol during pregnancy and suggest that a maternal diet rich in folate and choline may help mitigate some of the harmful effects on the developing foetus.
Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Animais , Metilação de DNA/efeitos dos fármacos , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Camundongos , Humanos , Dieta , Masculino , Etanol/efeitos adversos , Etanol/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Transtornos do Espectro Alcoólico Fetal/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/embriologiaRESUMO
Intellectual drug doping in athletics by using stimulants that affect central nervous system functions has been diversified. Stimulants are regulated by the World Anti-Doping Agency according to their levels of urinary concentration. Positron emission tomography could evaluate how stimulants affect central nervous system functions. We aimed to evaluate the effect of stimulants on brain function by examining the difference in brain dopamine transporter occupancy by PET after administration of dl-methylephedrine or pseudoephedrine at the clinical maximum daily dose. Four PET scans without and with drug administration (placebo, dl-methylephedrine 150 mg and pseudoephedrine 240 mg) were performed. The concentrations of dl-methylephedrine and pseudoephedrine in plasma and urine were measured. DAT occupancies in the striatum with placebo, dl-methylephedrine and pseudoephedrine were calculated by PET images. The urinary concentration of dl-methylephedrine (12.7 µg/mL) exceeded the prohibited concentration (10 µg/mL), but the DAT occupancy with dl-methylephedrine (6.1%) did not differ (p = 0.92) from that with placebo (6.2%). By contrast, although the urinary concentration of pseudoephedrine (144.8 µg/mL) was below the prohibited concentration (150 µg/mL), DAT occupancy with pseudoephedrine was 18.4%, which was higher than that with placebo (p = 0.009). At the maximum clinical dose, dl-methylephedrine was shown to have weaker effects on brain function than pseudoephedrine.
Assuntos
Encéfalo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Tomografia por Emissão de Pósitrons , Pseudoefedrina , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Pseudoefedrina/farmacologia , Pseudoefedrina/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Adulto , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Adulto Jovem , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/urina , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dopagem Esportivo/prevenção & controle , Feminino , Efedrina/análogos & derivadosRESUMO
OBJECTIVE: The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. METHODS: Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. RESULTS: PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood-brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. CONCLUSION: By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. SIGNIFICANCE: This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.
Assuntos
Curcumina , Golpe de Calor , Nanopartículas , Curcumina/farmacologia , Curcumina/química , Animais , Golpe de Calor/tratamento farmacológico , Camundongos , Nanopartículas/química , Masculino , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Dendrímeros/química , Dendrímeros/farmacologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular , PoliaminasRESUMO
Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.
Assuntos
Acetofenonas , Doença de Alzheimer , Desenho de Fármacos , Imidazóis , Fármacos Neuroprotetores , Oximas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Oximas/química , Oximas/farmacologia , Oximas/síntese química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Animais , Relação Estrutura-Atividade , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Acetofenonas/química , Acetofenonas/farmacologia , Acetofenonas/síntese química , Estrutura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Acetilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Ratos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/químicaRESUMO
Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.
Assuntos
Ansiedade , Modelos Animais de Doenças , Hipocampo , Omeprazol , Receptor 5-HT1A de Serotonina , Estresse Psicológico , Animais , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Omeprazol/farmacologia , Masculino , Ratos , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ratos Wistar , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Serotonina/metabolismo , Núcleos da Rafe/metabolismo , Núcleos da Rafe/efeitos dos fármacos , RNA Mensageiro/metabolismo , Restrição Física , ImobilizaçãoRESUMO
High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open-field behavioral test was specially conducted to assess CBD's effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).
