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1.
Brain Behav ; 14(7): e3608, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38956886

RESUMO

INTRODUCTION: Cerebral ischemia reperfusion injury (CIRI) often leads to deleterious complications after stroke patients receive reperfusion therapy. Exercise preconditioning (EP) has been reported to facilitate brain function recovery. We aim to explore the specific mechanism of EP in CIRI. METHODS: Sprague-Dawley rats were randomized into Sham, middle cerebral artery occlusion (MCAO), and EP groups (n = 11). The rats in the EP group received adaptive training for 3 days (10 m/min, 20 min/day, with a 0° incline) and formal training for 3 weeks (6 days/week, 25 m/min, 30 min/day, with a 0° incline). Then, rats underwent MCAO surgery to establish CIRI models. After 48 h, neurological deficits and cerebral infarction of the rats were measured. Neuronal death and apoptosis in the cerebral cortices were detected. Furthermore, RNA sequencing was conducted to investigate the specific mechanism of EP on CIRI, and qPCR and Western blotting were further applied to confirm RNA sequencing results. RESULTS: EP improved neurological deficit scores and reduced cerebral infarction in MCAO rats. Additionally, pre-ischemic exercise also alleviated neuronal death and apoptosis of the cerebral cortices in MCAO rats. Importantly, 17 differentially expressed genes (DEGs) were identified through RNA sequencing, and these DEGs were mainly enriched in the HIF-1 pathway, cellular senescence, proteoglycans in cancer, and so on. qPCR and Western blotting further confirmed that EP could suppress TIMP1, SOCS3, ANGPTL4, CDO1, and SERPINE1 expressions in MCAO rats. CONCLUSION: EP can improve CIRI in vivo, the mechanism may relate to TIMP1 expression and HIF-1 pathway, which provided novel targets for CIRI treatment.


Assuntos
Infarto da Artéria Cerebral Média , Condicionamento Físico Animal , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/terapia , Ratos , Masculino , Condicionamento Físico Animal/fisiologia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Análise de Sequência de RNA , Modelos Animais de Doenças , Apoptose , Precondicionamento Isquêmico/métodos
2.
CNS Neurosci Ther ; 30(7): e14825, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38954749

RESUMO

AIMS: Ischemic stroke remains a challenge in medical research because of the limited treatment options. Recombinant human tissue plasminogen activator (rtPA) is the primary treatment for recanalization. However, nearly 50% of the patients experience complications that result in ineffective reperfusion. The precise factors contributing to ineffective reperfusion remain unclear; however, recent studies have suggested that immune cells, notably neutrophils, may influence the outcome of rtPA thrombolysis via mechanisms such as the formation of neutrophil extracellular traps. This study aimed to explore the nonthrombolytic effects of rtPA on neutrophils and highlight their contribution to ineffective reperfusion. METHODS: We evaluated the effects of rtPA treatment on middle cerebral artery occlusion in rats. We also assessed neutrophil infiltration and activation after rtPA treatment in vitro and in vivo in a small cohort of patients with massive cerebral ischemia (MCI). RESULTS: rtPA increased neutrophil infiltration into the brain microvessels and worsened blood-brain barrier damage during ischemia. It also increased the neutrophil counts of the patients with MCI. CONCLUSION: Neutrophils play a crucial role in promoting ischemic injury and blood-brain barrier disruption, making them potential therapeutic targets.


Assuntos
Fibrinolíticos , Neutrófilos , Proteínas Recombinantes , Ativador de Plasminogênio Tecidual , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Humanos , Masculino , Neutrófilos/efeitos dos fármacos , Ratos , Proteínas Recombinantes/farmacologia , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ratos Sprague-Dawley , Idoso , Barreira Hematoencefálica/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Infiltração de Neutrófilos/efeitos dos fármacos , Pessoa de Meia-Idade , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Modelos Animais de Doenças
3.
Sci Rep ; 14(1): 15175, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956251

