Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 17.093
Filtrar
1.
J Pharm Biomed Anal ; 177: 112874, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31542420

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects daily life. Schisandra chinensis (Turcz.) Baill. Fructus (SCF) and Alpinia oxyphylla Miq. Fructus (AOF) have been regarded as classical herbs for dementia since ancient times. Alpinia oxyphylla Miq.-Schisandra chinensis (Turcz.) Baill. herb pair (ASHP) is the compatible form of the two herbs. Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established for the simultaneous determination of protocatechuic acid, chrysin, schisandrin, gomisin A, gomisin B, nootkatone, deoxyschizandrin, schisandrin B and schisandrin C in rat plasma. The pharmacokinetic differences of the above nine active components in normal rats and AD model rats after oral administration of SCF, AOF, and ASHP ethanol extracts were investigated. Chloramphenicol and bifendate were used as the internal standards. Extraction of plasma sample was by liquid-liquid extraction with ethyl acetate. A SBC18 column (2.1 mm × 100 mm, 1.8 µm) was used in this experiment at a flow rate of 0.3 mL/min at 30 °C with linear gradient elution using acetonitrile and water containing 0.1% formic acid. This study showed ASHP can improve the absorption of protocatechuic acid, chrysin, schisandrin, gomisin B, nootkatone, deoxyschizandrin, schisandrin B and schisandrin C in vivo and slow down part of these components' elimination. In addition, compared with normal rats, the pharmacokinetic parameters changed significantly in AD model rats' plasma after oral administration of ASHP. Hence, these may be the pharmacokinetic mechanism of ASHP, in addition to serving as a potential agent in the treatment of AD.


Assuntos
Alpinia/química , Doença de Alzheimer/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Schisandra/química , Administração Oral , Doença de Alzheimer/sangue , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/toxicidade , Animais , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Humanos , Injeções Intraventriculares , Masculino , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Ratos , Espectrometria de Massas em Tandem/métodos
2.
Horm Metab Res ; 51(10): 678-685, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31487748

RESUMO

Nesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce ß3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the ß3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on ß3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.


Assuntos
Tecido Adiposo Marrom/fisiologia , Antagonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Metabolismo Energético , Propanolaminas/administração & dosagem , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Nervoso Simpático/efeitos dos fármacos , Termogênese/efeitos dos fármacos
3.
Int J Neurosci ; 129(12): 1203-1212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31393204

RESUMO

Purpose of the study: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it is well established that KM plays a protective role to develop Alzheimer's disease. The current study aimed at evaluating the effect of intracerebroventricular micro-injection of KM on memory retention of passive avoidance learning (MRPAM) and identifying the potentially related cholinergic mechanisms (ChMs) in rats. Materials and methods: In the current study, male Wistar rats randomly divided into control, vehicle and KM (10, 20 and 40 µg/rat) groups. Moreover, MRPAM was evaluated by shuttle box test. The role of ChM was studied using non-selective and selective acetylcholine antagonists (scopolamine [SCN], 4-DAMP and methoctramine [MN], respectively) as well as pirenzepine (PZ) in combination with KM. Results: The employment of KM (40 µg/rat) improved the SCN-induced memory impairment in MRPAM. Co-treatment with KM (40 µg/rat) plus 4-DAMP significantly increased the step-through latency (STL, P < 0.05; 167 ± 28 s) and decreased the total dark chamber (TDC, P < 0.05; 121 ± 31 s) compared with those of the 4-DAMP group (STL: 75 ± 13 s; TDC: 178 ± 46 s). Co-treatment with KM (40 µg/rat) plus PZ attenuated STL, and also increased TDC (P < 0.01; 220 ± 28 s) compared with those of the PZ group. Co-treatment with KM (10 and 20 µg/rat) and MN increased STL (P < 0.05), and deceased TDC compared with those of the MN group (P < 0.01). Conclusions: Totally, the results of the present study showed that cholinergic system may be involved in improving effect of KM on SCN-induced memory impairment.


