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1.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668340

RESUMO

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxazóis/farmacologia , Receptores sigma/agonistas , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 272: 119234, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607158

RESUMO

Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3ß/ß-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/metabolismo , Ginkgolídeos/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , China , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Catenina/metabolismo
3.
Nat Commun ; 12(1): 1274, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627658

RESUMO

High-throughput single-cell epigenomic assays can resolve cell type heterogeneity in complex tissues, however, spatial orientation is lost. Here, we present single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin, or sciMAP-ATAC, as a method for highly scalable, spatially resolved, single-cell profiling of chromatin states. sciMAP-ATAC produces data of equivalent quality to non-spatial sci-ATAC and retains the positional information of each cell within a 214 micron cubic region, with up to hundreds of tracked positions in a single experiment. We apply sciMAP-ATAC to assess cortical lamination in the adult mouse primary somatosensory cortex and in the human primary visual cortex, where we produce spatial trajectories and integrate our data with non-spatial single-nucleus RNA and other chromatin accessibility single-cell datasets. Finally, we characterize the spatially progressive nature of cerebral ischemic infarction in the mouse brain using a model of transient middle cerebral artery occlusion.


Assuntos
Encéfalo/metabolismo , Cromatina/metabolismo , Animais , Isquemia Encefálica/metabolismo , Núcleo Celular/metabolismo , Feminino , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/metabolismo , Camundongos
4.
Nutr Metab Cardiovasc Dis ; 31(1): 333-343, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500109

RESUMO

BACKGROUND AND AIMS: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. METHODS AND RESULTS: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. CONCLUSIONS: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.


Assuntos
Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Liraglutida/farmacologia , Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Estreptozocina
5.
Life Sci ; 271: 119111, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33513398

RESUMO

BACKGROUND: Sevoflurane (Sevo) is neuroprotective in brain damage, thus our objective was to further investigate the impact of Sevo treatment on nerve regeneration and repair of neurological deficit in brain damage rats by regulating miR-490-5p and cyclin-dependent kinases 1 (CDK1). METHODS: The rat middle cerebral artery occlusion model was established. miR-490-5p and CDK1 levels in brain tissues were tested. The behavioral changes, the number of glial fibrillary acidic protein (GFAP) positive cells, ionized calcium-binding adapter molecule-1 (Iba-1) and Nestin mRNA expression, the survival and apoptosis of neurons in peripheral tissues of infarct areas were detected by a series of assays. Furthermore, the target relationship between miR-490-5p and CDK1 was verified. RESULTS: miR-490-5p was reduced and CDK1 was raised in brain tissues of brain damage rats. Sevo raised miR-490-5p and decreased CDK1 to improve neurological deficits, reduce apoptotic neurons, suppress expression levels of GFAP and Iba-1, and increase Nestin expression and the number of surviving neurons in peripheral tissue in infarct area, and alleviate the pathological changes of brain tissues of brain damage rats. CDK1 was negatively regulated by miR-490-5p. CONCLUSION: Our study presents that Sevo treatment is involved in neurogenesis and repair of neurological deficit of brain damage rats via up-regulating miR-490-5p and inhibiting CDK1.


Assuntos
Proteína Quinase CDC2/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , MicroRNAs/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Doenças do Sistema Nervoso/metabolismo , Sevoflurano/uso terapêutico , Animais , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , MicroRNAs/antagonistas & inibidores , Regeneração Nervosa/fisiologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sevoflurano/farmacologia
6.
Life Sci ; 270: 119072, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33482187