Assuntos
Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Canabidiol , Camundongos Endogâmicos C57BL , Nicotina , Estresse Oxidativo , Animais , Canabidiol/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Camundongos , Nicotina/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Animal/efeitos dos fármacosRESUMO
OBJECTIVE: To probe into the protective effect of different dose of secoisolariciresinol diglucoside(SDG) on brain of offspring of mice anainst oxidative damage and inflammatory reaction induced by maternal exposure to trans fatty acids(TFA) during gestation, and observe the the changes of regulating Nrf2/Keap1 pathway in the course. METHODS: 30 healthy female mice(C57BL/6) were divided into 5 groups randomly, they are respectively control group, TFA-exposed group, and three SDG-intervention groups(low-(TFA+LSDG), medium-(TFA+MSDG) and high-(TFA+HSDG)). The pregnancy mice of control group and TFA group were treated with distilled water and 60 mg/kg·d TFA by gavage, in the same time, the mice of three SDG-intervention groups were treated with 60 mg/kg·d TFA by gavage and fed with feed included SDG(10, 20 and 30 mg/kg). The treatment to pregnancy mice continued to birth of offspring. After 21 days of lactation, the offspring were killed under anesthesia and the experiment was ended. The coefficient of brain was calculated. The levels of superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), malondialdehyde(MDA), tumor necrosis factor-α(TNF-α), interferon-γ(IFN-γ) and amyloid-ß(Aß)of brain were detected. RT-PCR and Western Blot was used to detected gene expression and protein levels of nuclear factor erythroid-2 related factor 2(Nrf2), kelch-like ECH-associated protein 1(Keap1), quinone oxidoreductase 1(NQO1) and hemeoxygenase-l(HO-1). RESULTS: Compared with control group, the brain coefficient and Aß1-40 of offspring of TFA-group had no significant changes(P>0.05), the activity of SOD and GSH-Px reduced, the content of MDA, IFN-γ, TNF-α and Aß1-42 increased, the level of mRNA and protein expression of Nrf2, NQO1 and HO-1 decreased and the level of mRNA and protein expression of Keap1 increase because of the exposion to TFA during gestation and all the differences were statistically significant(P<0.05). Compared with TFA-group, the brain coefficient, Aß1-40 and the level of NQO1 mRNA of offspring of three SDG-intervention groups had no significant changes(P>0.05), the activity of SOD(the middle and high dose SDG intervention groups) and GSH-Px(three SDG-intervention groups) increased, the content of MDA(the middle and high dose SDG intervention groups), IFN-γ(the middle and high dose SDG intervention groups), TNF-α(three SDG-intervention groups) and Aß1-42(the middle and high dose SDG intervention groups) decreased, the mRNA expression of Nrf2 and HO-1(the middle and high dose SDG intervention groups) was up-regulated, the mRNA expression of Keap1(the middle and high dose SDG intervention group) decreased, proteic expression of Nrf2, NQO1 and HO-1 of three SDG-intervention groups increase and the level of protein of Keap1 decreased because of the intervention of SDG during gestation(P<0.05). CONCLUSION: These result suggest that maternal TFA exposure during gestation can result in oxidative stress and inflammation to brain of offspring in a way. SDG can protect brain of mice of offspring from TFA-induced oxidative injury by up-regulating the expression of mRNA and protein of Nrf2, down-regulating the expression of Keap1, accelerating expression of protein of NQO1 and HO-1 which are antioxidant protein lying downstream of pathway of Nrf2/Keap1.
Assuntos
Encéfalo , Butileno Glicóis , Glucosídeos , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ácidos Graxos trans , Animais , Feminino , Camundongos , Glucosídeos/farmacologia , Gravidez , Fator 2 Relacionado a NF-E2/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Estresse Oxidativo/efeitos dos fármacos , Butileno Glicóis/farmacologia , Ácidos Graxos trans/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Inflamação/metabolismo , Inflamação/induzido quimicamente , Exposição Materna/efeitos adversos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Malondialdeído/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD(P)H Desidrogenase (Quinona)/genéticaRESUMO
BACKGROUND: Chronic brain dyscirculation is one of the frequent type 2 diabetes mellitus (DM) complications and leads to patients' disability. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have been proven to have advantages for cardiovascular system, but their effect on the central nervous system (CNS) has not been studied enough. AIM: To study empagliflozin effect on CNS damage functional and laboratory parameters in patients with type 2 DM and, under experimental conditions, to investigate the mechanisms of the drug neurotropic effect. MATERIALS AND METHODS: The clinical part of the study included patients with type 2 DM on metformin monotherapy (n=39). Patients with a target glycated hemoglobin level formed the "MET" group (n=19), in patients with a non-target glycated hemoglobin level empagliflozin was co-administered for the following 6 months (the "MET+EMPA" group, n=20). Healthy volunteers comprised the control group (n=16). The