Assuntos
Acetilcolina/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas Colinérgicos/administração & dosagem , Quempferóis/administração & dosagem , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Animais , Aprendizagem da Esquiva/fisiologia , Diaminas/administração & dosagem , Injeções Intraventriculares , Masculino , Memória/fisiologia , Microinjeções , Piperidinas/administração & dosagem , Pirenzepina/administração & dosagem , Ratos Wistar , Escopolamina/administração & dosagem
4.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340436

RESUMO

Status epilepticus may decrease mitochondrial biogenesis, resulting in neuronal cell death occurring in the hippocampus. Sirtuin 1 (SIRT1) functionally interacts with peroxisome proliferator-activated receptors and γ coactivator 1α (PGC-1α), which play a crucial role in the regulation of mitochondrial biogenesis. In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure activity. SIRT1, PGC-1α, and other key proteins involving mitochondrial biogenesis and the amount of mitochondrial DNA were investigated. SIRT1 antisense oligodeoxynucleotide was used to evaluate the relationship between SIRT1 and mitochondrial biogenesis, as well as the mitochondrial function, oxidative stress, and neuronal cell survival. Increased SIRT1, PGC-1α, and mitochondrial biogenesis machinery were found in the hippocampus following experimental status epilepticus. Downregulation of SIRT1 decreased PGC-1α expression and mitochondrial biogenesis machinery, increased Complex I dysfunction, augmented the level of oxidized proteins, raised activated caspase-3 expression, and promoted neuronal cell damage in the hippocampus. The results suggest that the SIRT1 signaling pathway may play a pivotal role in mitochondrial biogenesis, and could be considered an endogenous neuroprotective mechanism counteracting seizure-induced neuronal cell damage following status epilepticus.


Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Estado Epiléptico/genética , Animais , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Injeções Intraventriculares , Ácido Caínico/administração & dosagem , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Técnicas Estereotáxicas
5.
World Neurosurg ; 130: 470-473, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302272

RESUMO

BACKGROUND: Ventriculoperitoneal (VP) shunt infection, which is 1 of the most important complications of VP shunt is observed at a rate of 4%-17%. Staphylococcus epidermidis is the most common causative agent. Vancomycin-resistant Enterococcus (VRE) is an increasingly common nosocomial pathogen that rarely causes central nervous system infections globally. Current treatment options that have shown appreciable activity against various VRE infections include daptomycin, linezolid, inquinupristin/dalfopristin, and tigecycline. Daptomycin has a particular mode of action and a potent bactericidal activity, making it a useful addition to the clinician's antibiotic collection. Global surveillance data indicate <1.0% rates of daptomycin resistance in enterococci. CASE DESCRIPTION: Here, we describe, to the best of our knowledge, the first case of successful intraventricular plus intravenous use of tigecycline to treat VP shunt infections caused by daptomycin resistant VRE faecium. CONCLUSION: Tigecycline is a life-saving option in the treatment of resistant nosocomial infections but it has not yet been approved for use and there are not enough data in terms of dose and side effects associated with its use in children.


Assuntos
Antibacterianos/administração & dosagem , Infecção Hospitalar/tratamento farmacológico , Daptomicina/administração & dosagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Tigeciclina/administração & dosagem , Enterococos Resistentes à Vancomicina/patogenicidade , Derivação Ventriculoperitoneal/efeitos adversos , Administração Intravenosa , Feminino , Infecções por Bactérias Gram-Positivas/etiologia , Humanos , Lactente , Injeções Intraventriculares , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/microbiologia , Resultado do Tratamento
6.
Drug Des Devel Ther ; 13: 1957-1967, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354241

RESUMO

Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro. Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis). Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain-blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals. Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Compostos de Vanádio/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Injeções Intraventriculares , Masculino , Exame Neurológico , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Compostos de Vanádio/administração & dosagem
7.
Nat Commun ; 10(1): 2717, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222048

RESUMO

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.


Assuntos
Leptina/metabolismo , Fígado/metabolismo , Bulbo/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Infusões Intraventriculares , Injeções Intraventriculares , Leptina/administração & dosagem , Lipogênese/fisiologia , Lipoproteínas VLDL , Fígado/inervação , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Simpatectomia , Nervo Vago/fisiologia , Nervo Vago/cirurgia
8.
Cell Mol Life Sci ; 76(20): 3953-3967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250034

RESUMO

The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient's own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.