RESUMO

BACKGROUND: Accumulating evidence has reported the role of microRNA (miR) on ischemic brain injury. We aim to investigate the mechanism of miR-376b-5p/Sex-determining region Y-box 7 (SOX7)/Wnt/ß-catenin axis in mice with ischemic brain injury. METHODS: Transient middle cerebral artery occlusion (tMCAO) model was established by suture method. Expression levels of miR-376b-5p, SOX7, and Wnt/ß-catenin pathway-related proteins (Wnt3a and ß-catenin) in brain tissues of tMCAO mice were determined by RT-qPCR and western blot analysis. The target relationship between miR-376b-5p and SOX7 was tested by bioinformatics analysis and luciferase activity assay. The neurological scores of mice were recorded and their behaviors were observed. Moreover, the brain damage, oxidative stress indices, hemoglobin (Hb) content, content of brain water, infarct area, TUNEL positive cells, blood-brain barrier permeability and the number of intact neurons in the ischemic-side brain tissues of tMCAO mice were detected via upregulated miR-376b-5p or downregulated SOX7. RESULTS: In mice with ischemic brain injury, miR-376b-5p targeted and downregulated SOX7 in brain tissues, thus activating the Wnt/ß-catenin pathway. The tMCAO mice showed higher neurological scores, severe brain damage, decreased number of neurons, as well as elevated blood-brain barrier permeability, Hb content, cerebral edema and infarct area. These symptoms could be alleviated by miR-376b-5p elevation or SOX7 inhibition. SOX7 overexpression reversed the effects of miR-376b-5p elevation on tMCAO mice. CONCLUSION: Our study suggests that miR-376b-5p could improve the blood-brain barrier permeability, relieve brain edema and decrease infarct area, thus improve ischemic brain injury via the inhibition of SOX7 and activation of Wnt/ß-catenin pathway.


Assuntos
Lesões Encefálicas/genética , Isquemia Encefálica/genética , MicroRNAs/genética , Fatores de Transcrição SOXF/metabolismo , Via de Sinalização Wnt , Animais , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Fatores de Transcrição SOXF/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
7.
Life Sci ; 270: 119033, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33497737

RESUMO

AIMS: Physical exercise is beneficial to the recovery of patients with ischemic stroke. However, the underlying mechanism by which exercise promotes dendritic remodeling and synaptic plasticity is still obscure. This study explored the mechanism by which treadmill exercise enhances synaptic plasticity and dendritic remodeling in the ischemic penumbra. MAIN METHODS: A middle cerebral artery occlusion (MCAO) model was generated in C57BL/6 mice, and lentivirus-mediated cytoplasmic FMRP-associated protein 1 (CYFIP1) shRNA expression was utilized to confirm the role of CYFIP1 in the exercise-induced increase in synaptic plasticity and dendritic remodeling. Neurological deficits were measured using the Zea Longa scale. Hematoxylin-eosin (H&E) staining and Nissl staining were performed to assess cerebral ischemic injury. Golgi-Cox staining was used to observe changes in dendritic remodeling and synaptic plasticity. Transmission electron microscopy (TEM) was performed to observe the synaptic ultrastructure. Molecular mechanisms were explored using immunofluorescence staining and western blotting. KEY FINDINGS: Treadmill training enhanced synaptic plasticity in the penumbra. Additionally, we observed significant increases in the expression of CYFIP1 and calcium/calmodulin-dependent kinase 2a (Camk2a); enhanced neurological recovery and a decreased infarct volume. However, the injection of a lentivirus containing CYFIP1 shRNA into the lateral ventricle exerted negative effects on synaptic plasticity. Moreover, the exercise-induced neuroprotective effects were abolished by lentivirus-mediated CYFIP1 shRNA expression, consistent with the downregulation of Camk2a expression and the deterioration of neurological function. SIGNIFICANCE: Treadmill training enhances synaptic plasticity and dendritic remodeling in the ischemic penumbra by inducing the expression of Camk2a via upregulation of CYFIP1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Isquemia Encefálica/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Plasticidade Neuronal/fisiologia , Esforço Físico/fisiologia , Animais , Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dendritos/metabolismo , Teste de Esforço , Infarto da Artéria Cerebral Média/metabolismo , Isquemia/metabolismo , Isquemia/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia
8.
J Stroke Cerebrovasc Dis ; 30(3): 105485, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33360253