RESUMO

In the current study, we aimed to investigate whether disulfiram (DSF) exerts a neuroprotective role in cerebral ischemiareperfusion (CI-RI) injury by modulating ferredoxin 1 (FDX1) to regulate copper ion (Cu) levels and inhibiting inflammatory responses. To simulate CI-RI, a transient middle cerebral artery occlusion (tMCAO) model in C57/BL6 mice was employed. Mice were administered with or without DSF before and after tMCAO. Changes in infarct volume after tMCAO were observed using TTC staining. Nissl staining and hematoxylin-eosin (he) staining were used to observe the morphological changes of nerve cells at the microscopic level. The inhibitory effect of DSF on initial inflammation was verified by TUNEL assay, apoptosis-related protein detection and iron concentration detection. FDX1 is the main regulatory protein of copper death, and the occurrence of copper death will lead to the increase of HSP70 stress and inflammatory response. Cuproptosis-related proteins and downstream inflammatory factors were detected by western blotting, immunofluorescence staining, and immunohistochemistry. The content of copper ions was detected using a specific kit, while electron microscopy was employed to examine mitochondrial changes. We found that DSF reduced the cerebral infarction volume, regulated the expression of cuproptosis-related proteins, and modulated copper content through down regulation of FDX1 expression. Moreover, DSF inhibited the HSP70/TLR-4/NLRP3 signaling pathway. Collectively, DSF could regulate Cu homeostasis by inhibiting FDX1, acting on the HSP70/TLR4/NLRP3 pathway to alleviate CI/RI. Accordingly, DSF could mitigate inflammatory responses and safeguard mitochondrial integrity, yielding novel therapeutic targets and mechanisms for the clinical management of ischemia-reperfusion injury.


Assuntos
Cobre , Dissulfiram , Homeostase , Inflamação , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Dissulfiram/farmacologia , Camundongos , Cobre/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Modelos Animais de Doenças , Proteínas Ferro-Enxofre/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptor 4 Toll-Like/metabolismo
4.
CNS Neurosci Ther ; 30(7): e14747, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38973085

RESUMO

AIM: To explore the regulatory mechanisms of microglia-mediated cytotoxic CD8+ T-cell infiltration in the white matter injury of perioperative stroke (PIS). METHODS: Adult male C57BL/6 mice were subjected to ileocolic bowel resection (ICR) 24 h prior to permanent distant middle cerebral artery occlusion (dMCAO) to establish model PIS. White matter injury, functional outcomes, peripheral immune cell infiltration, and microglia phenotype were assessed up to 28 days after dMCAO using behavioral phenotyping, immunofluorescence staining, transmission electron microscopy, western blot, and FACS analysis. RESULTS: We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8+ T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8+ T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor-interacting protein kinase 1 (RIPK1) activity could alleviate CD8+ T-cell infiltration and demyelination in PIS mice. CONCLUSION: Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8+ T cells and microglia necroptosis, suggesting that modulating interactions of CD8+ T cells and microglia could be a novel therapeutic target of long-term neurological deficits of PIS.


Assuntos
Linfócitos T CD8-Positivos , Infarto da Artéria Cerebral Média , Camundongos Endogâmicos C57BL , Substância Branca , Animais , Masculino , Camundongos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/imunologia , Substância Branca/patologia , Substância Branca/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/imunologia , Microglia/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ativação Linfocitária , Modelos Animais de Doenças
5.
Neurotox Res ; 42(4): 35, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39008165

RESUMO

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.


Assuntos
Apoptose , Autofagia , Proteína 3 Ligante de Ácido Graxo , Mitocôndrias , Neurônios , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Apoptose/fisiologia , Autofagia/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Mitocôndrias/metabolismo , Masculino , Proteína 3 Ligante de Ácido Graxo/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Camundongos Endogâmicos C57BL , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estresse Oxidativo/fisiologia
6.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39000490

RESUMO

Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.


Assuntos
Infarto Cerebral , Modelos Animais de Doenças , AVC Isquêmico , Metaloproteinase 3 da Matriz , Camundongos Knockout , Animais , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Masculino , Feminino , Camundongos , AVC Isquêmico/genética , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Infarto Cerebral/metabolismo , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Camundongos Endogâmicos C57BL , Transcriptoma , Regulação da Expressão Gênica , Encéfalo/metabolismo , Encéfalo/patologia
7.
Neuromolecular Med ; 26(1): 22, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824254

RESUMO

Stroke is a significant public health issue, and research has consistently focused on studying the mechanisms of injury and identifying new targets. As a CDK5 activator, p39 plays a crucial role in various diseases. In this article, we will explore the role and mechanism of p39 in cerebral ischemic injury. We measured the level of p39 using western blot and QPCR at various time points following cerebral ischemia-reperfusion (I/R) injury. The results indicated a significant reduction in the level of p39. TTC staining and behavioral results indicate that the knockout of p39 (p39KO) provides neuroprotection in the short-term. Interestingly, the behavioral dysfunction in p39KO mice was exacerbated after the repair phase of I/R. Further study revealed that this deterioration may be due to demyelination induced by elevated p35 levels. In summary, our study offers profound insights into the significance of p39 in both the acute and repair stages of ischemic injury recovery and a theoretical foundation for future therapeutic drug exploration.