cognitive status and neuron-specific enolase (NSE) and neurofilament light chains (NLC) concentration were studied. DM was modeled in rats, thereafter the rats were treated with empagliflozin for 8 weeks. Microglia activation was assessed using anti-Iba-1 antibodies and morphological changes in neurons when stained by the Nissl method. RESULTS: Both in the "MET+EMPA" and the "MET" groups cognitive deficits were observed, according to the Montreal Cognitive Assessment (MOCA) (24.0 (23.0; 27.0) and 25.0 (21.0; 27.0) points) and the Mini-Mental State Examination (MMSE) (23.75 (23.0; 27.0) and 25.0 (21.0; 27.0) points). Empagliflozin therapy led to the cognitive status normalization after 6 months (26.5 (24.0; 27.0) points according to the MOCA scale and 27.5 (24.0; 28.0) points according to the MMSE). Initially, all patients had a significant increase of NSE (3.60 (2.66; 3.76) ng/ml in the "MET" group, 3.22 (2.94; 3.54) ng/ml in the "MET+EMPA¼ group, 2.72 (2.13; 2.72) ng/ml in the «Control¼ group) and NLC (4.50 (3.31; 5.56) ng/ml in the «MET¼ group, 5, 25 (3.75; 6.25) ng/ml in the «MET+EMPA¼ group comparing with 3.50 (2.25; 3.50) ng/ml in the «Control¼ group). Empagliflozin therapy led to a significant decrease in NLC already after 3 months (3.80 (3.25; 3.87) ng/ml), without significant influence on the NSE level. In the experiment, DM was characterized by an increased number of activated microgliocytes and destructured neurons and a decreased number of neurons with a normal structure. Empagliflozin therapy was accompanied by a decrease in the number of immunopositive microgliocytes in the CA1 zone of the hippocampus and an increase in the number of structured neurons. CONCLUSION: Type 2 diabetes mellitus is characterized by functional and biochemical changes in the central nervous system even under satisfactory glycemic control. Therapy with empagliflozin has a neuroprotective effect, manifested in an improvement in cognitive status and a decrease in NLC level. Empagliflozin reduces neuronal damage and abnormal microglial activation.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Ratos , Animais , Masculino , Feminino , Pessoa de Meia-Idade , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
Disorders of consciousness (DoC) represent a challenging and complex group of neurological conditions characterised by profound disturbances in consciousness. The current range of treatments for DoC is limited. This has sparked growing interest in developing new treatments, including the use of psychedelic drugs. Nevertheless, clinical investigations and the mechanisms behind them are methodologically and ethically constrained. To tackle these limitations, we combined biologically plausible whole-brain models with deep learning techniques to characterise the low-dimensional space of DoC patients. We investigated the effects of model pharmacological interventions by including the whole-brain dynamical consequences of the enhanced neuromodulatory level of different neurotransmitters, and providing geometrical interpretation in the low-dimensional space. Our findings show that serotonergic and opioid receptors effectively shifted the DoC models towards a dynamical behaviour associated with a healthier state, and that these improvements correlated with the mean density of the activated receptors throughout the brain. These findings mark an important step towards the development of treatments not only for DoC but also for a broader spectrum of brain diseases. Our method offers a promising avenue for exploring the therapeutic potential of pharmacological interventions within the ethical and methodological confines of clinical research.
Assuntos
Encéfalo , Transtornos da Consciência , Humanos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Transtornos da Consciência/tratamento farmacológico , Transtornos da Consciência/metabolismo , Transtornos da Consciência/fisiopatologia , Modelos Neurológicos , Aprendizado Profundo , MasculinoRESUMO
In this study, we investigated the neuroprotective effect of a water extract of ginseng (WEG) obtained via low-temperature extraction of the brain of mice with Parkinson's disease (PD) and the ameliorative effect on the damaged intestinal system for the treatment of dyskinesia in PD mice. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was injected intraperitoneally into male C57BL/6 mice to establish a PD model, and WEG was given via oral gavage. The results indicated that WEG could protect the damaged neuronal cells of the mice brain, inhibit the aggregation of α-synuclein (α-Syn) in the brain, and increase the positive expression rate of tyrosine hydroxylase (TH). WEG significantly improved intestinal damage and regulated intestinal disorders (P<0.05). WEG intervention increased the levels of beneficial bacteria, such as Lactobacillus, and normalized the abundance and diversity of colonies in the intestine of mice. Our results suggested that WEG protected neurons in the brain of PD mice via inhibiting the aggregation of α-Syn in the brain and increasing the positive expression level of TH in the brain. WEG regulated the gut microbiota of mice, improved the behavioral disorders of PD mice, and offered some therapeutic effects on PD mice.