RESUMO

PURPOSE: Cerebral ischemic injury contributes to severe dysfunction of the brain, which triggers extremely high mortality and disability. The role of microRNA (miR)-181a-5p is documented in cerebral ischemic injury. Therefore, this study intended to further figure out the mechanism of miR-181a-5p in cerebral ischemic injury. METHODS: miR-181a-5p expression in middle cerebral artery occlusion (MCAO) mouse model, oxygen-glucose-deprivation/reoxygenation (OGD/R) N2a cell model, and serum from acute ischemic injury (ACI) patients was evaluated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Gain- and loss-of-function assays were implemented in MCAO mice and OGD/R-induced N2a cells. In mice, the cerebral infarction area was assessed with 2,3,5-triphenyltetrazolium chloride staining, the number of damaged neurons by Nissl staining, and apoptosis by TdT-mediated dUTP-biotin nick end-labeling staining. Moreover, N2a cell apoptosis and proliferation were determined with flow cytometry or 5-ethynyl-2'-deoxyuridine staining, respectively. The expression of En2 and Wnt/ß-catenin pathway-related factors was determined with RT-qPCR and Western blot analysis. The targeting relationship between miR-181a-5p and En2 was evaluated by dual luciferase reporter gene assay. RESULTS: miR-181a-5p was highly expressed in serum of ACI patients, MCAO mice, and OGD/R-induced N2a cells. En2, lowly expressed in MCAO mice, was targeted by miR-181a-5p, and miR-181a-5p down-regulation activated the Wnt/ß-catenin pathway. Furthermore, miR-181a-5p inhibition or En2 overexpression reduced cerebral infarction area, the number of damaged neurons, and apoptosis in MCAO mice, and also diminished apoptosis and accelerated proliferation of OGD/R-induced N2a cells. CONCLUSION: miR-181a-5p suppression activated Wnt/ß-catenin pathway and sequentially attenuated cerebral ischemic injury by targeting En2.


Assuntos
Encéfalo/metabolismo , Proteínas de Homeodomínio/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Via de Sinalização Wnt , Animais , Apoptose , Encéfalo/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Proteínas de Homeodomínio/genética , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , Neurônios/patologia
9.
Neurosci Lett ; 743: 135547, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352290

RESUMO

Cerebral ischemia-reperfusion (I/R)-induced brain tissue injury is a major obstacle for acute stroke management. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is reported to play a critical role in the regulation of myocardial or hepatic I/R injury. However, its role in cerebral I/R remains elusive. The mouse model of middle cerebral artery occlusion (MCAO) was applied in the study. The cerebral I/R mice were received either PBS or diaminopimelic acid (DAP)-pretreatment. All sham, MCAO, and MCAO + DAP mice were subject to the neurological behavior tests. The proinflammatory cytokines and autophagy-related proteins were determined by ELISA, RT-qPCR, and Western blot analysis, respectively. We found that NOD1 was substantially upregulated in the hippocampus of MCAO mice. DAP treatment significantly enhanced proinflammatory cytokine production and autophagy-related protein expression, leading to enlarged cerebral infarction size and poor neurological performance in MCAO + DAP mice compared to MCAO mice. We concluded that activation of NOD1 promotes cerebral I/R injury suggesting that NOD1 may serve as a promising target for alleviating the adverse effects of cerebral I/R.


Assuntos
Isquemia Encefálica/metabolismo , Disfunção Cognitiva/metabolismo , Ácido Diaminopimélico/toxicidade , Infarto da Artéria Cerebral Média/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Infarto da Artéria Cerebral Média/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
10.
Arterioscler Thromb Vasc Biol ; 41(3): 1127-1145, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33327747

RESUMO

OBJECTIVE: Extracellular vesicles (EVs) derived from neural progenitor cells enhance poststroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced poststroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of neural progenitor cells, we examined if neural progenitor cell-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process. Approach and Results: Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain ECs (ECs) and astrocytes exposed to oxygen glucose deprivation, we examined the effects of EVs or vehicle on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ABCB1 (ATP-binding cassette transporter B1) levels when exposed to oxygen glucose deprivation, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB (nuclear factor-κB) pathway. Using a BBB co-culture model of ECs and astrocytes exposed to oxygen glucose deprivation, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway, and downstream matrix metalloproteinase 9 (MMP-9) activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a poststroke modulation of immune responses. CONCLUSIONS: Our findings suggest that EVs enhance poststroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/fisiologia , NF-kappa B/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Glucose/metabolismo , Hipóxia/metabolismo , Hipóxia/patologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Oxigênio/metabolismo , Acidente Vascular Cerebral/patologia , Fator de Transcrição RelA/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
11.
Stroke ; 51(10): 3095-3106, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32933419

RESUMO

BACKGROUND AND PURPOSE: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. METHODS: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRß (platelet-derived growth factor receptor ß) heterozygous knockout (Pdgfrb+/-) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. RESULTS: Localization of PDGFRß-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb+/- mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb+/- mice. Cultured pericytes expressed Ccl2 and Csf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFRß inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb+/- mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFRß signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb+/- mice, parallel with the extent of tissue repair. CONCLUSIONS: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.