Assuntos
Camundongos Endogâmicos C57BL , Camundongos Knockout , Bainha de Mielina , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/genética , Infarto da Artéria Cerebral Média/patologia , Fosfotransferases , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
8.
Fitoterapia ; 176: 106045, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823597

RESUMO

Notoginseng leaf triterpenes (PNGL), derived from the dried stems and leaves of P. notoginseng, is a phytoestrogen that exerts many neuroprotective effects in vivo and in vitro of ischemic stroke. However, its impact on neurological restoration specifically in relation to angiogenesis following ischemic stroke remains unexplored. The aim of this study was to assess the effects of PNGL on angiogenesis subsequent to ischemic stroke. Male Sprague-Dawley rats were utilized in this study and were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Post-ischemia, PNGL were administered through intraperitoneal (i.p.) injection. The high-performance liquid chromatography (HPLC) fingerprinting, triphenyltetrazolium chloride (TTC) staining, immunofluorescent staining, network pharmacology and western blot analyses were assessed to determine the therapeutical effect and molecular mechanisms of PNGL on cerebral ischemia/reperfusion injury. Our findings demonstrate that PNGL effectively reduced infarct volume, enhanced cerebral blood flow, and induced angiogenesis in rats subjected to MCAO/R. Notably, PNGL also facilitated neuronal proliferation and migration in HUMECs in vitro. The proangiogenic effects of PNGL were found to be linked to the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the AMPK/SIRT1-mediated PGC-1/ERα axis, as well as the activation of neurological function. Our study provides evidence that PNGL hold promise as an active ingredient of inducing proangiogenic effects, potentially through the activation of the Nrf2 pathway and the AMPK/SIRT1-mediated PGC-1/ERα axis. These findings contribute to the understanding of novel mechanisms involved in the restoration of neurological function following PNGL treatment for ischemic stroke.


Assuntos
AVC Isquêmico , Fator 2 Relacionado a NF-E2 , Panax notoginseng , Folhas de Planta , Ratos Sprague-Dawley , Sirtuína 1 , Triterpenos , Animais , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Sirtuína 1/metabolismo , AVC Isquêmico/tratamento farmacológico , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , Panax notoginseng/química , Folhas de Planta/química , Humanos , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , China , Traumatismo por Reperfusão/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Angiogênese
9.
Neuroreport ; 35(12): 780-789, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-38935074

RESUMO

This study aims to investigate how electroacupuncture regulates the learning and memory abilities of poststroke cognitive impairment (PSCI) rats through the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia. Thirty male rats were randomly divided into three groups: sham surgery group, PSCI model group, and electroacupuncture group, with 10 rats in each group. Middle cerebral artery occlusion was used to establish the PSCI model. The Zea Longa method was used to score the rats' neurological function. Electroacupuncture was utilized for 21 days to improve PSCI. The learning and memory abilities of rats were tested using the Morris water maze. Hematoxylin-eosin staining and immunofluorescence were used to find the hippocampus' pathological changes. The concentration of interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-18 were detected by ELISA. The mRNA expression levels of associated inflammatory corpuscles were measured by quantitative real-time PCR. The protein expression levels of TLR4, MyD88, NF-κB, and NLRP3 were measured using western blotting. Electroacupuncture improved not only the learning and memory abilities of PSCI rats but also hippocampal morphology. Electroacupuncture inhibited the activation of microglia and the TLR4/NF-κB/NLRP3 signaling pathway. Electroacupuncture also reduced proinflammatory factors and restrained the mRNA levels of NLRP3-associated inflammatory cytokines. Its mechanism was related to inhibiting the expression of the TLR4/NF-κB/NLRP3 signaling pathway, attenuating the release of inflammatory factors, and regulating the activation of hippocampal microglia in the brain.


