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1.
Methods Mol Biol ; 2761: 623-633, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427265

RESUMO

Stroke is the third-leading cause of death and the leading cause of acquired adult disability worldwide. Several ischemic stroke models are currently available. However, mimicking focal cerebral ischemia (FCI) is the most common. The formation of an embolic or thrombotic occlusion at or near the middle cerebral artery causes most events in FCI. The current protocol closely mimics the etiology of human stroke and ensures that the results obtained are highly relevant. The method described in this protocol yields reproducible results. The success of this model in ischemic research can be examined through the utilization of Doppler blood flow imaging equipment.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Humanos , Animais , Infarto da Artéria Cerebral Média/complicações , Modelos Animais de Doenças , Isquemia Encefálica/etiologia , Artéria Cerebral Média/diagnóstico por imagem
2.
Physiol Res ; 73(1): 127-138, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38466011

RESUMO

MicroRNAs have been shown to potentially function in cerebral ischemia/reperfusion (IR) injury. This study aimed to examine the expression of microRNA-320 (miR-320) in cerebral IR injury and its involvement in cerebral mitochondrial function, oxidative stress, and inflammatory responses by targeting the HMGB1/NF-kappaB axis. Sprague-Dawley rats were subjected to middle cerebral artery occlusion to simulate cerebral IR injury. The cerebral expression of miR-320 was assessed using qRT-PCR. Neurological function, cerebral infarct volume, mitochondrial function, oxidative stress, and inflammatory cytokines were evaluated using relevant methods, including staining, fluorometry, and ELISA. HMGB1 expression was analyzed through Western blotting. The levels of miR-320, HMGB1, neurological deficits, and cerebral infarction were significantly higher after IR induction. Intracerebral overexpression of miR-320 resulted in substantial neurological deficits, increased infarct volume, elevated levels of 8-isoprostane, NF-kappaBp65, TNF-alpha, IL-1beta, ICAM-1, VCAM-1, and HMGB1 expression. It also promoted the loss of mitochondrial membrane potential and ROS levels while reducing MnSOD and GSH levels. Downregulation of miR-320 and inhibition of HMGB1 activity significantly reversed the outcomes of cerebral IR injury. MiR-320 plays a negative role in regulating cerebral inflammatory/oxidative reactions induced by IR injury by enhancing HMGB1 activity and modulating mitochondrial function.


Assuntos
Proteína HMGB1 , MicroRNAs , Traumatismo por Reperfusão , Animais , Ratos , Proteína HMGB1/genética , Infarto da Artéria Cerebral Média/genética , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo
3.
J Mol Neurosci ; 74(1): 29, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478127

RESUMO

Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen-glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.


Assuntos
Disfunção Cognitiva , Vesículas Extracelulares , Células-Tronco Mesenquimais , Células-Tronco Neurais , Acidente Vascular Cerebral , Camundongos , Animais , Células-Tronco Neurais/metabolismo , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Disfunção Cognitiva/metabolismo
4.
Int J Nanomedicine ; 19: 2285-2299, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482520