Assuntos
Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Pericitos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/metabolismo , Cicatrização/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Meios de Cultivo Condicionados , Infarto da Artéria Cerebral Média/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Pericitos/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Acidente Vascular Cerebral/patologia
12.
J Stroke Cerebrovasc Dis ; 29(10): 105126, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912499

RESUMO

BACKGROUND: Long non-coding RNAs (LncRNAs) have been reported to play important roles in the pathogenesis and development of many diseases, including cerebral ischemia and reperfusion (I/R) injury. In this study, we aimed to investigate the role of LncRNA-Potassium Voltage-Gated Channel Subfamily Q Member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) in cerebral I/R induced neuronal injury, and its underlying mechanisms. METHODS: Primary mouse cerebral cortical neurons treated with oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro and mice subjected to middle cerebral artery occlusion (MCAO) and reperfusion were used to mimic cerebral I/R injury. Small inference RNA (siRNA) was used to knockdown KCNQ1OT1 or microRNA-153-3p (miR-153-3p). Dual-luciferase assay was performed to detect the interaction between KCNQ1OT1 and miR-153-3p and interaction between miR-153-3p and Fork head box O3a (Foxo3). Flow cytometry analysis was performed to detect neuronal apoptosis. qRT-PCR and Western blotting were performed to detect RNA and protein expressions. RESULTS: KCNQ1OT1 and Foxo3 expressions were significantly increased in neurons subjected to I/R injury in vitro and in vivo, and miR-153-3p expression were significantly decreased. Knockdown of KCNQ1OT1 or overexpression of miR-153-3p weakened OGD/R-induced neuronal injury and regulated Foxo3 expressions. Dual-luciferase analysis showed that KCNQ1OT1 directly interacted with miR-153-3p and Foxo3 is a direct target of miR-153-3p. CONCLUSIONS: Our results indicate that LncRNA-KCNQ1OT1 promotes OGD/R-induced neuronal injury at least partially through acting as a competing endogenous RNA (ceRNA) for miR-153-3p to regulate Foxo3a expression, suggesting LncRNA-KCNQ1OT1 as a potential therapeutic target for cerebral I/R injury.


Assuntos
Córtex Cerebral/metabolismo , Proteína Forkhead Box O3/metabolismo , Infarto da Artéria Cerebral Média/terapia , MicroRNAs/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Traumatismo por Reperfusão/metabolismo , Reperfusão/efeitos adversos , Animais , Hipóxia Celular , Células Cultivadas , Córtex Cerebral/patologia , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica , Glucose/deficiência , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/patologia , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais
13.
Stroke ; 51(10): 3138-3141, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32819195

RESUMO

BACKGROUND AND PURPOSE: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. METHODS: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. RESULTS: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. CONCLUSIONS: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.


Assuntos
Encéfalo/patologia , Infarto da Artéria Cerebral Média/genética , Acidente Vascular Cerebral/genética , alfa-Sinucleína/metabolismo , Fatores Etários , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , RNA Interferente Pequeno , Recuperação de Função Fisiológica , Fatores Sexuais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , alfa-Sinucleína/genética
14.
J Stroke Cerebrovasc Dis ; 29(9): 105041, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807453