Assuntos
Lesões Encefálicas/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Interneurônios/citologia , Doenças Neurodegenerativas/terapia , Regeneração/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Transdiferenciação Celular , Reprogramação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Injeções Intraventriculares , Interneurônios/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurogênese/genética , Transplante de Células-Tronco/métodos
9.
Transl Psychiatry ; 9(1): 158, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164628

RESUMO

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ouabaína/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Compostos de Lítio/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos Wistar
10.
Acta Neurobiol Exp (Wars) ; 79(1): 73-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038486

RESUMO

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co­preconditioning effect of toll­like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co­preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty­eight hours after LPS and twenty­four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5­triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co­preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co­preconditioning with LPS and NTX resulted in a synergistic protective effect.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Precondicionamento Isquêmico/métodos , Lipopolissacarídeos/administração & dosagem , Naltrexona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Hipocampo/irrigação sanguínea , Injeções Intraventriculares , /prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estimulação Luminosa/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Resultado do Tratamento
11.
Drug Des Devel Ther ; 13: 1163-1170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043769

RESUMO

Purpose: Umbelliferone (Umb), a member of coumarin family, is found in many plants and is a promising molecule with potential anti-inflammatory, anti-oxidative, and anti-tumor activities. However, the effect of Umb on arthritis remains unclear. Methods: A rat model with Freund's complete adjuvant (FCA)-induced arthritis was developed and used to test the efficacy of Umb on arthritis rats. Rats were given an intragastric injection of Umb (20 and 40 mg/kg) once daily from days 21 to 28 after the administration of FCA. Hind paw volume was assessed using a volume meter. The pro-inflammatory cytokine levels and prostaglandin E2 (PEG2) level in serum and synovial fluid were detected by ELISA. HE staining was used to determine representative histological changes in joint tissues, and Western blot analysis was employed to study the effects of Umb on MAPK/NF-κB signaling pathway. Results: Our results showed that Umb suppressed the release of IL-6, IL-1ß, tumor necrosis factor-alpha, and PEG2. In addition, Umb could also dramatically ameliorate the pathological changes observed in rat joints. Based on the results of Western blot, we also observed that Umb could strikingly suppress the expression of MAPK/NF-κB pathway molecules. Conclusion: These results proved that treatment with Umb is very effective for arthritis and inhibiting the MAPK/NF-κB signaling pathway may be a potential therapeutic target for treatment of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Umbeliferonas/farmacologia , Animais , Artrite Experimental/metabolismo , Citocinas/biossíntese , Citocinas/sangue , Injeções Intraventriculares , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Umbeliferonas/administração & dosagem , Umbeliferonas/química
12.
Neuroscience ; 410: 1-15, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078686

RESUMO

The contribution of Dopamine (DA) to minimal hepatic encephalopathy (MHE) has been demonstrated. However, recent studies have revealed that cholesterol (CHO) treatment substantially increased the risk of dementia. The objectives of this study were to investigate whether CHO was induced by DA overload and its involvement in DA-induced cognitive impairment in MHE. Our study showed that DA treatment triggered CHO biosynthesis via the activation of JNK3/SREBP2 signaling pathway in primary cultured astrocytes. Conditioned media from DA-treated astrocytes increased CHO uptake by primary cultured neurons and disrupted synaptic formations; at the same time, inhibition of CHO synthesis and transportation from astrocytes diminished the disruption of synaptogenesis, which indicates the involvement of CHO in the perturbation of neural synaptogenesis in vitro. Secondary secretion of DA from primary cultured neurons was stimulated by CHO secreted from astrocytes. DA induced synergistic decreases of PPARγ/pERK/pCREB expressions in the presence of CHO in neurons, leading to synergistic synaptic impairment. Memory impairments were observed in MHE/DA-treated rats, which were partially rescued by atorvastatin (ATVS) treatment, confirming the involvement of CHO burden in vivo. Overall, our study suggests that DA overload triggers obvious CHO production from astrocytes. Excessive CHO in turn triggered neurons to secrete abundant DA and DA burden in combination with CHO overload elicit the cognitive decline and memory loss via PPARγ/ERK/CREB pathway in MHE.