RESUMO

Purpose: Ischemic stroke is a high-incidence disease that threatens human well-being. The potent neuroprotective effects render reactive oxygen species (ROS) scavengers potential agents for acute ischemic stroke therapy. Challenges such as inadequate permeability across the blood-brain barrier (BBB), limited half-life, and adverse effects hinder the widespread utilization of small molecule and inorganic ROS scavengers. Thus, there is an urgent demand for efficacious neuroprotective agents targeting ischemic stroke. Our study discovered the superoxide dismutase (SOD)-mimetic activity of recombinant human heavy chain ferritin (rHF) nanoparticles expressed from Escherichia coli (E. coli). Subsequent investigations delved into the ROS-scavenging proficiency of rHF within neural cells, its therapeutic efficacy against ischemic stroke, and the elucidation of its neuroprotective mechanisms. Methods: rHF protein nanoparticles were expressed in E. coli and purified via size-exclusion chromatography. The superoxide anion (•O2-) scavenging SOD-mimetic activity of rHF nanoparticles was measured using a SOD detection kit. The ROS scavenging ability and protection effects against oxidative damage of rHF nanoparticles were studied in H2O2-induced PC12 cells. Therapeutic effects and neuroprotective mechanisms of rHF against ischemic stroke were investigated with transient middle cerebral artery occlusion (MCAO) reperfusion mice model. Results: rHF nanoparticles can eliminate excessive ROS in nerve cells and alleviate oxidative damage. The results of animal experiments demonstrated that rHF nanoparticles passed across BBB, reduced infarct areas in brain tissue, and lowered the neurological deficit score of ischemia-reperfusion model mice. Additionally, rHF nanoparticles mitigated neuronal apoptosis and ferroptosis, suppressed microglial activation, maintained oxygen homeostasis, and exhibited negligible organ toxicity. Conclusion: rHF nanoparticle could be developed as a new ROS scavenger for nerve cells and has therapeutic potential as a drug for cerebral ischemia-reperfusion injury.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Nanopartículas , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Ratos , Humanos , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Escherichia coli/metabolismo , Peróxido de Hidrogênio , Infarto da Artéria Cerebral Média/tratamento farmacológico , Superóxido Dismutase , Nanopartículas/química , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico
5.
PLoS One ; 19(3): e0299042, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427657

RESUMO

Epigallocatechin gallate (EGCG) is a polyphenolic component of green tea that has anti-oxidative and anti-inflammatory effects in neurons. Ischemic stroke is a major neurological disease that causes irreversible brain disorders. It increases the intracellular calcium concentration and induces apoptosis. The regulation of intracellular calcium concentration is important to maintain the function of the nervous system. Hippocalcin is a neuronal calcium sensor protein that controls intracellular calcium concentration. We investigated whether EGCG treatment regulates the expression of hippocalcin in stroke animal model and glutamate-induced neuronal damage. We performed middle cerebral artery occlusion (MCAO) to induce cerebral ischemia. EGCG (50 mg/kg) or phosphate buffered saline was injected into the abdominal cavity just before MCAO surgery. The neurobehavioral tests were performed 24 h after MCAO surgery and cerebral cortex tissue was collected. MCAO damage induced severe neurobehavioral disorders, increased infarct volume, and decreased the expression of hippocalcin in the cerebral cortex. However, EGCG treatment improved these deficits and alleviated the decrease in hippocalcin expression in cerebral cortex. In addition, EGCG dose-dependently alleviated neuronal cell death and intracellular calcium overload in glutamate-exposed neurons. Glutamate exposure reduced hippocalcin expression, decreased Bcl-2 expression, and increased Bax expression. However, EGCG treatment mitigated these changes caused by glutamate toxicity. EGCG also attenuated the increase in caspase-3 and cleaved caspase-3 expressions caused by glutamate exposure. The effect of EGCG was more pronounced in non-transfected cells than in hippocalcin siRNA-transfected cells. These findings demonstrate that EGCG protects neurons against glutamate toxicity through the regulation of Bcl-2 family proteins and caspase-3. It is known that hippocalcin exerts anti-apoptotic effect through the modulation of apoptotic pathway. Thus, we can suggest evidence that EGCG has a neuroprotective effect by regulating hippocalcin expression in ischemic brain damage and glutamate-exposed cells.


Assuntos
Catequina , AVC Isquêmico , Fármacos Neuroprotetores , Animais , Apoptose , Cálcio/metabolismo , Caspase 3/metabolismo , Catequina/análogos & derivados , Ácido Glutâmico/metabolismo , Hipocalcina/genética , Hipocalcina/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , AVC Isquêmico/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Modelos Animais de Doenças
6.
Crit Rev Immunol ; 44(4): 1-12, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505917