Assuntos
Eletroacupuntura , Hipocampo , Microglia , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Eletroacupuntura/métodos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 4 Toll-Like/metabolismo , Masculino , Hipocampo/metabolismo , Ratos , NF-kappa B/metabolismo , Microglia/metabolismo , Transdução de Sinais/fisiologia , Memória/fisiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/terapia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/metabolismo
10.
J Vis Exp ; (207)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38884468

RESUMO

The middle cerebral artery occlusion reperfusion (MCAO/R) model is crucial for understanding the pathological mechanisms of stroke and for drug development.However, among the commonly used modeling methods, the Koizumi method often faces scrutiny due to its ligation of the common carotid artery (CCA) and its inability to achieve adequate reperfusion. Similarly, the Longa method has been criticized for disconnecting and ligating the external carotid artery (ECA). This study aims to introduce a modified model preparation method that preserves the integrity of the ECA, involves inserting a monofilament nylon suture through the CCA, repairing the ligated CCA incision, and maintaining reperfusion from the CCA. Reperfusion of blood flow was confirmed using laser speckle flow imaging. Evaluation methods such as the Longa scale, Modified Neurological Severity Score, triphenyltetrazolium chloride (TTC) staining, and immunofluorescence labeling of neurons demonstrated that this approach could induce stable ischemic nerve damage. This modified MCAO/R model protocol is simple and stable, providing valuable guidance for practitioners in the field of cerebral ischemia.


Assuntos
Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Animais , Infarto da Artéria Cerebral Média/cirurgia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Reperfusão/métodos , Masculino , Traumatismo por Reperfusão
11.
Molecules ; 29(12)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38930905

RESUMO

BACKGROUND: Achyranthes bidentata (AR) is a traditional Chinese herb used for the treatment of hypertension and cerebral ischemia, but its pharmacological effects are not known. AIM OF STUDY: We aimed to detect and accurately identify the components and metabolites of AR in the plasma and brain tissue of Sprague Dawley rats. METHODS: We employed ultrahigh performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HR-MS) to detect AR components in the plasma and brain tissue of rats. The absorption and metabolites in the plasma and brain tissue of normal control rats and rats that underwent middle cerebral artery occlusion (MCAO) were characterized and compared. RESULTS: A total of 281 compounds, including alkaloids, flavonoids, terpenoids, phenylpropanes, sugars and glycosides, steroids, triterpenes, amino acids, and peptides, was identified in samples of Achyranthes bidentata (TCM-AR). Four types of absorbable prototype components and 48 kinds of metabolites were identified in rats in the normal control plasma group which were given AR (AR plasma group), and five kinds of metabolites were identified in rats of the normal control brain tissue group which were given AR (AR brain group). Three absorbed prototype components and 13 metabolites were identified in the plasma of rats which underwent MCAO and were given AR (MCAO + AR plasma group). Six absorbed prototype components and two metabolites were identified in the brain tissue of rats who underwent MCAO and were administered AR (MCAO + AR brain group). These results showed that, after the oral administration of AR, the number of identified components in plasma was more than that in brain tissue. The number of prototype components in the AR plasma group was higher than that in the MCAO + AR plasma group, which may indicate that metabolite absorption in rats undergoing MCAO was worse. The number of prototype components in the MCAO + AR brain group was higher than that in the AR brain group, indicating that the blood-brain barrier was destroyed after MCAO, resulting in more compounds entering brain tissue. CONCLUSIONS: UHPLC-HR-MS was used to rapidly analyze the components and metabolites of AR in the blood and brain of rats under normal and pathologic conditions, and to comprehensively characterize the components of TCM-AR. We also analyzed and compared the absorbable components and metabolites of normal rats under cerebral ischemia-reperfusion injury to explore the potential mechanism of action. This method could be applied to various Chinese herbs and disease models, which could promote TCM modernization.