RESUMO

BACKGROUND AND PURPOSE: Ischemia-reperfusion injuries (IRIs) can aggravate the condition of some patients with acute occlusion of major intracranial artery (AOMIA) who received endovascular thrombectomy. Here, we provided data confirming the association of Repressor Element-1 Silencing Transcription factor (REST) with the long-term neuroprotective effect of the middle cerebral artery occlusion (MCAO) rats underwent Gradual Flow Restoration (GFR). METHODS: Long term neuroprotective effects of GFR intervention were evaluated on MCAO rats model after 3d and 7d reperfusion. The neurological deficit score and TTC staining were performed to evaluate the degree of brain damage in GFR and other interventions at different time. Differentially expressed genes related to cerebral ischemia reperfusion injury (CIRI) were initially screened and identified using GSE32529 microarray analysis. REST protein expression in rat brain cortex infarction was detected by Western blot analysis. RESULTS: MCAO rats intervened with GFR exhibited reduced neurological deficit (P < 0.05) and alleviated brain infarction volume (P < 0.01). The REST gene with up-regulated expression and its downstream genes with down-regulated expression were screened by Microarray analysis. The brain cortex infarction in MCAO rats produced high levels of REST expression. The GFR intervention inhibited REST expression, and alleviated brain injury on MCAO rats. CONCLUSION: Our results demonstrated that GFR intervention plays a long-term neuroprotective role and reduces brain edema and damage at reperfusion, possibly by inhibiting REST expression.


Assuntos
Edema Encefálico/prevenção & controle , Córtex Cerebral/metabolismo , Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/terapia , Traumatismo por Reperfusão/prevenção & controle , Reperfusão/métodos , Proteínas Repressoras/metabolismo , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Sprague-Dawley , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
15.
J Stroke Cerebrovasc Dis ; 29(9): 105071, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807473

RESUMO

BACKGROUND: Chinese medicine Tongxinluo capsule (TXL) has been extensively used to treat ischemic stroke in China, and one of its mechanisms is to protect against blood brain barrier (BBB) disruption after stroke. However, the underlying protective mechanisms are not fully illuminated. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP-1) is involved in BBB disruption after brain ischemia. In this study, we explored whether TXL could downregulate LRP-1 expression and subsequently protect against BBB disruption after stroke using permanent middle cerebral artery occlusion (pMCAO) in mice. METHODS: The animal model of ischemic stroke was induced by pMCAO in male adult C57BL/6J mice. The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 h after pMCAO. Meanwhile, the LRP-1 antagonist receptor associated protein (RAP) was intracerebroventricularly injected at 1 and 21 h after stroke. We measured the following parameters at 6 and 24 h: LRP-1 protein level, BBB leakage, and the expression of tight junction (TJ) proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1). RESULTS: Our results showed that TXL downregulated LRP-1 level, upregulated these TJ proteins level, and reduced BBB leakage in peri-infarct regions after pMCAO. Further study found that the inhibitor RAP played the same role as did TXL in upregulating these TJ proteins level and reducing BBB leakage after stroke. CONCLUSION: Our study demonstrates that TXL protects against BBB disruption after stroke via inhibiting the LRP-1 pathway.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Administração Oral , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Cápsulas , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
16.
Cerebrovasc Dis ; 49(4): 346-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756048

RESUMO

BACKGROUND: Inflammatory response exerts an important role in ischemia/reperfusion (I/R) injury. TLR4 and myeloid differentiation factor 88 (MyD88) are key components in inflammation and are involved in the cerebral I/R injury. Irisin is a skeletal muscle-derived myokine produced after exercise, which was found to suppress inflammation. In this study, we investigated whether irisin could protect the brain from I/R injury through the TLR4/MyD88 pathway. METHODS: Male Sprague Dawley rats (20 months, 190 ∼ 240 g) were pretreated with irisin at 10, 50, or 100 mg/kg for consecutive 3 days and then subjected to surgery of middle cerebral artery occlusion or sham operation. Infarct size and neuron loss were measured to evaluate brain damage. The mRNA and protein levels of TLR4 and MyD88 were measured by in situ hybridization and immunohistochemistry, respectively. NF-κB activation was assessed by electrophoretic mobility shift assay. Neurological function was evaluated by neurobehavior score test and passive avoidance test. RESULTS: Irisin could reduce neuronal damage and neurofunctional impairment after I/R injury. This effect was mediated by downregulating the TLR4/MyD88 and inhibiting NF-κB activation. CONCLUSION: Irisin plays a beneficial effect in I/R injury through regulating the TLR4/MyD88 pathway.