RESUMO

Stroke remained the leading cause of disability in the world, and the most important non-modifiable risk factor was age. The treatment of stroke for elder patients faced multiple difficulties due to its complicated pathogenesis and mechanism. Therefore, we aimed to identify the potential differentially expressed genes (DEGs) and singnalling pathways for aged people of stroke. To compare the DEGs in the aged rats with or without middle cerebral artery occlusion (MCAO) and to analyse the important genes and the key signaling pathways involved in the development of cerebral ischaemia in aged rats. The Gene Expression Omnibus (GEO) analysis tool was used to analyse the DEGs in the GSE166162 dataset of aged MCAO rats compared with aged sham rats. Differential expression analysis was performed in aged MCAO rats and sham rats using limma. In addition, the 74 DEGs (such as Fam111a, Lcn2, Spp1, Lgals3 and Gpnmb were up-regulated; Egr2, Nr4a3, Arc, Klf4 and Nr4a1 were down-regulated) and potential compounds corresponding to the top 20 core genes in the Protein-Protein Interaction (PPI) network was constructed using the STRING database (version 12.0). Among these 30 compounds, resveratrol, cannabidiol, honokiol, fucoxanthin, oleandrin and tyrosol were significantly enriched. These DEGs were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the most significantly enriched pathway in aged MCAO rats. Moreover, innate immune response, the complement and coagulation cascades signaling pathway, the IL-17 and other signaling pathways were significantly correlated with the aged MCAO rats. Our study indicates that multiple genes and pathological processes involved in the aged people of stroke. The immune response might be the key pathway in the intervention of cerebral infarction in aged people.


Assuntos
Infarto da Artéria Cerebral Média , Acidente Vascular Cerebral , Ratos , Humanos , Animais , Idoso , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Perfilação da Expressão Gênica , Resveratrol , Expressão Gênica , Glicoproteínas de Membrana/genética
7.
CNS Neurosci Ther ; 30(3): e14676, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38488446

RESUMO

AIM: To explore the neuroprotective effects of ARA290 and the role of ß-common receptor (ßCR) in a mouse model of middle cerebral artery occlusion (MCAO). METHODS: This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO-induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5-triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry-based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and ßCR were measured by western blot. RESULTS: ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against ßCR. CONCLUSION: ARA290 provided a neuroprotective effect via ßCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention.


Assuntos
Isquemia Encefálica , Eritropoetina , AVC Isquêmico , Fármacos Neuroprotetores , Oligopeptídeos , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Camundongos , Masculino , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos Endogâmicos C57BL , Eritropoetina/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Peptídeos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Citocinas , Encéfalo , Isquemia Encefálica/tratamento farmacológico
8.
Acta Neurochir (Wien) ; 166(1): 137, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38485848

RESUMO

BACKGROUND: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites. METHODS: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified. RESULTS: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either. CONCLUSIONS: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Traumatismo por Reperfusão , Camundongos , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Encéfalo/metabolismo , Heparina/farmacologia , Heparina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico
9.
J Cell Mol Med ; 28(8): e18246, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38520223

RESUMO

Here, it was aimed to investigate the effects of intracerebroventricular (ICV) Brain Derived Neurotrophic Factor (BDNF) infusion for 7 days following cerebral ischemia (CI) on autophagy in neurons in the penumbra. Focal CI was created by the occlusion of the right middle cerebral artery. A total of 60 rats were used and divided into 4 groups as Control, Sham CI, CI and CI + BDNF. During the 7-day reperfusion period, aCSF (vehicle) was infused to Sham CI and CI groups, and BDNF infusion was administered to the CI + BDNF group via an osmotic minipump. By the end of the 7th day of reperfusion, Beclin-1, LC3, p62 and cleaved caspase-3 protein levels in the penumbra area were evaluated using Western blot and immunofluorescence. BDNF treatment for 7 days reduced the infarct area after CI, induced the autophagic proteins Beclin-1, LC3 and p62 and suppressed the apoptotic protein cleaved caspase-3. Furthermore, rotarod and adhesive removal test times of BDNF treatment started to improve from the 4th day, and the neurological deficit score from the 5th day. ICV BDNF treatment following CI reduced the infarct area by inducing autophagic proteins Beclin-1, LC3 and p62 and inhibiting the apoptotic caspase-3 protein while its beneficial effects were apparent in neurological tests from the 4th day.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ratos Sprague-Dawley , Caspase 3 , Proteína Beclina-1 , Isquemia Encefálica/metabolismo , Apoptose , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Autofagia , Infarto , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico
10.
Neurol Res ; 46(4): 367-377, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38468466

