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1.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Life Sci ; 240: 117099, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760098

RESUMO

Obviously, delivery of the medications to the brain is more difficult than other tissues due to the existence of a strong obstacle, which is called blood-brain barrier (BBB). Because of the lipophilic nature of this barrier, it would be a complex (and in many cases impossible) process to cross the medications with hydrophilic behavior from BBB and deliver them to the brain. Thus, novel intricate drug-carriers in nano scales have been recently developed and suitably applied for this purpose. One of the most important categories of these hydrophilic medications, are reactivators for acetyl cholinesterase (AChE) enzyme that facilitates the breakdown of acetylcholine (as a neurotransmitter). The AChE function is inhibited by organophosphorus (OP) nerve agents that are extremely used in military conflicts. In this review, the abilities of the nanosized drug delivery systems to perform as suitable vehicles for AChE reactivators are comprehensively discussed.


Assuntos
Encefalopatias/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/uso terapêutico , Sistemas de Liberação de Medicamentos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Portadores de Fármacos , Humanos , Nanoestruturas , Relação Estrutura-Atividade
3.
Fitoterapia ; 140: 104447, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31805306

RESUMO

According to the basic theories of traditional Chinese medicine, Gastrodia elata (GE) is clinically utilized for the treatment of cephalalgia and migraine. The gastrodigenin (p-hydroxybenzyl alcohol, HBA), one of the effective components of GE, may pass through the blood-brain barrier (BBB) to exert its pharmacological effects. This study aimed to investigate BBB permeability of HBA via in vitro hCMEC/D3 BBB model and in vivo microdialysis in rats. For the establishment of in vitro BBB model, hCMEC/D3 cells were used to construct the monolayer. The integrity of the monolayer was evaluated by TEER measurements, expression analysis of tight junction proteins (claudin-5, zo-1 and occludin) and apparent permeability coefficients (Papp) of fluorescein disodium. During the 6-day incubation of hCMEC/D3 cells, the values of TEER gradually increased and maintained above 100 Ω·cm2. Besides, the expression levels of claudin-5 and zo-1 in hCMEC/D3 cells increased over time, and tended to be stable, suggesting that integrity of the monolayer has been completely established. Moreover, the Papp of fluorescein disodium was 3.94 × 10-7 cm·s-1 after administration for 180 min, indicating that the monolayer retains the characteristics of BBB and can restrict the diffusion of hydrophilic small-molecule compounds. A sensitive HPLC method was established for HBA detection, and the transport rate of HBA was assessed by a transwell system. HBA crossed the hCMEC/D3 BBB model rapidly, but a plateau was observed when HBA concentrations were relatively similar between the two sides of transwell. Permeability assay revealed that 32.91% of HBA could penetrate the in vitro BBB model after 240 min of administration. In vivo BBB permeability was evaluated by determining the concentrations of HBA in blood and brain simultaneously. Following HBA administration, the samples of microdialysis were collected at 20, 40 and 60 min, and then every 30 min until the procedure ended. Pharmacokinetic parameters of HBA showed that HBA could pass through BBB and reach its maximum concentration at 40 min in blood and brain tissue. Furthermore, AUC0-t and AUC0-inf for the brain-to-blood distribution ratio of HBA were 0.1925 and 0.2083, respectively, indicating that approximately 20% of HBA in blood could pass through the BBB and subsequently transported into the brain. Both in vitro and in vivo experiments confirmed that HBA could penetrate the BBB. In summary, the findings of this study highlight that a promising amount of HBA in blood can pass through the BBB and exerts its pharmacological effects on central nervous system (CNS) diseases.


Assuntos
Álcoois Benzílicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Animais , Transporte Biológico , Linhagem Celular , Humanos , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley
4.
Toxicol Lett ; 319: 138-147, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730887

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that can be induced by heavy metals such as lead. However, there is limited information on the role of blood-brain barrier (BBB) in lead induced AD-like pathology. This study investigates the potential mechanism of lead exposure aggravating the progression of Alzheimer's disease in mice through the BBB. 200 mg/L and 500 mg/L lead acetate were given to C57BL/6J and APP/PS1 mice through drinking water from a week before mating, until the offspring were 7-months-old. 8 female juvenile mice in each group were selected for this investigation. Lead exposure increased blood lead concentration which revealed the internal exposure level, accelerated Aß1-42 deposition in APP/PS1 mouse cortexes and abnormal change in Zonula Occludin-1 (ZO-1) and Claudin-5 protein. It also increased the expression of p-tau in both the C57BL/6J and APP/PS1 mice, and decreased mRNA and protein expression in low-density lipoprotein receptor (LRP-1). Additionally, it increased the mRNA and protein expression of amyloid beta precursor protein (APP) and beta secretase 1 (BACE-1). The activated astrocytes increased in the brains of APP/PS1 mice, and coalesced around the Aß1-42 deposition after lead exposure. The main vessels in deutocerebrum were attached with Aß1-42 deposition. These results offer insight into the mechanism of preventing lead induced AD through cerebrovascular pathways.


Assuntos
Doença de Alzheimer/patologia , Barreira Hematoencefálica/patologia , Exposição Ambiental/efeitos adversos , Chumbo/toxicidade , Doença de Alzheimer/induzido quimicamente , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Claudina-5/efeitos dos fármacos , Claudina-5/genética , Progressão da Doença , Feminino , Chumbo/sangue , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/toxicidade , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/genética
5.
Chemosphere ; 239: 124751, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31518922

RESUMO

Bisphenol A (BPA) is a chemical monomer widely used in the production of hard plastics for food containers and personal items. Through improper industrial control and disposal, BPA has become a pervasive environmental contaminant, and toxicological studies have shown potent xenobiotic endocrine disruptor activity. Prenatal exposure in particular can lead to infertility and nervous system disorders characterized by behavioral aggression, depression, and cognitive impairment, thus necessitating careful hazard assessment. In this study, we evaluated BPA accumulation rate, blood-brain barrier (BBB) permeability, lethality, cardiotoxicity, behavioral effects, and impacts on multiple neurochemical pathways in zebrafish larvae. The bioconcentration factor (BCF) ranged from 1.95 to 10.0, resulting in a high rate of accumulation in the larval body. Also, high BBB permeability allowed BPA to accumulate at similar rates in both zebrafish and adult mouse (blood to brain concentration ratios of 3.2-6.7 and 1.8 to 5.5, respectively). In addition, BPA-exposed zebrafish larvae exhibited developmental deformities, reduced heart rate, and impaired behavioral patterns, including decreased total distance traveled, slower movement velocity, and altered color-preference. These impairments were associated with inhibition of the phenylalanine to dopamine synthesis pathway and an imbalance between excitatory and inhibitory neurotransmitter systems. Our results suggest that behavioral alteration in BPA-exposed zebrafish result from high accumulation and ensuing dysregulation of serotonergic, kynurenergic, dopaminergic, cholinergic, and GABAergic neurotransmitter systems. In conclusion, similarities in toxic responses to mammalian models highlight the utility of the zebrafish larva as a convenient model for screening environmental toxins.


Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Barreira Hematoencefálica/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Neurotransmissores/metabolismo , Fenóis/toxicidade , Peixe-Zebra/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Larva/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade
6.
Life Sci ; 242: 117210, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874166

RESUMO

OBJECTIVES: Exposure of healthy subjects to ambient airborne dusty particulate matter (PM) causes brain dysfunction. This study aimed to investigate the effect of sub-chronic inhalation of ambient PM in a designed special chamber to create factual dust storm (DS) conditions on spatial cognition, hippocampal long-term potentiation (LTP), inflammatory cytokines, and oxidative stress in the brain tissue. METHODS: Adult male Wistar rats (250-300 g) were randomly divided into four groups: Sham (clean air, the concentration of dusty PM was <150 µg/m3), DS1 (200-500 µg/m3), DS2 (500-2000 µg/m3) and DS3 (2000-8000 µg/m3). Experimental rats were exposed to clean air or different sizes and concentrations of dust PM storm for four consecutive weeks (exposure was during 1-4, 8-11, 15-16 and 20-23 days, 30 min, twice daily) in a real-ambient dust exposure chamber. Subsequently, cognitive performance, hippocampal LTP, blood-brain barrier (BBB) permeability and brain edema of the animals evaluated. As well as, inflammatory cytokines and oxidative stress indexes in the brain tissue measured using ELISA assays. RESULTS: Exposing to dust PM impaired spatial memory (p < 0.001), hippocampal LTP (p < 0.001). These disturbances were in line with the severe damage to respiratory system followed by disruption of BBB integrity (p < 0.001), increased brain edema (p < 0.001), inflammatory cytokines (p < 0.001) excretion and oxidative stress (p < 0.001) in brain tissue. CONCLUSIONS: Our study showed that exposure to ambient dust PM increased brain edema and BBB permeability, induced memory impairment and hippocampal LTP deficiency by increasing the inflammatory responses and oxidative stress in the brain of the rats.


Assuntos
Edema Encefálico/induzido quimicamente , Encéfalo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/efeitos adversos , Memória Espacial/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Exposição por Inalação/efeitos adversos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
7.
J Enzyme Inhib Med Chem ; 34(1): 712-727, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852270

RESUMO

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid - DBMA hybrids (1-13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), ß-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone - DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Metilaminas/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Masculino , Metilaminas/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química
8.
BMC Complement Altern Med ; 19(1): 320, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747940

RESUMO

BACKGROUND: Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation. METHODS: We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210-230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively. RESULTS: Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1ß, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation. CONCLUSIONS: QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.


Assuntos
Isquemia Encefálica/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Eur J Med Chem ; 183: 111694, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561044

RESUMO

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors.


Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Glioma/tratamento farmacológico , Isocitrato Desidrogenase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Eur J Med Chem ; 182: 111643, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31514017

RESUMO

Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides selective access to required nutrients and hormones, while removing waste and restricting exposure to potential harmful toxins, pathogens, and xenobiotics. Consequently, designing and selecting molecules that can overcame this protection system are unique and critical aspects of the CNS drug discovery. Here we review modern CNS pharmacokinetic concepts and methods suitable for early drug discovery, and medicinal chemistry strategies towards molecules with optimal CNS exposure.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Descoberta de Drogas , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
11.
Mol Cell Biochem ; 462(1-2): 85-96, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446614

RESUMO

Heat shock proteins (HSPs) may be induced by hypoxia and alleviate blood-brain barrier (BBB) damage. The neuroprotective effect of propofol has been reported. We aimed to identify whether propofol induced HSPs expression and protected BBB integrity. Mouse astrocytes and microglia cells were cultured and exposed to hypoxia and propofol. The expression of HSP27, HSP32, HSP70, and HSP90, and the translocation of heat shock factor 1 (HSF1) and Nuclear factor-E2-related factor 2 (Nrf2) were investigated. Mouse brain microvascular endothelial cells, astrocytes, and microglial cells were co-cultured to establish in vitro BBB model, and the effects of hypoxia and propofol as well as HSPs knockdown/overexpression on BBB integrity were measured. Hypoxia (5% O2, 5% CO2, 90% humidity) treatment for 6 h and 12 h induced HSP27, HSP32, and HSP70 expression. Propofol (25 µΜ) increased HSP27 and HSP32 expression, starting with exposure to hypoxia for 3 h. Propofol induced HSF1 translocation from cytoplasmic to nuclear compartment, and blockade of HSF1 inhibited HSP27 expression in mouse astrocytes when they were exposed to hypoxia for 3 h. Propofol induced Nrf2 translocation, and blockade of Nrf2 inhibited HSP32 expression in mouse microglial cells when they were exposed to hypoxia for 3 h. Propofol protected hypoxia-impaired BBB integrity, and the effects were abolished by blockade of HSF1 and Nrf2. Overexpression of HSP27 and HSP32 alleviated hypoxia-impaired BBB integrity, and blockade of HSP27 and HSP32 expression ameliorated propofol-mediated protection against BBB impairment. Propofol may protect hypoxia-mediated BBB impairment. The mechanisms may involve HSF1-mediated HSP27 expression and Nrf2-mediated HSP32 expression.


Assuntos
Barreira Hematoencefálica/metabolismo , Proteínas de Choque Térmico/metabolismo , Propofol/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Permeabilidade , Substâncias Protetoras/farmacologia
12.
Anticancer Res ; 39(8): 4265-4271, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31366516

RESUMO

BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed. PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed. RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months. CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/secundário , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
13.
Nanoscale ; 11(32): 15057-15071, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369016

RESUMO

To date, the delivery of therapeutic agents for malignant brain tumors (such as glioblastoma multiforme (GBM)) remains a significant obstacle due to the existence of the blood-brain barrier (BBB). A multitude of delivery systems (hydrogels, micelles, polymeric nanoparticles, etc.) have been proposed, yet many of them exhibit limited tumor-specific inhibition effects. Herein, a drug-encapsulated dual-functionalized thermosensitive liposomal system (DOX@P1NS/TNC-FeLP) was developed for targeted delivery across the BBB. Specifically, a GBM-specific cell-penetrating peptide (P1NS) and an anti-GBM antibody (TN-C) were conjugated onto the liposome surface for targeted delivery. In addition, superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin (DOX) were co-loaded inside the liposomes to achieve thermo-triggered drug release when applying an alternating magnetic field (AMF). Results demonstrated that P1NS/TNC-FeLPs readily transported across an in vitro BBB model and displayed a thermo-responsive and GBM-specific cellular uptake as well as drug release profile. Additionally, results from immunofluorescent (IF) staining and RT-qPCR further demonstrated that DOX@P1NS/TNC-FeLPs specifically entered U-87 human GBM cells and suppressed tumor cell proliferation without causing any significant impact on healthy brain cell function. As such, the novel DOX@P1NS/TNC-FeLPs presented potent and precise anti-GBM capability and, therefore, are suggested here for the first time as a promising DDS to deliver therapeutic agents across the BBB for GBM treatment.


Assuntos
Barreira Hematoencefálica/metabolismo , Doxorrubicina/química , Lipossomos/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Glioma/metabolismo , Glioma/patologia , Hemólise/efeitos dos fármacos , Nanopartículas de Magnetita/química , Camundongos , Temperatura Ambiente
14.
World Neurosurg ; 131: 234-241, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31351210

RESUMO

BACKGROUND: High-dose bevacizumab delivered via super selective intra-arterial cerebral infusion (SIACI) is one promising clinical trial combination for patients with glioblastoma (GBM). Although both continuous intravenous and intra-arterial administration of bevacizumab, and rechallenge with intravenous bevacizumab, have demonstrated improved survival, this is the first description of rechallenging GBM with SIACI of bevacizumab. CASE DESCRIPTION: We report a case of a 43-year-old woman with recurrent GBM who had received treatment from 3 clinical trials, including a rechallenge with SIACI of bevacizumab. First, she enrolled into a phase I/II trial for patients newly diagnosed with GBM (NCT01811498) and received 3 doses of SIACI bevacizumab over 180 days in addition to standard of care chemotherapy and radiation. Following progression, as indicated on her magnetic resonance imaging scan, she consented for a separate clinical trial for her disease and received 2 cycles of temozolomide with an investigational agent. The patient was removed from the study on tumor progression. Subsequently, she was rechallenged with SIACI of bevacizumab via a third clinical trial (NCT01269853) and then completed 3 intravenous infusions. After completing the third trial, her magnetic resonance imaging scan demonstrated improvement based on Response Assessment In Neuro-Oncology criteria. CONCLUSIONS: This is the first report to highlight the effect of rechallenging a patient with SIACI of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus intravenous bevacizumab for GBM and further explore theories of bevacizumab resistance.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Ensaios Clínicos como Assunto , Terapia Combinada , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/administração & dosagem , Evolução Fatal , Feminino , Glioblastoma/radioterapia , Glioblastoma/cirurgia , Humanos , Infusões Intra-Arteriais , Infusões Intravenosas , Imagem por Ressonância Magnética , Retratamento/métodos , Resultado do Tratamento
15.
Inflammopharmacology ; 27(5): 933-940, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313075

RESUMO

The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells. Injury of human brain endothelial cells can cause disruption of the BBB and severe injury to brain tissue. Signals mediated cysteinyl leukotrienes (cysLTs) and their receptors are involved in a variety of pathological conditions. In the current study, our results show that oxygen glucose-deprivation/reoxygenation (OGD/R) induced the expression of leukotriene receptor type 1 (cysLT1R) in brain endothelial cells. Blockage of cysLT1R by its specific antagonist montelukast suppressed OGD/R-induced altered permeability of the human brain endothelial cell (EC) monolayer. Mechanistically, montelukast treatment reversed OGD/R-induced reduction of the tight junction proteins occludin and zonula occludens-1 (ZO-1). Montelukast also ameliorated OGD/R-induced reduction of inhibitors of matrix metalloproteinases (TIMPs), such as TIMP-1 and TIMP-2. On the other hand, montelukast suppressed the expression and production of matrix metalloproteinases (MMPs) and cytokines including MMP-2, MMP-9, interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6). Using a murine middle cerebral artery occlusion brain injury model, we demonstrated that the administration of montelukast improved the surgery-induced brain injury and protected against disruption of brain endothelial junction proteins such as occludin and ZO-1. Collectively, our data suggest that montelukast might confer protective roles against injury in brain endothelial cells.


Assuntos
Acetatos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Sci Total Environ ; 689: 662-678, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279213

RESUMO

Microcystin-leucine-arginine (MC-LR), which produced by toxic cyanobacteria and widely present in eutrophic waters, has been shown to have potent acute hepatotoxicity. MC-LR has been revealed to inflict damage to brain, while the neurotoxicity of chronic exposure to MC-LR and mechanisms underlying it are still confusing. Here, the mice were exposed to MC-LR dissolved in drinking water at dose of 1, 7.5, 15, and 30 µg/L for consecutive 180 days. MC-LR accumulated in mouse brains and impaired the blood-brain barrier by inducing the expression of matrix metalloproteinase-8 (MMP-8), which was regulated by NF-κB, c-Fos and c-Jun. Furthermore, MC-LR exposure induced microglial and astrocyte activation and resultant neuroinflammatory response. This study highlights the risks to human health of the current microcystin exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Inflamação/fisiopatologia , Microcistinas/toxicidade , Junções Íntimas/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/fisiologia , Junções Íntimas/metabolismo
17.
Eur J Med Chem ; 179: 753-764, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284085

RESUMO

Over the latest years phytochemical consumption has been associated to a decreased risk of both the onset and the development of a number of pathological conditions. In this context indicaxanthin, a betalain pigment from Opuntia ficus-indica fruit, has been the object of sound research. Explored, at first, for its mere antioxidant potential, Indicaxanthin is now regarded as a redox-active compound able to exert significant poly-pharmacological effects against several targets in a number of experimental conditions both in vivo and in vitro. This paper aims to provide an overview on the therapeutical effects of indicaxanthin, ranging from the anti-inflammatory to the neuro-modulatory and anti-tumoral ones and favored by its high bioavailability. Moreover, biochemical and molecular modelling investigations are aimed to identify the pharmacological targets the compound is able to interact with and to address the challenging development in the future research.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Betaxantinas/farmacologia , Produtos Biológicos/farmacologia , Frutas/química , Neoplasias/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Compostos Fitoquímicos/farmacologia , Piridinas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Betaxantinas/química , Betaxantinas/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Neoplasias/patologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Opuntia/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Piridinas/química , Piridinas/isolamento & purificação , Relação Estrutura-Atividade
18.
Int J Pharm ; 567: 118485, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260781

RESUMO

Glioblastoma is a grade IV malignant glioma with high recurrence and metastasis and faces a therapeutic obstacle that the blood-brain barrier (BBB) severely hinders the brain entry and efficacy of therapeutic drugs. Previous studies suggest that borneol (BO) has been used to enhance interested drugs to penetrate the BBB. In this study, a borneol-modified nanomicelle delivery system was established to facilitate the brain entry of doxorubicin for glioblastoma therapy. Herein, we firstly conjugated borneol molecules with DSPE-PEG2000-COOH to synthesize a novel carrier DSPE-PEG2000-BO and also characterized its structure. Doxorubicin-loaded nanomicelles (DOX BO-PMs) were prepared using DSPE-PEG2000-BO via electrostatic interaction and the physicochemical properties were investigated. The average particle size and zeta potential of DOX BO-PMs were respectively (14.95 ±â€¯0.17)nm and (-1.27 ±â€¯0.06)mV, and the drug encapsulation efficiency and loading capacity in DOX BO-PMs were (95.69 ±â€¯0.49)% and (14.62 ±â€¯0.39)%, respectively. The drug release of the DOX BO-PMs exhibited a both time- and pH-dependent pattern. The results demonstrated that DOX BO-PMs significantly enhanced the transport efficiency of DOX across the BBB and also exhibited a quick accumulation in the brain tissues. The in vitro anti-proliferation assay results suggested that DOX BO-PMs exerted a strong inhibitory effect on proliferation of glioblastoma cells. Importantly, in vivo antitumor results demonstrated that DOX BO-PMs significantly inhibited the tumor growth and metastasis of glioblastoma. In conclusion, DOX BO-PMs can improve the glioblastoma therapeutic outcomes and become a promising nanodrug candidate for the application of doxorubicin in the field of glioblastoma therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Doxorrubicina/administração & dosagem , Glioblastoma/tratamento farmacológico , Micelas , Nanoestruturas/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos ICR , Nanoestruturas/química , Ratos , Cicatrização/efeitos dos fármacos
19.
Fluids Barriers CNS ; 16(1): 18, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31256757

RESUMO

BACKGROUND: Immune cell trafficking into the CNS is considered to contribute to pathogenesis in MS and its animal model, EAE. Disruption of the blood-brain barrier (BBB) is a hallmark of these pathologies and a potential target of therapeutics. Human embryonic stem cell-derived mesenchymal stem/stromal cells (hES-MSCs) have shown superior therapeutic efficacy, compared to bone marrow-derived MSCs, in reducing clinical symptoms and neuropathology of EAE. However, it has not yet been reported whether hES-MSCs inhibit and/or repair the BBB damage associated with neuroinflammation that accompanies EAE. METHODS: BMECs were cultured on Transwell inserts as a BBB model for all the experiments. Disruption of BBB models was induced by TNF-α, a pro-inflammatory cytokine that is a hallmark of acute and chronic neuroinflammation. RESULTS: Results indicated that hES-MSCs reversed the TNF-α-induced changes in tight junction proteins, permeability, transendothelial electrical resistance, and expression of adhesion molecules, especially when these cells were placed in direct contact with BMEC. CONCLUSIONS: hES-MSCs and/or products derived from them could potentially serve as novel therapeutics to repair BBB disturbances in MS.


Assuntos
Barreira Hematoencefálica/metabolismo , Células-Tronco Embrionárias/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Transformada , Células-Tronco Embrionárias/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos
20.
Pharmacol Rep ; 71(4): 669-675, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195344

RESUMO

BACKGROUND: Neurotrophins, especially brain-derived neurotrophic factor (BDNF) have gained significant therapeutic interest particularly in neurologic and psychiatric disorders and they have been found in human breast milk of mothers who suffered from adverse outcomes in pregnancy. This study tested the hypothesis that oral administration of BDNF/GDNF (glial cell line-derived neurotrophic factor) can exert a biological effect in a rat model of severe neuropathology induced by olfactory bulbectomy (OBX), which exhibits dysregulation of BDNF signaling and impaired blood-brain barrier. METHODS: Adult male albino Sprague-Dawley rats underwent the OBX surgery and separate groups of OBX and sham-operated controls received one oral dose of vehicle, BDNF (0.005 mg/kg), GDNF (0.03 mg/kg) or their combination. One week after neurotrophin dosing the rats were sacrificed and BDNF level was assessed by ELISA in the blood serum and cerebrospinal fluid. RESULTS: A significant decrease of serum BDNF level was found in the OBX model. This alteration was normalized by all types of treatment BDNF, GDNF, or their combination. No influence of sham surgery or treatment was observed in the control rats. BDNF levels in cerebrospinal fluid were below detection limit. CONCLUSION: This study indicates that oral administration of neurotrophins is able to exert a biological effect in the OBX model. There is a number of potential mechanisms, which remain to be elucidated.


Assuntos
Barreira Hematoencefálica/metabolismo , Encefalopatias/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Fatores de Crescimento Neural/sangue , Administração Oral , Animais , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/líquido cefalorraquidiano , Modelos Animais de Doenças , Masculino , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/líquido cefalorraquidiano , Bulbo Olfatório/cirurgia , Estudo de Prova de Conceito , Ratos Sprague-Dawley , Proteínas Recombinantes
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