Assuntos
Encéfalo/efeitos dos fármacos , Fibronectinas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Receptor 4 Toll-Like/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
17.
Turk Neurosurg ; 30(4): 483-490, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32672342

RESUMO

AIM: To study miR-24 effects on cerebral infarction in rats. MATERIAL AND METHODS: A rat middle cerebral artery occlusion model (MCAO) was constructed. Intracerebroventricular stereotactic injection of miR-24 agomir/antagomir was performed in the rat MCAO model. According to different experiences, rats were divided into normal, sham, MCAO, miR-24 agomir and miR-24 antagomir groups. Serum TCH, HDL and TG levels were detected. RESULTS: Comparingthe normal and sham groups, we observed decreased relative miR-24 expression (p < 0.05) and increased cerebral infarction area percentage, apoptotic cells and relative caspase-3 protein expression (p < 0.05) in theMCAO, miR-24 agomirand miR-24 antagomir groups. TC, TG and HDL-C levels of the MCAO and miR-24 antagomir groups were higher than those of normal and sham groups (p < 0.05).Compared with the MCAO group, increased relative miR-24 expression (p < 0.05) and decreased TC, TG and HDL-C levels,cerebral infarction area percentage, number of apoptotic cells and caspase-3 expression (p < 0.05) were found in themiR-24 agomir group, contrasting with theobservations from the miR-24 antagomir group. CONCLUSION: miR-24 reduced serum TCH, HDL and TG levels and inhibited brain tissue cell apoptosis in rats with cerebral infarction.


Assuntos
Infarto da Artéria Cerebral Média/patologia , MicroRNAs/metabolismo , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Caspase 3/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue
18.
J Stroke Cerebrovasc Dis ; 29(8): 104848, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689584

RESUMO

BACKGROUND: Dapsone prevents ischemic injury, inhibits apoptosis and shows functional improvement post-ischemia. However, its effect on proapoptotic or survival proteins in delayed ischemia remains unclear. METHODS: Male adult Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by 24 h of ischemic reperfusion (I/R). Dapsone [9.375 or 12.5 mg/kg, intraperitoneally (IP)] was administered at 3, 6 and 12 h of I/R followed by behavioural assessment, brain infarction, histological alteration and cell viability study. Further, dapsone (25 and 50 µM) was added at 3, 6 and 12 h after L-glutamate (100 µM) in primary cortical culture (DIV 14) and cell viability, cytotoxicity, apoptosis was observed. Proteins expression were observed using immunocytochemistry. All experiments were performed after 24 h of I/R (In-Vivo) and 24 h of recovery post glutamate insult (In-Vitro). RESULTS: Reduced brain infarction, improved neurobehavioural functions in addition to reduction in abnormal morphological structures of ischemic brain and improvement in cell viability was observed with treatment of dapsone (12.5 mg/kg) administered upto 6 h. Similarly, dapsone (25, 50 µM) increased cell survival post glutamate insult in cortical culture (In-vitro). Further, dapsone treatment at delayed hours (6 h) reduced apoptotic nuclei and proapoptotic proteins JNK, PTEN, Calpain, Caspase 3 expression along with activation of prosurvival protein BDNF expression post-glutamate insult. CONCLUSION: Our results suggest that dapsone has the potential to limit the neuronal damage post-glutamate insult in delayed hours (6 h) through repressing proapoptotic proteins JNK, PTEN, Calpain, Caspase-3 of cerebral ischemia along with activation of pro-survival protein BDNF.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Dapsona/farmacologia , Ácido Glutâmico/toxicidade , Infarto da Artéria Cerebral Média/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
19.
J Stroke Cerebrovasc Dis ; 29(8): 104977, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689608

RESUMO

BACKGROUND: Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. MATERIALS AND METHODS: To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. RESULTS: The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1ß in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. CONCLUSIONS: Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Monoterpenos Bicíclicos/farmacologia , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
J Stroke Cerebrovasc Dis ; 29(8): 104818, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32439352

RESUMO

BACKGROUND: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear. METHODS: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO. RESULTS: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice. CONCLUSION: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Cinamatos/farmacologia , Depsídeos/farmacologia , Suplementos Nutricionais , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Aldeídos/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL
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