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1.
Chem Biol Interact ; 312: 108819, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499052

RESUMO

Cannabidiol (CBD), a compound obtained from Cannabis sativa, has wide range of therapeutic properties, including mitigation of diabetes and neurodegeneration. Cerebral ischemia and consequent learning disabilities are aggravated in elderly diabetic subjects. However, there are no studies showing the effect of CBD treatment in elderly diabetes patients suffering cerebral ischemia. The present work tested the hypothesis that CBD treatment improves metabolic dysfunctions in middle-aged diabetic rats submitted to chronic cerebral hypoperfusion. In this work, 350-day-old male Wistar streptozotocin-induced diabetic rats were used. To induce cerebral ischemia was used a chronic cerebral hypoperfusion (CCH), surgically, via the four-vessel occlusion/internal carotid artery (4-VO/ICA). Four diabetic groups were established: Non-CCH Treated Diabetic (DNT), CCH Treated Diabetic (DCT), Non-CCH Vehicle Diabetic (DNV), and CCH Vehicle Diabetic (DCV). Vehicle groups were not treated with CBD. The animals were treated during 30 days with 10 mg CBD/Kg bw/day. After treatment, the animals were euthanized, and blood levels of glucose, insulin, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, fructosamine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were evaluated. DCT group presented reduction of hyperglycemia and an increase of insulinemia. Also was observed lower fructosamine, LDL, HDL, triglycerides and total cholesterol levels. AST and ALT concentration were reduced in CBD treated groups. CBD may be used as therapeutic tool to protect metabolism against injuries from diabetes aggravated by cerebral ischemia.


Assuntos
Isquemia Encefálica/patologia , Canabidiol/uso terapêutico , Diabetes Mellitus Experimental/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/análise , Isquemia Encefálica/complicações , Colesterol/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Insulina/sangue , Masculino , Ratos , Ratos Wistar
2.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 275-281, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31496159

RESUMO

OBJECTIVE: To investigate the clinical features and implication of restless legs syndrome (RLS) in ischemic stroke patients. METHODS: A total of 199 ischemic stroke patients were enrolled and assessed by polysomnography (PSG). RLS was identified according to criteria of International Restless Legs Syndrome Study Group. Epworth Sleepiness Scale (ESS), Mini-mental State Examination (MMSE) and Patient Health Questionnaire (PHQ-9) were used to evaluate the sleep quality, cognitive function and post-stroke depression, respectively. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the neurological function 3 months after stroke onset. Gender-and age-matched non-ischemic stroke patients with RLS (primary PLS) were selected as controls. RESULTS: Twenty-two cases of RLS were identified among 199 ischemic stroke patients (11.1%). Generalized linear model and logistic regression showed that low serum ferritin level (ß=-133.3 mg/L, 95%CI:-200.4--0.1, P<0.01), subcortical infarction (OR=4.05, 95%CI:1.15-14.18, P<0.05) and female (OR=2.54, 95%CI:1.04-6.23, P<0.05) were identified as the risk factors of RLS in ischemic stroke patients. Compared with ischemic stroke patients without RLS, ESS increased by 4.37 (95%CI:2.33-6.41, P<0.01), PHQ-9 increased by 2.17 (95%CI:0.39--3.94, P<0.05), and reduced NIHSS from the baseline deceased by 0.97 (95%CI:-1.79--0.15, P<0.05) in ischemic stroke patients with RLS. In addition, the incidence of moderate-severe depression increased (OR=4.27, 95%CI:1.40-13.10, P<0.05) in ischemic stroke patients with RLS. The index of periodic leg movements of sleep (PLMS) with arousal in ischemic stroke patients with RLS was significantly higher than that in patients with primary RLS (ß=12.85, 95%CI:2.04-23.67, P<0.05). CONCLUSIONS: RLS is common in ischemic stroke patients and has adverse influences on patients.