RESUMO

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Microglia , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Di-Hidroergotamina/farmacologia , Di-Hidroergotamina/uso terapêutico , Camundongos Endogâmicos C57BL , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Macrófagos , Inflamação/tratamento farmacológico
11.
Methods Mol Biol ; 2754: 581-600, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512691

RESUMO

Cerebral ischemia produces a decrease, loss, or instability of the assembly processes in the neuronal cytoskeleton, related to the alteration in the normal processes of phosphorylation of the Tau protein, triggering its hyperphosphorylation and altering the normal processes of formation of neuronal microtubules. Here we describe the methods used to study the impact of middle cerebral artery occlusion (MCAo) on neurological functions and Tau phosphorylation in Wistar rat brain.


Assuntos
Isquemia Encefálica , Proteínas tau , Ratos , Animais , Proteínas tau/metabolismo , Fosforilação , Ratos Wistar , Isquemia Encefálica/metabolismo , Isquemia/metabolismo , Reperfusão , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo
12.
Eur J Pharmacol ; 969: 176427, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38428662

RESUMO

Acute ischemic stroke (AIS) is a leading cause of global incidence and mortality rates. Oxidative stress and inflammation are key factors in the pathogenesis of AIS neuroinjury. Therefore, it is necessary to develop drugs that target neuroinflammation and oxidative stress in AIS. The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), primarily expressed on microglial cell membranes, plays a critical role in reducing inflammation and oxidative stress in AIS. In this study, we employed a high-throughput screening (HTS) strategy to evaluate 2625 compounds from the (Food and Drug Administration) FDA library in vitro to identify compounds that upregulate the TREM2 receptor on microglia. Through this screening, we identified Baicalin as a potential drug for AIS treatment. Baicalin, a flavonoid compound extracted and isolated from the root of Scutellaria baicalensis, demonstrated promising results. Next, we established an in vivo mouse model of cerebral ischemia-reperfusion injury (MCAO/R) and an in vitro microglia cell of oxygen-glucose deprivation reperfusion (OGD/R) to investigate the role of Baicalin in inflammation injury, oxidative stress, and neuronal apoptosis. Our results showed that baicalin effectively inhibited microglia activation, reactive oxygen species (ROS) production, and inflammatory responses in vitro. Additionally, baicalin suppressed neuronal cell apoptosis. In the in vivo experiments, baicalin not only improved neurological functional deficits and reduced infarct volume but also inhibited microglia activation and inflammatory responses. Overall, our findings demonstrate the efficacy of Baicalin in treating MCAO/R by upregulating TREM2 to reduce inflammatory responses and inhibit neuronal apoptosis.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Traumatismo por Reperfusão , Camundongos , Animais , AVC Isquêmico/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/metabolismo , Inflamação/tratamento farmacológico , Isquemia Encefálica/metabolismo , Microglia , Infarto da Artéria Cerebral Média/metabolismo
13.
Int Immunopharmacol ; 130: 111742, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38452414