Assuntos
Encéfalo/metabolismo , Colesterol/metabolismo , Dopamina/toxicidade , Encefalopatia Hepática/metabolismo , Neurogênese/fisiologia , Sinapses/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Dopamina/administração & dosagem , Encefalopatia Hepática/patologia , Injeções Intraventriculares , Lipogênese/efeitos dos fármacos , Lipogênese/fisiologia , Neurogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/patologia
13.
Biomed Pharmacother ; 116: 108996, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132670

RESUMO

Our previous studies demonstrated that chronic systemic blockade of renin-angiotensin system (RAS) lowered blood pressure (BP) of Ren-2 transgenic rats (TGR) by the attenuation of both angiotensin II-dependent and sympathetic vasoconstriction. Since systemic RAS blockade also inhibits brain RAS, we were interested which effects on these two types of vasoconstriction will have the central RAS blockade in hypertensive TGR rats. Adult male heterozygous TGR rats and their Hannover Sprague Dawley (HanSD) controls were subjected to chronic systemic or intracerebroventricular administration of either angiotensin type 1 receptor blocker losartan or direct renin inhibitor aliskiren for 4 weeks. Additional groups of TGR and HanSD rats were used for the evaluation of acute peripheral and brain effects of angiotensin II. Both chronic systemic and intracerebroventricular administrations of losartan or aliskiren normalized BP of TGR animals. BP effect of brain RAS blockade was based solely on the reduced sympathetic vasoconstriction, while systemic RAS blockade attenuated both angiotensin II-dependent and sympathetic vasoconstriction. Surprisingly, neither peripheral nor central pressor effects of acute angiotensin II administration were enhanced in TGR compared to HanSD rats. In conclusion, sympathoinhibition represents the main mechanism of BP reduction in heterozygous TGR rats subjected to chronic brain or systemic RAS blockade, while peripheral attenuation of angiotensin II-dependent vasoconstriction during systemic RAS blockade is less important. Our data suggest that the participation of angiotensin II in BP control of adult heterozygous TGR rats is shifted from peripheral vasoconstriction to central sympathoexcitation. Similar mechanisms cannot be excluded in human essential hypertension.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Encéfalo/patologia , Coração/efeitos dos fármacos , Heterozigoto , Injeções Intraventriculares , Masculino , Óxido Nítrico/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
14.
Org Biomol Chem ; 17(21): 5305-5315, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31094391

RESUMO

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED50 values ranging from 0.32-0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg-1, p.o.) administration. A higher oral dose (30 mg kg-1. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.


Assuntos
Analgésicos Opioides/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Encefalina Metionina/farmacologia , Receptores Opioides/agonistas , Tiazóis/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Ciclização , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Ala(2)-MePhe(4)-Gly(5)-Encefalina/química , Encefalina Metionina/administração & dosagem , Encefalina Metionina/química , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Taxa Respiratória , Tiazóis/administração & dosagem , Tiazóis/química
15.
Neuroscience ; 409: 111-119, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047979

RESUMO

Benzodiazepines are one of the most commonly prescribed anxiolytic drugs in America, and between 2006 and 2015 prescription rates increased by an estimated 27.1%. Weight gain is a common side effect of these drugs and it may result from increased feeding caused by drug-enhanced food palatability. We investigated the role of specific GABAA receptor subtypes involved with benzodiazepine-induced food consumption through third ventricle injections of L-838,417, a partial agonist of GABAA α2, α3, and α5 subunits, and a full antagonist of the α1 receptor subunit. A microanalysis of the licking behavior of adult male rats to a sucrose solution was used to isolate drug effects on specific consummatory behaviors that include: hedonic taste evaluation, food approach behavior, and oromotor function. L-838,417 dose-dependently increased intake through increases in the motivation to approach the solution (shorter pause intervals between bouts of licking) and through enhancement of measures associated with hedonic taste evaluation. Oromotor depressant effects previously associated with broad-spectrum benzodiazepine receptor agonists were not observed. These results indicate that nuclei in proximity to the ventricles respond to GABAA α2, α3, or α5 activation to induce motivation to feed, absent of α1 receptor subunit activation. Furthermore, activation of the α1 subunit is not necessary for benzodiazepine hyperphagia and may instead contribute to the oromotor depressant and sedative properties of classic benzodiazepine agonists. Hypothalamic nuclei such as the paraventricular nucleus may be involved in the benzodiazepine-increased motivation to feed, while the parabrachial nucleus of the hindbrain could contribute to benzodiazepine-induced enhancement of taste palatability.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Fluorbenzenos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Motivação/efeitos dos fármacos , Triazóis/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Sacarose
16.
Neurobiol Learn Mem ; 162: 9-14, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047997