Assuntos
Isquemia Encefálica , Síndrome das Pernas Inquietas , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Depressão/complicações , Feminino , Humanos , Masculino , Polissonografia , Síndrome das Pernas Inquietas/complicações , Síndrome das Pernas Inquietas/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
3.
Life Sci ; 232: 116599, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247210

RESUMO

AIM: Ischemia/reperfusion (I/R) injury is the major cause of neurological deficit following stroke. Our previous study showed neuroprotective effects of hispidulin against cerebral ischemia reperfusion injury (IRI). In this study, we further examined the involvement of pyroptosis in this neuroprotective function. MATERIALS AND METHODS: IRI was simulated in a rat model by middle cerebral artery occlusion (MCAO) surgery, and the animals were treated with different doses of hispidulin. The neurological function of the rats was evaluated by the neural function defect score (NFDS), balance beam test and limb placement test. The infarct volume and brain water content were measured 72 h following IRI. Neuronal cell survival and pyroptosis in the ischemic cortex were respectively detected by Nissl staining and TUNEL assay. The relative expression of pyroptosis markers was determined by qRT-PCR, Western blotting and ELISA as appropriate. IRI was simulated in vitro in primary cerebral astrocytes using the OGD/R procedure. AMPKα was blocked genetically or pharmacologically using siRNA and compound C respectively. CCK-8 and LDH release assays were performed using suitable kits. RESULTS: Hispidulin improved the neurological symptoms of the rats after IRI, in addition to decreasing the infarct size and brain edema. Mechanistically, hispidulin exerted its neuroprotective effects in vivo and in vitro by suppressing NLRP3-mediated pyroptosis by modulating the AMPK/GSK3ß signaling pathway. CONCLUSION: Hispidulin is a neuroprotective agent with clinical potential against IR-induced neurological injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Flavonas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sobrevivência Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico
4.
Life Sci ; 231: 116517, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150684

RESUMO

Our previous study indicated that microRNA 145 (miR-145) and its predicated target, erythropoietin-producing hepatoma (EPH) receptor A4 (EPHA4), was closely associated with ischemic stroke. In this study, we aimed to further explore their function in a model of oxygen-glucose deprivation (OGD). The expression of miR-145 in the blood of 44 patients with ischemic stroke and 37 normal controls was detected by qRT-PCR. After transfection with either the wild- or mutant-type pGL3-promoter EPHA4 3'UTR into the miR-145 mimic and miR-145 inhibitor, a dual-luciferase reporter assay was performed to explore the interaction between miR-145 and EPHA4. qRT-PCR and Western blot were performed to further explore the effects of miR-145 on EPHA4 expression after an miR-145 mimic, an miR-145 inhibitor or LV-sh-EPHA4 was transfected into cerebral cortical neurons. The expression of miR-145 was significantly upregulated in the blood of patients with ischemic stroke compared to that of normal controls. Dual-luciferase reporter assay, qRT-PCR and Western blot results indicated that miR-145 indeed targets EPHA4 through its 3'-UTR and regulates the expression level of EPHA4 at both the mRNA and protein levels. Moreover, the OGD model was successfully constructed, and miR-145 exerted a protective effects in cell viability in the OGD model by downregulating EPHA4. The expression of LOC105376244 could be regulated by the miR-145-EPHA4 interaction. MiR-145 exerted a protective effects in cell viability in the OGD model by downregulating EPHA4, which suggested their potential roles in ischemic stroke and requires further research.


Assuntos
Isquemia Encefálica/metabolismo , Córtex Cerebral/citologia , MicroRNAs/genética , Neurônios/citologia , Receptor EphA4/metabolismo , Idoso , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Hipóxia Celular/fisiologia , Sobrevivência Celular/genética , Córtex Cerebral/metabolismo , Regulação para Baixo , Feminino , Glucose/metabolismo , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Neurônios/metabolismo , Oxigênio/metabolismo , Cultura Primária de Células , RNA Mensageiro/metabolismo , Acidente Vascular Cerebral/metabolismo
5.
J Stroke Cerebrovasc Dis ; 28(9): e132-e134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31239223

RESUMO

Intravascular lymphomatosis (IVL) is a rare subtype of large B-cell lymphoma that follows an aggressive course with rapidly progressive neurological involvement and potentially fatal outcome.1 We report on a 64-year-old man with progressive myelopathy at T6-T7 and recurrent cerebral infarctions. This case is illustrative of the clinical course that is seen in IVL. It aims to present a timeline of imaging findings that demonstrate the progression of disease and characteristic pathology findings. We emphasize the importance of IVL on the differential diagnosis of spinal cord infarction.