Assuntos
Achyranthes , Encéfalo , Ratos Sprague-Dawley , Animais , Achyranthes/química , Cromatografia Líquida de Alta Pressão/métodos , Ratos , Encéfalo/metabolismo , Masculino , Espectrometria de Massas/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/química , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/sangue , Flavonoides/sangue , Flavonoides/farmacocinética , Flavonoides/metabolismo , Alcaloides/sangue , Alcaloides/farmacocinética , Alcaloides/química , Alcaloides/metabolismo
12.
Physiol Rep ; 12(12): e16118, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38923318

RESUMO

Stroke is a pervasive and debilitating global health concern, necessitating innovative therapeutic strategies, especially during recovery. While existing literature often focuses on acute interventions, our study addresses the uniqueness of brain tissue during wound healing, emphasizing the chronic phase following the commonly used middle cerebral artery (MCA) occlusion model. Using clinically relevant endpoints in male and female mice such as magnetic resonance imaging (MRI) and plasma neurofilament light (NFL) measurement, along with immunohistochemistry, we describe injury evolution. Our findings document significant alterations in edema, tissue remodeling, and gadolinium leakage through MRI. Plasma NFL concentration remained elevated at 30 days poststroke. Microglia responses are confined to the region adjacent to the injury, rather than continued widespread activation, and boron-dipyrromethene (BODIPY) staining demonstrated the persistent presence of foam cells within the infarct. Additional immunohistochemistry highlighted sustained B and T lymphocyte presence in the poststroke brain. These observations underscore potentially pivotal roles played by chronic inflammation brought on by the lipid-rich brain environment, and chronic blood-brain barrier dysfunction, in the development of secondary neurodegeneration. This study sheds light on the enduring consequences of ischemic stroke in the most used rodent stroke model and provides valuable insights for future research, clinical strategies, and therapeutic development.


Assuntos
AVC Isquêmico , Camundongos Endogâmicos C57BL , Animais , Masculino , Camundongos , Feminino , AVC Isquêmico/patologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/metabolismo , AVC Isquêmico/sangue , Infarto da Artéria Cerebral Média/patologia , Modelos Animais de Doenças , Inflamação/patologia , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/metabolismo , Imageamento por Ressonância Magnética , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Proteínas de Neurofilamentos
13.
Eur J Pharmacol ; 977: 176724, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851559

RESUMO

INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the blood‒brain barrier and has potential in the treatment of nervous system diseases. These findings suggest that mangiferin protects the neurological function in ischemic stroke rats by targeting multiple signaling pathways. However, little is known about the effect and mechanism of mangiferin in alleviating poststroke cognitive impairment. METHODS: Cerebral ischemia/reperfusion (I/R) rats were generated via middle cerebral artery occlusion. Laser speckle imaging was used to monitor the cerebral blood flow. The I/R rats were intraperitoneally (i.p.) injected with 40 mg/kg mangiferin for 7 consecutive days. Neurological scoring, and TTC staining were performed to evaluate neurological function. Behavioral experiments, including the open field test, elevated plus maze, sucrose preference test, and novel object recognition test, were performed to evaluate cognitive function. Metabolomic data from brain tissue with multivariate statistics were analyzed by gas chromatography‒mass spectrometry and liquid chromatography‒mass spectrometry. RESULTS: Mangiferin markedly decreased neurological scores, and reduced infarct areas. Mangiferin significantly attenuated anxiety-like and depression-like behaviors and enhanced learning and memory in I/R rats. According to the metabolomics results, 13 metabolites were identified to be potentially regulated by mangiferin, and the differentially abundant metabolites were mainly involved in lipid metabolism. CONCLUSIONS: Mangiferin protected neurological function and relieved poststroke cognitive impairment by improving lipid metabolism abnormalities in I/R rats.


Assuntos
Disfunção Cognitiva , Metabolismo dos Lipídeos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Xantonas , Animais , Xantonas/farmacologia , Xantonas/uso terapêutico , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Ratos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/complicações , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos
14.
PLoS One ; 19(6): e0305541, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38885233