RESUMO

BACKGROUND: Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with protein damage. The flavonoid fisetin has good therapeutic effects on cerebral IRI. However, the role of fisetin in regulating protein damage during cerebral IRI development remains unclear. This study investigated the pharmacological effects of fisetin on protein damage during cerebral IRI progression and defined the underlying mechanism of action. METHODS: In vivo and in vitro models of cerebral IRI were established by middle cerebral artery occlusion/reperfusion (MACO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) treatment, respectively. Triphenyl tetrazolium chloride staining was performed to detect cerebral infarct size, and the modified neurologic severity score was used to examine neurological deficits. LDH activity and protein damage were assessed using kits. HT22 cell vitality and apoptosis were examined using CCK-8 assay and TUNEL staining, respectively. Interactions between Foxc1, Ubqln1, Sirt1, and Ezh2 were analyzed using CoIP, ChIP and/or dual-luciferase reporter gene assays. RESULTS: Fisetin alleviated protein damage and ubiquitinated protein aggregation and neuronal death caused by MCAO/R and OGD/R. Ubqln1 knockdown abrogated the inhibitory effect of fisetin on OGD/R-induced protein damage, ubiquitinated protein aggregation, and neuronal death in HT22 cells. Further experiments demonstrated that Foxc1 functions as a transcriptional activator of Ubqln1 and that Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its activity. Furthermore, Sirt1 knockdown abrogated fisetin-mediated biological effects on OGD/R-treated HT22 cells. CONCLUSION: Fisetin improved proteostasis during cerebral IRI by regulating the Sirt1/Foxc1/Ubqln1 signaling axis. Our findings strongly suggest that fisetin-mediated inhibition of protein damage after ischemic stroke is a part of the mechanism through which fisetin is neuroprotective in cerebral IRI.


Assuntos
Isquemia Encefálica , Flavonóis , Traumatismo por Reperfusão , Humanos , Isquemia Encefálica/metabolismo , Proteostase , Sirtuína 1/metabolismo , Agregados Proteicos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Apoptose , Traumatismo por Reperfusão/metabolismo
14.
Brain Res ; 1829: 148845, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38452845

RESUMO

Formononetin has been demonstrated to protect against cerebral ischemia-reperfusion injury, however its mechanism has to be further researched. This study examined the effect of formononetin on cerebral ischemia-reperfusion injury in rats using the PARP-1/PARG/Iduna signaling pathway. In male SD rats, a model of cerebral ischemia-reperfusion injury was developed. Animals were randomly assigned to one of eight groups: Sham operation, Sham operation + formononetin, MCAO, MCAO + formononetin, PARP inhibitor (PJ34) + MCAO, formononetin + PJ34 + MCAO, PARG inhibitor (Ethacridine lactate) + MCAO, and ethacridine lactate + formononetin. The neurological deficit test, TTC staining, HE staining, Nissl staining, TUNEL staining, and western blotting were utilized to assess formononetin's protective effects in MCAO rats. The data show that formononetin can effectively alleviate neurological dysfunction and pathological changes in brain tissue in rats with cerebral ischemia-reperfusion injury, reduce the area of cerebral infarction and neuronal apoptosis, decrease the protein levels of PARP-1, PARG, Caspase-3, P53, and AIF in brain tissue, and increase the protein levels of Iduna and p-AKT. As a result, we concluded that formononetin improves brain ischemia-reperfusion injury in rats by modulating the PARP-1/PARG/Iduna signaling pathway.


Assuntos
Isquemia Encefálica , Isoflavonas , Fenantrenos , Traumatismo por Reperfusão , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Etacridina/farmacologia , Etacridina/uso terapêutico , Transdução de Sinais , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo
15.
J Neuroinflammation ; 21(1): 70, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515139

RESUMO

Myeloperoxidase (MPO) plays critical role in the pathology of cerebral ischemia-reperfusion (I/R) injury via producing hypochlorous acid (HOCl) and inducing oxidative modification of proteins. High-mobility group box 1 (HMGB1) oxidation, particularly disulfide HMGB1 formation, facilitates the secretion and release of HMGB1 and activates neuroinflammation, aggravating cerebral I/R injury. However, the cellular sources of MPO/HOCl in ischemic brain injury are unclear yet. Whether HOCl could promote HMGB1 secretion and release remains unknown. In the present study, we investigated the roles of microglia-derived MPO/HOCl in mediating HMGB1 translocation and secretion, and aggravating the brain damage and blood-brain barrier (BBB) disruption in cerebral I/R injury. In vitro, under the co-culture conditions with microglia BV cells but not the single culture conditions, oxygen-glucose deprivation/reoxygenation (OGD/R) significantly increased MPO/HOCl expression in PC12 cells. After the cells were exposed to OGD/R, MPO-containing exosomes derived from BV2 cells were released and transferred to PC12 cells, increasing MPO/HOCl in the PC12 cells. The HOCl promoted disulfide HMGB1 translocation and secretion and aggravated OGD/R-induced apoptosis. In vivo, SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus different periods of reperfusion. Increased MPO/HOCl production was observed at the reperfusion stage, accomplished with enlarged infarct volume, aggravated BBB disruption and neurological dysfunctions. Treatment of MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH) and HOCl scavenger taurine reversed those changes. HOCl was colocalized with cytoplasm transferred HMGB1, which was blocked by taurine in rat I/R-injured brain. We finally performed a clinical investigation and found that plasma HOCl concentration was positively correlated with infarct volume and neurological deficit scores in ischemic stroke patients. Taken together, we conclude that ischemia/hypoxia could activate microglia to release MPO-containing exosomes that transfer MPO to adjacent cells for HOCl production; Subsequently, the production of HOCl could mediate the translocation and secretion of disulfide HMGB1 that aggravates cerebral I/R injury. Furthermore, plasma HOCl level could be a novel biomarker for indexing brain damage in ischemic stroke patients.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Proteína HMGB1 , AVC Isquêmico , Traumatismo por Reperfusão , Humanos , Ratos , Animais , Ácido Hipocloroso , Microglia/metabolismo , Proteína HMGB1/metabolismo , Ratos Sprague-Dawley , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Neurônios/metabolismo , Traumatismo por Reperfusão/metabolismo , Peroxidase/metabolismo , Taurina , Dissulfetos
16.
Sci Rep ; 14(1): 3145, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326384

RESUMO

Indole-3-carbinol(I3C) is a tumor chemopreventive substance that can be extracted from cruciferous vegetables. Indole-3-carbinol (I3C) has been shown to have antioxidant and anti-inflammatory effects. In this study, we investigated the cerebral protective effects of I3C in an in vivo rats model of middle cerebral artery occlusion (MCAO). 8-10 Week-Old male SD rat received I3C (150 mg/kg, once daily) for 3 days and underwent 3 h of middle cerebral artery occlusion (MCAO) followed by reperfusion. The results showed that I3C pretreatment (150 mg/kg, once daily) prevented CIRI-induced cerebral infarction in rats. I3C pretreatment also decreased the mRNA expression levels of several apoptotic proteins, including Bax, caspase-3 and caspase-9, by increasing the mRNA expression levels of the anti-apoptotic protein Bcl-2. Inhibited apoptosis in the brain cells of MCAO rats. In addition, we found that I3C pretreatment reduced neuronal loss, promoted neurological recovery after ischemia-reperfusion injury and increased seven-day survival in MCAO rats. I3C pretreatment also significantly reduced the expression of inducible nitric oxide synthase (INOS), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) mRNA in ischemic brain tissue; Increased expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNA. At the same time, I3C pretreatment significantly decreased the expression of the M1 microglial marker IBA1 after cerebral ischemia-reperfusion injury and increased the expression of these results in the M2 microglial marker CD206. I3C pretreatment also significantly decreased apoptosis and death of HAPI microglial cells after hypoxia induction, decreased interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) mRNA The expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNAs was increased. These results suggest that I3C protects the brain from CIRI by regulating the anti-inflammatory and anti-apoptotic effects of microglia.


Assuntos
Isquemia Encefálica , Indóis , Traumatismo por Reperfusão , Ratos , Masculino , Animais , Microglia/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Ratos Sprague-Dawley , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Interleucina-1beta/metabolismo , Traumatismo por Reperfusão/patologia , Isquemia Encefálica/patologia , Apoptose , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico , RNA Mensageiro/metabolismo
17.
Clin Appl Thromb Hemost ; 30: 10760296241231944, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38327150

RESUMO

This study aimed to investigate the influence of prothrombotic risk factors on long-term outcomes of patients with perinatal arterial ischemic stroke. The study was conducted through an analysis of monitoring results that were regularly maintained for approximately 20 years at a tertiary stroke-monitoring center. The study assessed prothrombotic risk factors, radiological area of involvement, clinical presentation, treatments, clinical outcomes, and long-term outcomes of the 48 patients included in the study, with a mean monitoring time of 77.6 ± 45.7 months (range: 6-204). Our results showed that the presence of prothrombotic risk factors did not affect long-term outcomes. However, patients with middle cerebral artery infarction had the highest risk of developing cerebral palsy, whereas those with presumed stroke had the highest risk of developing epilepsy. This study suggests that prothrombotic risk factors should not be evaluated during the acute stage unless there is a strong suspicion of the patient's history, and prevention or early diagnosis of presumed stroke patients will positively impact their long-term prognosis.


Assuntos
Isquemia Encefálica , Doenças do Recém-Nascido , AVC Isquêmico , Acidente Vascular Cerebral , Trombofilia , Humanos , Recém-Nascido , Feminino , Gravidez , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Infarto da Artéria Cerebral Média , Trombofilia/complicações , Trombofilia/diagnóstico , Doenças do Recém-Nascido/diagnóstico , Fatores de Risco , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiologia
18.
BMJ Open ; 14(2): e080738, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38417967

RESUMO

OBJECTIVES: To investigate the impact of the COVID-19 pandemic as well as concomitant COVID-19 itself on stroke care, focusing on middle cerebral artery (MCA) territory infarctions. DESIGN: Registry-based study. SETTING: We used the National Inpatient Sample (NIS) database, which covers a wide range of hospitals within the USA. PARTICIPANTS: The NIS was queried for patients with MCA strokes between 2016 and 2020. In total, 35 231 patients were included. OUTCOME MEASURES: Outcome measures were postprocedural complications, length of stays (LOSs), in-hospital mortality and non-routine discharge. Propensity score matching using all available baseline variables was performed to reduce confounders when comparing patients with and without concomitant COVID-19. RESULTS: Mechanical thrombectomy (MT) was performed in 48.4%, intravenous thrombolysis (IVT) in 38.2%, and both MT and IVT (MT+IVT) in 13.4% of patients. A gradual increase in the use of MT and an opposite decrease in the use of IVT (p<0.001) was detected during the study period. Overall, 25.0% of all patients were admitted for MCA strokes during the pandemic period (2020), of these 209 (2.4%) were concomitantly diagnosed with COVID-19. Patients with MCA strokes and concomitant COVID-19 were significantly younger (64.9 vs 70.0; p<0.001), had significantly worse NIH Stroke Severity scores, and worse outcomes in terms of LOS (12.3 vs 8.2; p<0.001), in-hospital mortality (26.3% vs 9.8%; p<0.001) and non-routine discharge (84.2% vs 76.9%; p=0.013), as compared with those without COVID-19. After matching, only in-hospital mortality rates remained significantly higher in patients with COVID-19 (26.7% vs 8.5%; p<0.001). Additionally, patients with COVID-19 had higher rates of thromboembolic (12.3% vs 7.6%; p=0.035) and respiratory (11.3% vs 6.6%; p=0.029) complications. CONCLUSIONS: Among patients with MCA stroke, those with concomitant COVID-19 were significantly younger and had higher stroke severity scores. They were more likely to experience thromboembolic and respiratory complications and in-hospital mortality compared with matched controls.


Assuntos
Isquemia Encefálica , COVID-19 , Acidente Vascular Cerebral , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/epidemiologia , Infarto da Artéria Cerebral Média/terapia , Pandemias , Trombectomia , Resultado do Tratamento , COVID-19/complicações , COVID-19/terapia , Acidente Vascular Cerebral/complicações , Sistema de Registros , Terapia Trombolítica , Isquemia Encefálica/complicações , Fibrinolíticos/uso terapêutico
19.
J Integr Neurosci ; 23(2): 34, 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38419443