Assuntos
Isquemia Encefálica/etiologia , Infarto/etiologia , Linfoma de Células B/complicações , Medula Espinal/irrigação sanguínea , Acidente Vascular Cerebral/etiologia , Neoplasias Vasculares/complicações , Biópsia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Evolução Fatal , Humanos , Infarto/diagnóstico por imagem , Infarto/patologia , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/patologia
6.
Cell Mol Biol Lett ; 24: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168302

RESUMO

Background: Accumulating evidence has shown that altered microRNA (miR) modulation is implicated in the pathologies of ischemic stroke. However, it is unclear whether and how hsa-miR-19a-3p mediates cerebral ischemic injury. Herein, we investigated the functional role of miR-19a-3p in cerebral ischemic injury and explored its underlying regulatory mechanism. Methods: In vivo ischemic/reperfusion (I/R) neuronal injury and in vitro oxygen-glucose deprivation (OGD) were established. Expression of miR-19a-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Glucose uptake, lactate production, and apoptosis were determined. ADIPOR2 was predicted as a target of miR-19a-3p in silico and experimentally validated by qRT-PCR, Western blot analysis and luciferase assay assays. Results: MiR-19a expression was significantly downregulated and upregulated in rat neurons and astrocytes, respectively (P < 0.01). A significantly elevated level of miR-19a-3p was found in I/R and OGD models in comparison to sham/control groups (P < 0.01). Expression of the glycolysis enzyme markers LDHA, PKM2, HK2, Glut1 and PDK1, apoptosis-related factors levels, apoptosis, glucose uptake, and lactate production were significantly repressed by both I/R and OGD (P < 0.01 in each case). Moreover, miR-19a-3p mimic aggravated, while miR-19a-3p inhibitor alleviated, the above observations. Adipor2 was predicted and confirmed to be a direct target of miR-19a. Furthermore, restoration of Adipor2 reversed miR-19a-3p-induced effects. Conclusions: Collectively, our results indicate that elevated miR-19a-3p mediates cerebral ischemic injury by targeting ADIPOR2. MiR-19a-3p attenuation thus might offer hope of a novel therapeutic target for ischemic stroke injury treatment.


Assuntos
Apoptose , Isquemia Encefálica/patologia , Glucose/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção , Acidente Vascular Cerebral/patologia , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Sequência de Bases , Modelos Animais de Doenças , MicroRNAs/genética , Oxigênio , Ratos Sprague-Dawley , Receptores de Adiponectina/metabolismo , Regulação para Cima/genética
7.
Croat Med J ; 60(2): 121-126, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044583

RESUMO

Due to very limited therapeutic options, ischemic brain injury is one of the leading causes of death and lifelong disability worldwide, which imposes enormous public health burden. One of the main events occurring with ischemic brain stroke is cell death. Necroptosis is a type of cell death described as a regulated necrosis characterized by cell membrane disruption mediated by phosphorylated mixed lineage kinase like protein (MLKL). It can be triggered by activation of death receptors (eg, FAS, TNFR1), which lead to receptor-interacting serine/threonine-protein kinase 3 (RIPK3) activation by RIPK1 in the absence of active caspase-8. Here, we review articles that have reported that necroptosis significantly contributes to negative events occurring with the ischemic brain stroke, and that its inhibition is protective both in vitro and in vivo. We also review articles describing positive effects obtained by reducing necroptosis, including the reduction of infarct volume and improved functional recovery in animal models. Since necroptosis is characterized by cell content leakage and subsequent inflammation, in addition to reducing cell death, inhibition of necroptosis in ischemic brain stroke also reduces some inflammatory cytokines. By comparing various approaches in inhibition of necroptosis, we analyze the achieved effects from the perspective of controlling necroptosis as a part of future therapeutic interventions in brain ischemia.


Assuntos
Isquemia Encefálica/fisiopatologia , Morte Celular , Inibidores Enzimáticos/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Inibidores Enzimáticos/farmacologia , Humanos , Inflamação/metabolismo , Necrose , Fosforilação , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral , Acidente Vascular Cerebral
8.
J Clin Neurosci ; 64: 206-213, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31023573

RESUMO

Stroke induced white matter injury can induce marked neurological deficits even after relatively small infarcts, due to the tightly packed nature of white matter tracts especially in certain areas in the brain. Many drugs which were successful in the pre-clinical trials failed in clinical trials, which was attributed in part to the focus on grey matter injury completely and ignoring their effect on white matter. In this work we selected two known neuroprotective drugs (minocycline and progesterone) and examined their effect on white matter injury after focal cerebral ischemia/reperfusion injury in rats. Focal cerebral ischemia was induced in male Wistar rats (one-hour ischemia followed by reperfusion). Progesterone and minocycline were administered immediately after reperfusion onset. Infarct size, microglial activation and white matter injury were assessed and compared between the treatment and no-treatment groups and Sham operated animals. Our data showed that both progesterone and minocycline reduced infarct size, microglial activation and white matter injury. This work shows a new neuroprotective mechanism of both drugs, via white matter injury reduction, that can be exploited for stroke management. While the utility of either drugs as a sole agent in the management of stroke is questionable, there is a value of using either drugs as an adjuvant therapy to traditional stroke therapy, making use of the white matter protective effect that would improve outcome and facilitate healing after stroke.


Assuntos
Minociclina/farmacologia , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Acidente Vascular Cerebral/patologia , Substância Branca/efeitos dos fármacos , Animais , Isquemia Encefálica/patologia , Feminino , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Substância Branca/patologia
9.
Phytomedicine ; 59: 152922, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981186

RESUMO

BACKGROUND: Inflammation is a major contributor to stroke pathology, making it a promising strategy for intervention. Microglia, the resident macrophages in the brain, play essential roles in both the generation and resolution of neuroinflammation. In particular, mitochondrial homeostasis is critical for microglial function and its dysregulation is involved in the pathogenesis of ischemic stroke. Atractylenolide III (A III), a sesquiterpene lactone found in Atractylodes macrocephala Koidz, has been shown to have an inhibitory effect on inflammation. However, its effect specifically on neuroinflammation and microglial mitochondrial homeostasis following stroke remains elusive. HYPOTHESIS: We hypothesized that A III protects against brain ischemia through inhibition of neuroinflammation mediated by JAK2/STAT3/Drp1-dependent mitochondrial fission. METHODS: The neuroprotective and anti-neuroinflammatory effects of A III were investigated in vivo in mice with transient occlusion to the middle cerebral artery (MCAO) and in vitro in oxygen glucose deprivation-reoxygenation (OGDR)-stimulated primary microglia from mice. RESULTS: A III and AG490, an inhibitor of JAK2, treatment reduced brain infarct size, restored cerebral blood flow (CBF), ameliorated brain edema and improved neurological deficits in MCAO mice. Furthermore, A III and AG490 inhibited mRNA and protein expressions of proinflammatory (IL-1ß, TNF-α, and IL-6) and anti-inflammatory cytokines in both MCAO mice and OGDR-stimulated primary microglia. The JAK2/STAT3 pathway was effectively suppressed by A III, similar to the effect of AG490 treatment. In addition, A III and AG490 treatments significantly decreased Drp1 phosphorylation, translocation and mitochondrial fission in primary microglia stimulated with OGDR for 24 h. CONCLUSION: Our study demonstrated that A III was able to reduce complications associated with ischemia through inhibiting neuroinflammation, which was mediated in part by JAK2/STAT3-dependent mitochondrial fission in microglia.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Dinaminas/metabolismo , Inflamação/tratamento farmacológico , Janus Quinase 2/metabolismo , Lactonas/farmacologia , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/farmacologia , Animais , Isquemia Encefálica/patologia , Citocinas/metabolismo , Dinaminas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Interleucina-1beta/metabolismo , Janus Quinase 2/genética , Masculino , Camundongos , Microglia/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo
11.
Mater Sci Eng C Mater Biol Appl ; 100: 485-492, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948085

RESUMO

α-Fe2O3 Magnetic nanoparticles (MNPs) have been synthesized, functionalized at silica that ends up with -NH2 group to form FMNPs. Conjugation of FMNPs with a fluorescently-labeled poly-caspase inhibitor valylalanylaspartic acid fluoromethyl ketone (SR-FLICA) which serves as a pan-caspase inhibitor was carried out to form finally a hybrid probe SR-FLICA-FMNPs. This probe could be used as a multimodal magneto-fluorescent platform for live apoptotic cells monitoring using MR and fluorescence imaging techniques. Characterization results of the as-synthesized MNPs and functionalized FMNPs by SEM, TEM, N2 isotherm, XRD and magnetic VSM showed that, a controlled morphological structure of MNPs could be synthesized with cubic-shaped, ferromagnetic, base-centered orthorhombic space group R3c and average size of 45.8 ±â€¯3.2 and 50.3 ±â€¯1.6 nm for MNPs and FMNPs, respectively. Phantom MRI experimental results of the examined MNPs and FMNPs confirmed the concentration dependency nature of T2 signal reduction. In addition, in vitro and in vivo sensing studies on our conjugated hybrid multifunctional probe SR-FLICA-FMNPs using 9 L gliosarcoma cells confirmed that; it could positively intact within the astrocytes and the nuclei of the apoptotic cells taking into account the starting material's cytotoxicity. Several histo-chemical protocols could be examined to confirm such behavior. Confocal and fluorescence microscopes' results of the histological stained apoptotic cells confirmed positive and specific expressions of our designed probe. MRI monitoring results of apoptotic rat models after focal brain transient cerebral ischemia showed a remarkable time-dependent reduction of T2* weighted signal up to 4 h indicating that our newly designed hybrid probe has long blood circulation and could be used as a future contrasting agent. Moreover, the distribution of our probe was evaluated by subtracting the T2* signal images before and after injection with SR-FLICA-FMNPs and was significantly correlated with the histological findings by staining via terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling. Moreover, clearance study confirmed that; our magneto-fluorescent hybrid probe could be cleared through liver Kupffer cells. Thus; the newly developed SR-FLICA-FMNPs could be considered as a future multifunctional probe for in vitro and in vivo apoptotic cells monitoring.


Assuntos
Apoptose , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/patologia , Corantes Fluorescentes/química , Nanopartículas de Magnetita/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Rastreamento de Células , Eritrócitos/metabolismo , Hemólise , Humanos , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/ultraestrutura , Ratos Sprague-Dawley , Razão Sinal-Ruído , Propriedades de Superfície , Fatores de Tempo
12.
Biomed Res Int ; 2019: 4273290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949500

RESUMO

No pharmacological treatment is currently available to protect brain from neuronal damage after ischemic stroke. Recent studies found that enkephalin may play an important role in neuron regeneration. We assembled a homogeneous size vesicle constituted by transferrin, exosomes, and enkephalin. Immunofluorescence assay showed that transferrin was combined with the exosomes and enkephalin was packaged into the vesicle; thus this complex was called tar-exo-enkephalin. In vitro studies were performed using rat primary hippocampal neurons and the results showed that enkephalin decreased p53 and caspase-3 levels to 47.6% and 67.2%, respectively, compared to neurons treated with glutamate, thus inhibiting neuron apoptosis caused by glutamate. An in vivo experiment in rats was also carried out using a transient middle cerebral artery occlusion (tMCAO)/reperfusion model and tar-exo-enkephalin treatment was performed after tMCAO. The results showed that tar-exo-enkephalin crossed the blood brain barrier (BBB) and decreased the levels of LDH, p53, caspase-3, and NO by 41.9, 52.6, 45.5, and 57.9% compared to the tMCAO rats, respectively. In addition, tar-exo-enkephalin improved brain neuron density and neurological score after tMCAO. These findings suggest that the use of exogenous enkephalin might promote neurological recovery after stroke.


Assuntos
Isquemia Encefálica , Caspase 3/metabolismo , Encefalinas/farmacologia , Neurônios , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral , Proteína Supressora de Tumor p53/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
13.
Int J Mol Med ; 43(6): 2420-2428, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017259

RESUMO

Mitochondria are crucial for neuronal cell survival and death through their functions in ATP production and the intrinsic pathway of apoptosis. Mitochondrial dysfunction is considered to play a central role in several serious human diseases, including neurodegenerative diseases, such as Parkinson's and Alzheimer's disease and ischemic neurodegeneration. The aim of the present study was to investigate the impact of transient global brain ischemia on the expression of selected proteins involved in mitochondrial dynamics and mitochondria­associated membranes. The main foci of interest were the proteins mitofusin 2 (Mfn2), dynamin­related protein 1 (DRP1), voltage­dependent anion­selective channel 1 (VDAC1) and glucose­regulated protein 75 (GRP75). Western blot analysis of total cell extracts and mitochondria isolated from either the cerebral cortex or hippocampus of experimental animals was performed. In addition, Mfn2 was localized intracellularly by laser scanning confocal microscopy. It was demonstrated that 15­min ischemia, or 15­min ischemia followed by 1, 3, 24 or 72 h of reperfusion, was associated with a marked decrease of the Mfn2 protein in mitochondria isolated from the cerebral cortex, but not in hippocampal mitochondria. Moreover, a translocation of the Mfn2 protein to the cytoplasm was documented immediately after global brain ischemia in the neurons of the cerebral cortex by laser scanning confocal microscopy. Mfn2 translocation was followed by decreased expression of Mfn2 during reperfusion. Markedly elevated levels of the VDAC1 protein were also documented in total cell extracts isolated from the hippocampus of rats after 15 min of global brain ischemia followed by 3 h of reperfusion, and from the cerebral cortex of rats after 15 min of global brain ischemia followed by 72 h of reperfusion. The mitochondrial Mfn2 release observed during the early stages of reperfusion may thus represent an important mechanism of mitochondrial dysfunction associated with neuronal dysfunction or death induced by global brain ischemia.


Assuntos
Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Hipocampo/patologia , Proteínas de Membrana/análise , Mitocôndrias/patologia , Proteínas Mitocondriais/análise , Animais , Masculino , Ratos , Ratos Wistar
14.
Adv Mater ; 31(21): e1808361, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957932

RESUMO

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Sirolimo/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/metabolismo , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Humanos , Micelas , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/química , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
15.
Int J Nanomedicine ; 14: 1979-1991, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936698

RESUMO

Background: Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms. Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA). Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed. Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P⩽0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm3; P⩽0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; P⩽0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (P⩽0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation. Conclusion: LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.


Assuntos
Acetatos/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Acetatos/química , Animais , Apoptose/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Infarto da Artéria Cerebral Média , Lipossomos/química , Imagem por Ressonância Magnética , Masculino , Neurogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia
16.
Restor Neurol Neurosci ; 37(2): 131-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988241

RESUMO

BACKGROUND: Cerebellar fastigial nucleus electrical stimulation (FNS) in rats has been shown to protect against brain ischemia/reperfusion (I/R) damage. Activation of telomerase has been reported to provide neuroprotection in animal models of stroke. OBJECTIVE: The aim of this study was to explore whether precondition FNS increases the expression of telomerase reverse transcriptase (TERT) and telomerase activity in rats after cerebral I/R injury. METHODS: One day after continuous stimulation of the fastigial cerebellar nucleus for 1 h, adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 24 h, 48 h and 72 h, while the I/R control groups received the same treatment without FNS. Ischemic lesion volumes were measured following TTC staining. The number of apoptotic cells was measured by using TUNEL assays. Subsequently, telomerase activity was examined by using TRAP-silver staining. Additionally, the expression level of TERT mRNA was assessed by using real-time fluorescence quantitative PCR. Finally, the expression of TERT protein was measured by using Western blotting. RESULTS: The results of our study demonstrated that FNS significantly decreased infarct volumes and improved neurological deficits when compared with the I/R control group. The telomerase activity in the I/R + FNS group was significantly increased compared with that in the I/R control group, particularly in the 24 h reperfusion subgroup (P < 0.05). FNS treatment significantly decreased the number of TUNEL-positive cells when compared with that in the I/R control group. Expression of TERT gradually increased, with the peak occurring after or before 48 h reperfusion and the 24 h and 72 h reperfusion subgroups demonstrating higher expression than each I/R control group (P < 0.05). CONCLUSIONS: Our results show that pre-FNS exerts neuroprotective effects that may be achieved by upregulating the expression of TERT and then by increasing telomerase activity.


Assuntos
Isquemia Encefálica/enzimologia , Isquemia Encefálica/terapia , Estimulação Encefálica Profunda , Telomerase/metabolismo , Animais , Isquemia Encefálica/patologia , Núcleos Cerebelares , Modelos Animais de Doenças , Masculino , Neuroproteção/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/terapia , Regulação para Cima
17.
Mol Med Rep ; 19(4): 3148-3158, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816516

RESUMO

Brain ischemia, including cerebral ischemia and cerebrovascular ischemia, leads to poor oxygen supply or cerebral hypoxia, and causes brain tissue death or cerebral infarction/ischemic stroke. The troxerutin and cerebroprotein hydrolysate injection (TCHI), is widely applied in China to improve blood supply in ischemic brain tissues and to enhance neuroprotective effects in clinical practice. However, the benefits and detailed underlying mechanism elaborating the effectiveness of TCHI in cerebrovascular diseases require further investigation. Therefore, in the present study, experimental in vivo and in vitro models were employed to investigate the potential mechanisms of TCHI on cerebral ischemic injury. The results demonstrated that TCHI increased the lactate dehydrogenase levels in the brain homogenate and conversely decreased lactic acid levels. TCHI was further observed to significantly increase superoxide dismutase activity and decrease malondialdehyde levels in ischemic brain tissues. In addition, TCHI significantly induced vascular maturation processes, including proliferation, adhesion, migration and tube formation in cultured human umbilical vein endothelial cells. Additionally, TCHI significantly stimulated microvessel formation in the rat aortic ring and chick chorioallantoic membrane assays. Taken together, these results provided strong evidence that TCHI stimulated angiogenesis at multiple steps, and indicated that TCHI attenuated cerebral ischemic damage through the amelioration of oxidative stress and promotion of angiogenesis.


Assuntos
Anticoagulantes/farmacologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hidroxietilrutosídeo/análogos & derivados , Neovascularização Patológica/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Adesão Celular , Movimento Celular , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidroxietilrutosídeo/farmacologia , Masculino , Ratos , Espécies Reativas de Oxigênio/metabolismo
18.
Mol Med Rep ; 19(4): 3009-3020, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816517

RESUMO

Stroke is the second most frequent cause of mortality, resulting in a huge societal burden worldwide. Timely reperfusion is the most effective therapy; however, it is difficult to prevent ischemia/reperfusion (I/R) injury. In traditional Chinese medicine, hydroxysafflor yellow A (HSYA) has been widely used for the treatment of cerebrovascular disease and as a protective therapy against I/R injury. Evidence has demonstrated that HSYA could reduce the levels of reactive oxygen species and suppress cellular apoptosis; however, whether HSYA alters the metabolic profile as its underlying mechanism for neuroprotection remains unknown. In the present study, using a metabolomic screening, phenylalanine was identified to significantly increase in an experimental model of mouse cerebral I/R injury. Notably, western blotting and qPCR analysis were conducted to test the expression level of apoptosis­associated factors, and HSYA was identified to be able to protect neuronal cells by reducing phenylalanine level associated with I/R injury. Additionally, these findings were confirmed in primary mouse neurons and PC12 cells exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) stress. Of note, HSYA was observed to regulate the mRNA expression of key metabolic enzymes, phenylalanine hydroxylase, tyrosine aminotransferase and aspartate aminotransferase, which are responsible for phenylalanine metabolism. Furthermore, by performing mitochondrial labeling and JC­1 fluorescence assay, HSYA was identified to promote mitochondrial function and biogenesis suppressed by OGD/R. The findings of the present study demonstrated that I/R injury could increase the levels of phenylalanine, and HSYA may inhibit phenylalanine synthesis to enhance mitochondrial function and biogenesis for neuroprotection. The present study proposed a novel metabolite biomarker for cerebral I/R injury and the evaluated the efficacy of HSYA as a potential therapeutic treatment I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Chalcona/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Fenilalanina/biossíntese , Quinonas/farmacologia , Traumatismo por Reperfusão/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Chalcona/farmacologia , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Resultado do Tratamento
19.
Trials ; 20(1): 167, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876432