RESUMO

Nociceptin/Orphanin FQ (N/OFQ) plays an important role in the regulation of spatial, fear and recognition memories. N/OFQ receptors are highly distributed in the perirhinal cortex, which is a key brain area involved in modulating novel object recognition (NOR) memory. However, the role of N/OFQ in NOR memory in the perirhinal cortex was still unknown. Moreover, the effects of N/OFQ on different stages of NOR memory were still unclear. In NOR task, we found that pre-training intracerebroventricular (icv) injection of N/OFQ (0.3 and 1 nmol) impaired long-term memory in a dose-dependent manner. However, icv infusion of N/OFQ immediately after training did not affect NOR memory consolidation even at a high dose of 3 nmol. Pre-test icv injection of N/OFQ (1 nmol) also did not influence NOR memory retrieval. These data indicate that N/OFQ negatively modulates long-term NOR memory during the acquisition phase. Furthermore, the amnesia effect of N/OFQ (1 nmol, icv) could be antagonist by pre-treatment with the selective N/OFQ receptor antagonist [Nphe1]N/OFQ(1-13)NH2 (10 nmol, icv), indicating pharmacological specificity. Then, we found that pre-training infusion of N/OFQ (0.1 and 0.3 nmol/side) into the bilateral perirhinal cortex impaired long-term NOR memory, suggesting the perirhinal cortex is a critical brain structure in mediating the amnesic effect of N/OFQ in NOR task. In conclusion, our data, for the first time, indicate that N/OFQ in the perirhinal cortex impairs NOR memory acquisition through the NOP receptors.


Assuntos
Memória de Longo Prazo/efeitos dos fármacos , Peptídeos Opioides/farmacologia , Córtex Perirrinal/efeitos dos fármacos , /efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Somatostatina/análogos & derivados , Somatostatina/farmacologia
17.
Bull Exp Biol Med ; 166(6): 811-815, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020581

RESUMO

We assessed changes of olfactory bulbs in rata with 6-hydroxydopamine destruction of the substantia nigra. The expression of marker proteins of immature and differentiated neurons and glia (vimentin, PSA-NCAM, tyrosine hydroxylase, and S100) was analyzed by immunohistochemical and morphometric methods. The number of periglomerular dopamine neurons and astroglia in the olfactory bulbs increased on the side of toxin injection and expression of PSA-NCAM and vimentin increased in the rostral migratory stream. Destruction of the substantia nigra shifted differentiation of neuronal progenitors towards the dopaminergic phenotype and increased their survival in the olfactory bulbs, which can be explained by increased expression of PSA-NCAM.


Assuntos
Neuroglia/patologia , Neurônios/patologia , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/patologia , Adaptação Fisiológica , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Atividade Motora/fisiologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/metabolismo , Oxidopamina/administração & dosagem , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Ratos , Ratos Wistar , Proteínas S100/genética , Proteínas S100/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Vimentina/genética , Vimentina/metabolismo
18.
Bull Exp Biol Med ; 166(6): 793-796, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028587

RESUMO

One of the most common models of sporadic form of Alzheimer's disease is injection of streptozotocin into the lateral ventricles of rat brain. In 3 months after this injection, an increase in the expression of astroglia in the corpus callosum and a decrease in the thickness of the corpus callosum and intensity of its staining with luxol fast blue were observed. This can reflect a decrease in the content of myelinated fibers. In layer V of the sensorimotor cortex, intensive degeneration of neurons was revealed. The lateral ventricles were significantly enlarged and the expression of PSA-NCAM protein, a marker of immature neurons, was reduced in subventricular zone, which can be associated with disturbed neurogenesi.