RESUMO

BACKGROUND: Ischemic stroke is the most common form of stroke and the second most common cause of death and incapacity worldwide. Its pathogenesis and treatment have been the focus of considerable research. In traditional Chinese medicine, the root of Mongolian astragalus has been important in the treatment of stroke since ancient times. Astragalus polysaccharide (APS) is a key active ingredient of astragalus and offers therapeutic potential for conditions affecting the neurological system, the heart, cancer, and other disorders. However, it is not yet known how APS works to protect against ischemic stroke. METHODS: Rats were subjected to middle cerebral artery occlusion (MCAO) to imitate localized cerebral ischemia. Each of four experimental groups (normal, sham, MCAO, and MCAO+APS) contained 12 adult male Sprague-Dawley (SD) rats selected randomly from a total of 48 rats. Following successful establishment of the model, rats in the MCAO+APS group received intraperitoneal injection of APS (50 mg/kg) once daily for 14 days, whereas all other groups received no APS. The Bederson nerve function score and the forelimb placement test were used to detect motor and sensory function defects, while Nissl staining was used to investigate pathological defects in the ventroposterior thalamic nucleus (VPN). Immunohistochemical staining and Western blot were used to evaluate the expression of Neurogenic locus notch homolog protein 1 (Notch1), hairy and enhancer of split 1 (Hes1), phospho-nuclear factor-κB p65 (p-NFκB p65), and nuclear factor-κB p65 (NFκB p65) proteins in the VPN on the ischemic side of MCAO rats. RESULTS: APS promoted the recovery of sensory and motor function, enhanced neuronal morphology, increased the number of neurons, and inhibited the expression of Notch1/NFκB signaling pathway proteins in the VPN of rats with cerebral ischemia. CONCLUSION: After cerebral ischemia, APS can alleviate symptoms of secondary damage to the VPN, which may be attributed to the suppression of the Notch1/NFκB pathway.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Masculino , Animais , Ratos Sprague-Dawley , NF-kappa B/metabolismo , Isquemia Encefálica/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Infarto da Artéria Cerebral Média/tratamento farmacológico , Acidente Vascular Cerebral/complicações , AVC Isquêmico/complicações , Receptor Notch1/metabolismo , Receptor Notch1/uso terapêutico
20.
CNS Neurosci Ther ; 30(2): e14551, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38421089

RESUMO

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a major source of morbidity and mortality after stroke, but the pathological mechanisms remain unclear. Previous studies have demonstrated that the CX3CR1 receptor plays a crucial role in maintaining an early protective microenvironment after stroke, but whether it persistently influences cognitive dysfunction in the chronic phase requires further investigation. METHODS: Mouse was used to establish a middle cerebral artery occlusion (MCAO)/reperfusion model to study PSCI. Cognitive function was assessed by the Morris water maze (MWM) and the novel object recognition test. Neurogenesis was assessed by immunofluorescence staining with Nestin+ /Ki67+ and DCX+ /BrdU+ double-positive cells. The cerebral damage was monitored by [18 F]-DPA-714 positron emission tomography, Nissel, and TTC staining. The pyroptosis was histologically, biochemically, and electron microscopically examined. RESULTS: Upon MCAO, at 28 to 35 days, CX3CR1 knockout (CX3CR1-/- ) mice had better cognitive behavioral performance both in MWM and novel object recognition test than their CX3CR1+/- counterparts. Upon MCAO, at 7 days, CX3CR1-/- mice increased the numbers of Nestin+ /Ki67+ and DCX+ /BrdU+ cells, and meanwhile it decreased the protein expression of GSDMD, NLRP3 inflammasome subunit, caspase-1, mature IL-1ß/IL-18, and p-P65 in the hippocampus as compared with CX3CR1+/- mice. In addition, CX3CR1-/- mice could reverse infarct volume in the hippocampus region post-stroke. CONCLUSION: Our study demonstrated that CX3CR1 gene deletion was beneficial to PSCI recovery. The mechanism might lie in inhibited pyroptosis and enhanced neurogenesis. CX3CR1 receptor may serve as a therapeutic target for improving the PSCI.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Microglia/patologia , Nestina/metabolismo , AVC Isquêmico/patologia , Piroptose , Bromodesoxiuridina/metabolismo , Antígeno Ki-67/metabolismo , Acidente Vascular Cerebral/patologia , Cognição , Infarto da Artéria Cerebral Média/patologia
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