RESUMO

BACKGROUND: Remote ischemic postconditioning (rIPostC) refers to the observation that repeated, short periods of ischemia protect remote areas against tissue damage during and after prolonged ischemia. Based on previous observations of a potential neuroprotective effect of rIPostC, the aim of this study is to evaluate whether repeated rIPostC after an ischemic stroke can reduce infarct size, which could be translated to an improvement in clinical outcomes. METHODS/DESIGN: We will enroll 200 ischemic stroke patients to daily rIPostC or sham conditioning during hospitalization into a randomized single-blind placebo-controlled trial. The intervention consists of twice daily exposure to four cycles of 5-min cuff inflation around the upper arm to > 20 mmHg above systolic blood pressure (i.e., rIPostC) or 50 mmHg (i.e., control), followed by 5 minutes of deflation. The primary outcome is infarct size, measured using an MRI diffusion-weighted image at the end of hospitalization. Secondary outcomes include the Modified Rankin Scale, National Institutes of Health Stroke Scale, quality of life, and cardiovascular and cerebrovascular morbidity and mortality. To explore possible underlying mechanisms of rIPostC, venous blood will be sampled to assess biomarkers of inflammation and vascular health. DISCUSSION: Previous studies in animals and humans, using a single bout of remote ischemic conditioning, report a potential effect of rIPostC in attenuating neural damage. Although repeated rIPostC has been investigated for cardiovascular disease patients and preclinical stroke models, no previous study has explored the potential physiological and clinical effects of repeatedly applying rIPostC during the hospitalization phase after a stroke. TRIAL REGISTRATION: Netherlands Trial Register, NTR6880 . Registered on 8 December 2017.


Assuntos
Isquemia Encefálica/terapia , Pós-Condicionamento Isquêmico/métodos , Oclusão Terapêutica/métodos , Extremidade Superior/irrigação sanguínea , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Imagem de Difusão por Ressonância Magnética , Humanos , Pós-Condicionamento Isquêmico/efeitos adversos , Países Baixos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fluxo Sanguíneo Regional , Método Simples-Cego , Oclusão Terapêutica/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
20.
Neuropathology ; 39(2): 156-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834588

RESUMO

An 80-year-old man with a history of diabetes mellitus and hypertension died of a progressive neurological disorder characterized by truncal ataxia, extraocular movement disturbance, and muscular rigidity. Neuroradiological examination showed progressive atrophy restricted to the pontine base. Autopsy revealed localized atrophy of the pontine base, in which both neurons and nerve fibers were lost, especially in the central region. Medium-sized and small arteries in the parenchyma of the pontine base showed marked fibro-hyalinous thickening of the walls with luminal stenosis, but no distinct tissue defect as seen in lacunar infarct was observed. Perivascular lymphocytic infiltration was mostly absent, and reactive astrocytic proliferation was weak. The pontine tegmentum, midbrain, and medulla oblongata were well preserved. Localized atrophy of the pontine base is a rare pathological condition, and its pathogenesis in the present case can be best explained by a prolonged ischemic state (hypoperfusion) due to marked sclerotic changes of perforating arteries. It is unique that the lesions were restricted to the pontine base and the formation of lacunas was not observed. Localized metabolic derangement resembling that seen in central pontine myelinolysis might have also contributed to the pathogenesis of this peculiar localized atrophy.


Assuntos
Isquemia Encefálica/patologia , Progressão da Doença , Ponte/patologia , Idoso de 80 Anos ou mais , Atrofia , Isquemia Encefálica/complicações , Diabetes Mellitus Tipo 2/complicações , Transtornos da Audição/complicações , Humanos , Hipertensão/complicações , Masculino , Fibras Nervosas/patologia , Neurônios/patologia
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