Assuntos
Doença de Alzheimer/patologia , Astrócitos/patologia , Corpo Caloso/patologia , Ventrículos Laterais/patologia , Fibras Nervosas Mielinizadas/patologia , Córtex Sensório-Motor/patologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores/metabolismo , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Indóis , Injeções Intraventriculares , Ventrículos Laterais/metabolismo , Masculino , Fibras Nervosas Mielinizadas/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Wistar , Córtex Sensório-Motor/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Estreptozocina/administração & dosagem
19.
Neurobiol Aging ; 79: 66-74, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029017

RESUMO

Metabolic conditions during brain development may have long-term consequences on brain metabolism, thereby influencing the risk of neurodegenerative disease in later life. To ascertain the long-term consequences of omega-3 (ω3) fatty acid deficiency during brain development on oxidative fatty acid degradation in the brain and the development of Alzheimer-like pathology, wild-type (WT) female mice were fed diets that were either replete or deficient in ω3 fatty acids for 5 weeks. These females were then mated with hemizygous 5xFAD male transgenic (TG) mouse models of Alzheimer's disease, and the progeny were continued on diets that were either ω3-replete or ω3-deficient. When the progeny were 6 months of age, they received radiolabeled arachidonic acid (ARA) by intracerebroventricular injection. Five days after these injections, the brains were harvested and oxidative degradation of the radiolabeled ARA was characterized. Among the progeny of female mice on an ω3-replete diet, TG progeny had lower PSD-95 expression and higher oxidative ARA degradation than WT progeny. Progeny on an ω3-deficient diet, however, had no significant differences in PSD-95 expression between TG and WT mice, or in the extent of ARA degradation. In TG mice, an ω3-deficient diet reduced oxidative ARA degradation to a greater extent than in WT mice. The reductions in oxidative ARA degradation occurred even if the progeny of female mice on an ω3-deficient diet resumed an ω3-replete diet immediately on weaning. These results demonstrate that dietary ω3 fatty acid deficiency during development can cause long-term changes in the expression of a synaptic marker and long-term reductions in the rate of ARA degradation in the WT brain, which are not completely alleviated by an ω3-replete diet after weaning. The elimination of differences between TG and WT mice by an ω3-deficient diet suggests that mechanisms regulating PSD-95 expression and the oxidative degradation of ARA are related and that the timing of dietary ω3 intake during development may influence Alzheimer's disease-related pathological changes later in life.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Ácidos Graxos Ômega-3/deficiência , Ácidos Graxos/metabolismo , Animais , Ácido Araquidônico/administração & dosagem , Ácido Araquidônico/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Expressão Gênica , Injeções Intraventriculares , Masculino , Camundongos Transgênicos , Oxirredução , Estresse Oxidativo
20.
Exp Neurol ; 316: 12-19, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30930097

RESUMO

MicroRNAs (miRNAs) have been widely reported to induce posttranscriptional gene silencing and led to an explosion of new strategies for the treatment of human disease. It has been reported that the expression of MicroRNA-132 (miR-132) are altered both in the blood and brain after stroke. However, the effect of miR-132 on blood-brain barrier (BBB) disruption in ischemia stroke has not been studied. Here we will investigate the effects of miR-132 on the permeability of BBB after ischemic stroke and explore the potential mechanism underlying observed protection. Eight week-old mice were injected intracerebroventricularly with miR-132, antagomir-132 or agomir negative control (agomir-NC) 2 h before middle cerebral artery occlusion (MCAO), followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. BBB permeability and integrity were measured by Evan's blue extravasation and brain water content. The expression of tight junction proteins was detected by immnostaining and Western blots. The level of MiR-132 and its targeted gene Mmp9 were assayed. Treatment with exogenous MiR-132 (agomir-132) decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control mice. Agomir-132 increased the level of MiR-132 in brain tissue, suppressed the expression of MMP-9 mRNA and decreased the degradation of tight junction proteins VE-cadherin and ß-Catenin in ischemic stroke mice. Inhibition of MMP-9 has a similar protective effect to agomir-132 on infraction volume, brain edema, and tight-junction protein expression after MCAO. Our results indicated that miR-132/MMP-9 axis might be a novel therapeutic target for BBB protection in ischemic stroke.


Assuntos
Arteriopatias Oclusivas/tratamento farmacológico , Barreira Hematoencefálica/patologia , MicroRNAs/uso terapêutico , Artéria Cerebral Média , Animais , Arteriopatias Oclusivas/patologia , Arteriopatias Oclusivas/psicologia , Edema Encefálico/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Isquemia Encefálica/psicologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/psicologia , Injeções Intraventriculares , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/administração & dosagem , Desempenho Psicomotor , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/psicologia , Proteínas de Junções Íntimas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA