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1.
J Enzyme Inhib Med Chem ; 35(1): 118-128, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694418

RESUMO

A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 µM for eeAChE; IC50 = 0.16 µM for hAChE), and it was also the best inhibitor to AChE-induced Aß aggregation (29.02% at 100 µM) and an efficient inhibitor to self-induced Aß aggregation (30.67% at 25 µM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Quinolonas/química , Tiocarbamatos/química , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Desenho de Drogas , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 823-827, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750825

RESUMO

Objective To study the characteristics of the expression of aquaporin-4 (AQP4) in the brains and astrocytes of rats with thermoplegia. Methods Sixty healthy male Sprague-Dawley rats weighing (250±30) g were randomly divided into control group and model group. The quiet exposure method with high temperature (40DegreesCelsius) and high humidity (70%) was used to make a typical rat model of thermoplegia to monitor rectal temperature and record onset time every 10 minutes. When the temperature of stressed rats reached 42.5 DegreesCelsius, it was regarded as onset time of the disease. The rats in both groups were placed at 26DegreesCelsius with humidity 60% later. After 5-hour observation and their behavior evaluation, the rats were killed and their brain tissues were taken for measuring the water content of the tissues. The astrocytes of the rats were cultured at 37DegreesCelsius and 41DegreesCelsius. AQP4 mRNA and protein expression were detected by reverse-transcription PCR and Western blot analysis. Results Compared with the control group, the expression of AQP4 mRNA and protein were significantly lower in the model group than in the control group. Conclusion High temperature may lead to the destruction of blood-brain barrier and the down-regulation of AQP4 mRNA and protein expression in experimental rats, which can induce the occurrence and development of cerebral edema in experimental rats.


Assuntos
Aquaporina 4/metabolismo , Barreira Hematoencefálica , Edema Encefálico/patologia , Golpe de Calor/patologia , Animais , Astrócitos , Encéfalo/metabolismo , Temperatura Alta , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
3.
Zhen Ci Yan Jiu ; 44(11): 854-7, 2019 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-31777238

RESUMO

Bloodletting puncture at twelve well-points is a characteristic emergency therapy in traditional Chinese medicine. This article reviewed the research advances in the clinical effect of this therapy in the treatment of acute central nervous injury and its mechanism of action over the past 30 years, and it is found that this therapy can effectively improve disturbance of consciousness, neurological defects, and cerebral edema caused by stroke, traumatic brain injury, and carbon monoxide poisoning. The mechanism involves the improvement of cerebral blood flow and tissue oxygen supply, repair of the blood-brain barrier, and regulation of local ion balance. Well-designed clinical trials and in-depth research on biological mechanisms should be performed in future to promote and guide its clinical application.


Assuntos
Sangria , Acidente Vascular Cerebral , Pontos de Acupuntura , Barreira Hematoencefálica , Humanos , Medicina Tradicional Chinesa
4.
Sheng Li Xue Bao ; 71(5): 732-740, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646327

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.


Assuntos
Inflamação/patologia , Doença de Parkinson/patologia , Substância Negra/patologia , Animais , Barreira Hematoencefálica , Neurônios Dopaminérgicos/patologia , Humanos , Microglia , alfa-Sinucleína
5.
Adv Exp Med Biol ; 1141: 407-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571171

RESUMO

Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.


Assuntos
Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
7.
Chem Pharm Bull (Tokyo) ; 67(9): 977-984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474737

RESUMO

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1), an endogenous µ-opioid receptor ligand with strong antinociceptive activity, is not in clinical use because of its limited metabolic stability and membrane permeability. In this study, we develop a short-peptide self-delivery system for brain targets with the capability to deliver EM-1 without vehicle. Two amphiphilic EM-1 derivatives, C18-SS-EM1 and C18-CONH-EM1, were synthesized by attaching a stearyl moiety to EM-1 via a disulfide and amide bond, respectively. The amphiphilicity of EM-1 derivatives enabled self-assembling into nanoparticles for brain delivery. The study assessed morphology, circular dichroism, and metabolic stability of the formulations, as well as their pharmacodynamics and in vivo distribution, directly monitored by near-IR fluorescence imaging in mouse brains. In aqueous solution, the C18-SS-EM1 derivative self-assembled into spherical nanostructures with a diameter of 10-20 nm. Near-IR fluorescence analysis visualized the accumulation of the peptides in the brain. Importantly, the analgesic effect of C18-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C18-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C18-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C18-SS-EM1 nanoparticles, which integrate the advantages of lipidization, nanoscale characteristics and, labile disulfide bonds, represent a promising strategy for brain delivery of short peptides.


Assuntos
Encéfalo/metabolismo , Nanomedicina , Oligopeptídeos/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagem , Dicroísmo Circular , Portadores de Fármacos/química , Meia-Vida , Masculino , Camundongos , Nanopartículas/química , Oligopeptídeos/sangue , Oligopeptídeos/química , Espectroscopia de Luz Próxima ao Infravermelho
8.
Br J Anaesth ; 123(5): 637-654, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31551115

RESUMO

The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.


Assuntos
Dor Crônica/microbiologia , Microbioma Gastrointestinal/fisiologia , Manejo da Dor/métodos , Barreira Hematoencefálica/fisiopatologia , Dor Crônica/fisiopatologia , Dor Crônica/terapia , Trato Gastrointestinal/inervação , Trato Gastrointestinal/microbiologia , Humanos , Inflamação/microbiologia , Neuroimunomodulação/fisiologia , Dor Visceral/microbiologia , Dor Visceral/terapia
9.
Adv Exp Med Biol ; 1161: 125-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562627

RESUMO

Ischemic strokes are caused by one or more blood clots that typically obstruct one of the major arteries in the brain, but frequently also result in leakage of the blood-brain barrier and subsequent hemorrhage. While it has long been known that the enzyme 12/15-lipoxygenase (12/15-LOX) is up-regulated following ischemic strokes and contributes to neuronal cell death, recent research has shown an additional major role for 12/15-LOX in causing this hemorrhagic transformation. These findings have important implications for the use of 12/15-LOX inhibitors in the treatment of stroke.


Assuntos
Araquidonato 15-Lipoxigenase , Isquemia Encefálica , Hemorragia , Acidente Vascular Cerebral , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Hemorragia/etiologia , Hemorragia/fisiopatologia , Humanos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia
10.
Pharm Res ; 36(11): 161, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529284

RESUMO

PURPOSE: Apolipoprotein E2 (ApoE2) gene therapy is a potential disease-modifying therapy for Alzheimer's disease (AD). We investigated the potential of plasmid encoding ApoE2 loaded brain-targeted functionalized-liposomes for treatment of AD. This was achieved via systemic administration of liposomes entrapping therapeutic gene targeting the brain of mice. METHODS: Targeting and transfection efficiency of designed liposomes were determined in bEnd.3, primary glial and primary neuronal cells. The ability of liposomal formulations to translocate across in vitro blood-brain barrier (BBB) and, thereafter, transfect primary neuronal cells was investigated using in vitro triple co-culture BBB model. We quantified ApoE expression in the brain of mice after single intravenous injection of brain-targeted liposomes loaded with plasmid ApoE2. RESULTS: Dual surface modification enhanced the in vitro transfection efficiency of designed liposomes. Successful delivery of therapeutic gene overcoming BBB by Transferrin-Penetratin- modified liposomes was demonstrated both in vitro and in vivo. Significant (p < 0.05) increase in ApoE levels in the brain of mice was observed after intravenous administration of Tf-Pen-liposomes encasing plasmid ApoE2. CONCLUSION: The results indicate that dual-ligand based liposomal gene delivery systems had both enhanced brain targeting and gene delivery efficiencies. Transferrin-Penetratin modified liposomes for delivery of plasmid ApoE2 has great potential for AD treatment.


Assuntos
Apolipoproteína E2/genética , Barreira Hematoencefálica/metabolismo , Terapia Genética , Lipossomos/química , Nanopartículas/química , Doença de Alzheimer/terapia , Animais , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Feminino , Humanos , Lipossomos/administração & dosagem , Lipossomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Transferrina/química , Transferrina/metabolismo
11.
Ultrason Sonochem ; 59: 104745, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473423

RESUMO

Microbubbles (MBs) are known to serve as an amplifier of the mechanical effects of ultrasound, which combined with ultrasound are widely used in brain. The goal of this study is to investigate the effect of oscillating MBs on the neuronal activity in the central nervous system (CNS) of mammals. The motor cortex of mice brain was subjected to ultrasound stimulation with and without MBs, and evoked electromyogram signals were recorded. A c-fos immunofluorescence assay was performed to evaluate the neuronal activation in the region of ultrasound stimulation. BBB integrity during ultrasound stimulation with MBs was assessed in this study. Moreover, the safety of ultrasound stimulation with MBs was examined. Using ultrasound at 620 kHz, the injection of MBs significantly increased the success rate of motor response from 0.065 ±â€¯0.06 to 0.28 ±â€¯0.10 when stimulation was applied at 0.12 MPa and from 0.38 ±â€¯0.09 to 0.77 ±â€¯0.18 at 0.25 MPa (p < 0.001). The results of the c-fos immunofluorescence assay showed that the mean densities of c-fos+ cells were significantly increased from 15.67 ±â€¯3.51 to 53.01 ±â€¯9.54 at 0.12 MPa acoustic pressure. At 0.25 MPa, the mean density of c-fos + cells was 81 ±â€¯10.97 without MBs and it significantly increased to 124.12 ±â€¯25.71 with MBs (p < 0.05). Enhanced neuronal activities were observed with 0.12 MPa ultrasound stimulation with MBs, while the integrity of BBB was not compromised, but 0.25 MPa ultrasound stimulation with MBs resulted in BBB disruption. These findings reveal that the oscillations of MBs can enhance neuronal activity in the CNS of mammals, and may provide an insight into the application of MBs combined with ultrasound in brain.


Assuntos
Microbolhas , Córtex Motor/citologia , Neurônios/citologia , Crânio , Ondas Ultrassônicas , Animais , Barreira Hematoencefálica/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Córtex Motor/metabolismo , Segurança
12.
Anticancer Res ; 39(8): 4265-4271, 2019 Aug.
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.
Adv Exp Med Biol ; 1155: 977-985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468461

RESUMO

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid. It is one of the most abundant free amino acids in many excitable tissues, including the brain, skeletal and cardiac muscles. Physiological actions of taurine are widespread and include regulation of plasma glucose levels, bile acid conjugation, detoxification, membrane stabilization, blood pressure regulation, osmoregulation, neurotransmission, and modulation of mitochondria function and cellular calcium levels. Taurine plays an important role in modulating glutamate and GABA neurotransmission and prevents excitotoxicity in vitro primarily through modulation of intracellular calcium homeostasis. Taurine supplementation prevents age-dependent decline of cognitive functions. Because of the wide spread actions of taurine, its levels are highly regulated through enzymatic biosynthesis or dietary intake. Furthermore, depletion of endogenous or dietary supplementation of exogenous taurine have been shown to induce wide spread actions on multiple organs. Cysteine sulfonic acid decarboxylase (CSAD) was first identified in the liver and is thought to be the rate-limiting enzyme in taurine biosynthesis. CSAD mRNA is expressed in the brain in astrocytes. Homozygous knockout mice lacking CSAD (CSAD-KO) have very reduced taurine content and show severe functional histopathology in the visual system, skeletal system, heart, pancreas and brain. Conversely, dietary supplementation of taurine results in significant health benefits acting through the same organ systems. Fluctuation of taurine bioavailability lead to changes in the expression levels of taurine transporters in neuronal plasma membranes, endothelial cells forming the blood-brain barrier and proximal cells of the kidneys. Suggesting a highly regulated mechanism for maintaining taurine homeostasis and organ systems function. Here we show how alterations in taurine levels directly affect the function of one organ system and through functional interaction and compensatory adaptation; these effects extend to another organ systems with focus on the nervous system.


Assuntos
Sistemas Neurossecretores/fisiologia , Taurina/farmacologia , Animais , Barreira Hematoencefálica , Membrana Celular , Células Endoteliais , Homeostase , Rim , Camundongos , Camundongos Knockout
14.
Int J Nanomedicine ; 14: 5541-5554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410002

RESUMO

Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid ß (Aß) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in cortical and limbic areas of the human brain. It is characterized by memory loss and progressive neurocognitive dysfunction. The anomalous processing of APP by ß-secretases and γ-secretases leads to production of Aß40 and Aß42 monomers, which further oligomerize and aggregate into senile plaques. The disease also intensifies through infectious agents like HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aß peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity of Aß, microglia get activated, endocytose Aß, and contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against the aggregation. In addition to a detailed report on causative factors leading to AD, the present review also discusses the current state of the art in AD therapeutics and diagnostics, including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology as an efficient therapeutic strategy to increase the bioavailability of drugs in the central nervous system.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/patologia , Epigênese Genética , Humanos , Nanotecnologia , Placa Amiloide/patologia
15.
Neuron ; 103(3): 367-379, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394062

RESUMO

Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Circulação Cerebrovascular , Microvasos/patologia , Doenças Neurodegenerativas/etiologia , Acoplamento Neurovascular , Animais , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/fisiopatologia , Isquemia Encefálica/etiologia , Progressão da Doença , Endotélio Vascular/fisiopatologia , Humanos , Microcirculação , Micronutrientes/farmacocinética , Modelos Animais , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/prevenção & controle , Neuroimagem
16.
Int J Nanomedicine ; 14: 5895-5909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440051

RESUMO

The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood-brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.


Assuntos
Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Liberação Controlada de Fármacos , Humanos , Nanopartículas/química
17.
Pharm Res ; 36(10): 141, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367840

RESUMO

PURPOSE: The purpose of the present study was to investigate changes of blood-brain barrier (BBB) and brain parenchymal protein expression due to type II diabetes mellitus (T2DM) induced by a high-fat diet (HFD) by using SWATH-based quantitative proteomics. METHODS: Mice were fed a HFD for 2 or 10 weeks, and then SWATH-based quantitative proteomic analysis, western blot analysis, immunohistochemistry and functional transport studies were performed. RESULTS: In brain capillaries, expression levels of BBB transporters (Glut1, P-glycoprotein) and tight-junction proteins (claudin-5, occludin) were significantly reduced in HFD mice at 2 weeks, but recovered to the levels in the normal diet (ND) group at 10 weeks. P-glycoprotein function at the BBB was reduced at 2 weeks. In the cerebral cortex and hippocampus, neurofilament, which is important for neuronal function, was decreased in HFD mice at 2 weeks, but recovered at 10 weeks. CONCLUSION: Our results suggest that changes in the status of insulin resistance influence expression of BBB transporters, which in turn may alter the expression of cognitive function-related proteins.


Assuntos
Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Insulina/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Capilares/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Filamentos Intermediários/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteômica , Proteínas de Junções Íntimas/metabolismo
18.
Adv Exp Med Biol ; 1173: 33-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456204

RESUMO

With the development of research, more and more evidences suggested that mutations in the genes associated with brain iron metabolism induced diseases in the brain. Brain iron metabolism disorders might be one cause of neurodegenerative diseases. This review mainly summarizes the normal process of iron entry into the brain across the blood-brain barrier, and the distribution and transportation of iron among neurons and glial cells, as well as the underlying regulation mechanisms. To understand the mechanisms of iron metabolism in the brain will provide theoretical basis to prevent and cure brain diseases related to iron metabolism disorders.


Assuntos
Encéfalo/metabolismo , Distúrbios do Metabolismo do Ferro , Ferro/metabolismo , Barreira Hematoencefálica , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo
19.
J Biomed Nanotechnol ; 15(10): 1997-2024, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462368

RESUMO

Alzheimer's disease affects millions of people worldwide and this figure is continuously increasing. Currently, there is no resolutive cure for this disorder, but a valid contribution could be provided by nanomedicine, utilizing multi-functionalized nanodevices as drug vehicles with additional features of specific brain targeting. Nanomedicine may represent also a practicable strategy for the pharmaceutical industry that moved from small MW pharmaceuticals to larger biologicals, such as antibodies and nucleotides, as the next generation of drugs, leading to the challenge of effective drug delivery. This review provides a survey on the nano-based strategies for Alzheimer's disease diagnosis and treatment, aiming at enhancing the passage of candidate pharmaceuticals across the BBB, and at supporting the evaluation of new therapeutic agents targeting this disease.


Assuntos
Doença de Alzheimer , Nanopartículas , Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina
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