RESUMO

BACKGROUND: The inflammatory response is a key factor in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI), and anti-inflammatory interventions may offer a promising therapeutic strategy. Forsythoside B (FB) is a phenylethanoid glycoside isolated from Forsythiae fructus, which has been reported to have anti-inflammatory effects. However, the mechanism of the neuroprotective effect of FB on CIRI remains unclear. METHODS: Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion/reperfusion (MCAO/R). FB was administered intraperitoneally for 3 days prior to MCAO/R. Cerebral infarct volume and neurological deficit score were used as indices to evaluate MCAO/R injury. The serum levels of inflammatory factors and antioxidant enzymes were measured. The activation of silent information regulator 2 homolog 1 (Sirt1) and the inhibition of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) pathway were assessed through western blot and immunohistochemistry analysis. Furthermore, the rats were treated with Sirt1 shRNA 3 days before MCAO/R by stereotactical injection into the ipsilateral hemispheric region to assess the impact of Sirt1 knockdown on the protection of FB during MCAO/R. RESULTS: FB reduced cerebral infarct volume and neurological deficit score in MCAO/R rats. FB reduced pathological changes and cell apoptosis in the hippocampal CA1 region and cortex on the ischemic side of rats. FB inhibited the serum levels of inflammatory factors and increased the activities of antioxidant enzymes. Further study showed that FB inhibited the activation of the NLRP3 pathway and induced Sirt1 activation. CONCLUSION: FB demonstrated neuroprotective and anti-inflammatory effects by inhibiting the NLRP3 pathway through Sirt1 activation in CIRI.


Assuntos
Infarto da Artéria Cerebral Média , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Masculino , Inflamassomos/metabolismo , Ratos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ácidos Cafeicos , Glucosídeos
15.
Exp Neurol ; 378: 114843, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38823675

RESUMO

Poststroke neuroinflammation exacerbates disease progression. [11C]PK11195-positron emission tomography (PET) imaging has been used to visualize neuroinflammation; however, its short half-life of 20 min limits its clinical use. [123I]CLINDE has a longer half-life (13h); therefore, [123I]CLINDE-single-photon emission computed tomography (SPECT) imaging is potentially more practical than [11C]PK11195-PET imaging in clinical settings. The objectives of this study were to 1) validate neuroinflammation imaging using [123I]CLINDE and 2) investigate the mechanisms underlying stroke in association with neuroinflammation using multimodal techniques, including magnetic resonance imaging (MRI), gas-PET, and histological analysis, in a rat model of ischemic stroke, that is, permanent middle cerebral artery occlusion (pMCAo). At 6 days post-pMCAo, [123I]CLINDE-SPECT considerably corresponded to the immunohistochemical images stained with the CD68 antibody (a marker for microglia/microphages), comparable to the level observed in [11C]PK11195-PET images. In addition, the [123I]CLINDE-SPECT images corresponded well with autoradiography images. Rats with severe infarcts, as defined by MRI, exhibited marked neuroinflammation in the peri-infarct area and less neuroinflammation in the ischemic core, accompanied by a substantial reduction in the cerebral metabolic rate of oxygen (CMRO2) in 15O-gas-PET. Rats with moderate-to-mild infarcts exhibited neuroinflammation in the ischemic core, where CMRO2 levels were mildly reduced. This study demonstrates that [123I]CLINDE-SPECT imaging is suitable for neuroinflammation imaging and that the distribution of neuroinflammation varies depending on the severity of infarction.


Assuntos
Modelos Animais de Doenças , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Ratos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Masculino , Ratos Sprague-Dawley , Doenças Neuroinflamatórias/diagnóstico por imagem , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia
16.
Exp Cell Res ; 440(1): 114127, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38857839

RESUMO

CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.


Assuntos
Apoptose , Heme Oxigenase-1 , AVC Isquêmico , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Neurônios/metabolismo , Neurônios/patologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Ratos , Masculino , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Transdução de Sinais , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Heme Oxigenase (Desciclizante)
17.
J Neuroinflammation ; 21(1): 155, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38872149

RESUMO

Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key component of the KKS - in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.


Assuntos
Calicreína Plasmática , Recuperação de Função Fisiológica , Animais , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Masculino , Calicreína Plasmática/antagonistas & inibidores , Calicreína Plasmática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto da Artéria Cerebral Média , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombose , AVC Isquêmico/tratamento farmacológico , Inflamação
18.
Brain Res Bull ; 214: 110999, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38851436

RESUMO

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.


Assuntos
Encéfalo , Vesículas Extracelulares , Transplante de Células-Tronco Mesenquimais , Acidente Vascular Cerebral , Animais , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Ratos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Astrócitos/metabolismo
19.
Brain Res Bull ; 214: 111006, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852654

RESUMO

BACKGROUND: Limb remote ischemic postconditioning (LRIP) and paeoniflorin (PF) both can ameliorate cerebral ischemia reperfusion (I/R) injury. At present, whether LRIP combined with PF can achieve better therapeutic effect is unknown. PURPOSE: This study explored the alleviating effect and mechanism of LRIP in combination with PF on cerebral I/R injury in rats. METHODS: Middle cerebral artery occlusion (MCAO) surgery was performed on rats except Sham group. Then PF (2.5 mg/kg, 5 mg/kg, 10 mg/kg) was administrated by intraperitoneal injection 10 min before the start of reperfusion. LRIP was operated on the left femoral artery at 0 h of reperfusion. Behavioral testing was used to assess neurological impairment, while TTC staining was used to examine infarct volume. Protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox in neutrophils from rat peripheral blood were tested by Western blot. Rat bone marrow neutrophils were extracted and incubated for 24 h with serum from rats after LRIP combined with PF. p38 MAPK inhibitor group was administrated SB203580 while the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor group was administrated Apocynin. Neutrophils were stimulated by fMLP (10 µM). Reactive oxygen species (ROS) production and protein expression of MyD88, TRAF6, p38 MAPK, and p47phox (ser 304 and ser 345) were detected. RESULTS: LRIP combined with PF (5 mg/kg) reduced cerebral infarct volume, ameliorated neurological deficit score (NDS), decreased fMLP-stimulated ROS release and downregulated the protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox (ser 304 and ser 345) in neutrophils. CONCLUSION: The protective effect of LRIP combined with PF on cerebral I/R injury was better than either alone. Taken together, we provided solid evidence to demonstrate that the combination of LRIP and PF had potential to alleviate cerebral I/R injury, which was regulated by MyD88-TRAF6-p38 MAPK pathway and neutrophil NADPH oxidase pathway.


Assuntos
Isquemia Encefálica , Glucosídeos , Pós-Condicionamento Isquêmico , Monoterpenos , Neutrófilos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Masculino , Pós-Condicionamento Isquêmico/métodos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Glucosídeos/farmacologia , Ratos , Monoterpenos/farmacologia , Monoterpenos/uso terapêutico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , NADPH Oxidases/metabolismo , Infarto da Artéria Cerebral Média , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , NADP/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Chem Biol Interact ; 398: 111090, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38825057

RESUMO

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play pivotal roles in the pathology of cerebral ischemia. In this study, we investigated whether phelligridimer A (PA), an active compound isolated from the medicinal and edible fungus Phellinus igniarius, ameliorates ischemic cerebral injury by restoring mitochondrial function and restricting ER stress. An in vitro cellular model of ischemic stroke-induced neuronal damage was established by exposing HT-22 neuronal cells to oxygen-glucose deprivation/reoxygenation (OGD/R). An in vivo animal model was established in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The results showed that PA (1-10 µM) dose-dependently increased HT-22 cell viability, reduced OGD/R-induced lactate dehydrogenase release, and reversed OGD/R-induced apoptosis. PA reduced OGD/R-induced accumulation of reactive oxygen species, restored mitochondrial membrane potential, and increased ATP levels. Additionally, PA reduced the expression of the 78-kDa glucose-regulated protein (GRP78) and the phosphorylation of inositol-requiring enzyme-1α (p-IRE1α) and eukaryotic translation-initiation factor 2α (p-eIF2α). PA also inhibited the activation of the mitogen-activated protein kinase (MAPK) pathway in the OGD/R model. Moreover, treatment with PA restored the expression of mitofusin 2 (Mfn-2), a protein linking mitochondria and ER. The silencing of Mfn-2 abolished the protective effects of PA. The results from the animal study showed that PA (3-10 mg/kg) significantly reduced the volume of cerebral infarction and neurological deficits, which were accompanied by an increased level of Mfn-2, and decreased activation of the ER stress in the penumbra of the ipsilateral side after MCAO/R in rats. Taken together, these results indicate that PA counteracts cerebral ischemia-induced injury by restoring mitochondrial function and reducing ER stress. Therefore, PA might be a novel protective agent to prevent ischemia stroke-induced neuronal injury.


Assuntos
Isquemia Encefálica , Estresse do Retículo Endoplasmático , GTP Fosfo-Hidrolases , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , GTP Fosfo-Hidrolases/metabolismo , Ratos , Masculino , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Chaperona BiP do Retículo Endoplasmático/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Glucose/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas de Choque Térmico/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fator de Iniciação 2 em Eucariotos/metabolismo
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