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1.
Adv Exp Med Biol ; 1232: 63-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893395

RESUMO

This seems to be the time to gain new knowledge about the meningeal lymphatic system and a deeper understanding of its anatomy and physiology. Although it is known that the meningeal lymphatics present in the layers of the brain, limited information is available about the role of this system in brain function. Here, for the first time we clearly demonstrate that the meningeal lymphatic pathway is involved in brain clearing from the blood after intracranial hemorrhage associated with hypoxia and forms a connective bridge between interstitial, cerebral spinal fluid and peripheral lymphatics. We also show that the development of methods to stimulate meningeal lymph flow after hemorrhagic evidence in the brain might be a neuroprotective strategy for effective recovery of the brain after a cerebrovascular catastrophe.


Assuntos
Hemorragias Intracranianas , Vasos Linfáticos , Meninges , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Sistema Linfático , Vasos Linfáticos/fisiologia , Meninges/metabolismo , Meninges/patologia
2.
Acta Neurochir Suppl ; 127: 47-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407062

RESUMO

BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats. METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats. RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage. CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , NADPH Oxidase 2 , NADPH Oxidase 4 , Traumatismo por Reperfusão , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , NADPH Oxidases , Ratos , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/metabolismo
3.
Acta Neurochir Suppl ; 127: 91-96, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407069

RESUMO

Toll-like receptor 4 (TLR4) is expressed in various cell types in the central nervous system and exerts maximal inflammatory responses among the TLR family members. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of a cerebral aneurysm, and therefore its activation is reasonable as an initial step of cascades to brain injuries after aneurysmal subarachnoid hemorrhage (SAH). TLR4 activation induces tenascin-C (TNC), a representative of matricellular proteins that are a class of inducible, nonstructural, secreted, and multifunctional extracellular matrix glycoproteins. TNC is also an endogenous activator and inducer of TLR4, forming positive feedback mechanisms leading to more activation of the signaling transduction. Our studies have demonstrated that TLR4 as well as TNC are involved in inflammatory reactions, blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm after experimental SAH. This article reviews recent understanding of TLR4 and TNC in SAH to suggest that the TLR4-TNC signaling may be an important therapeutic target for post-SAH brain injuries.


Assuntos
Lesões Encefálicas , Hemorragia Subaracnóidea , Tenascina , Receptor 4 Toll-Like , Vasoespasmo Intracraniano , Lesões Encefálicas/metabolismo , Matriz Extracelular , Humanos , Hemorragia Subaracnóidea/metabolismo , Tenascina/metabolismo , Receptor 4 Toll-Like/metabolismo , Vasoespasmo Intracraniano/metabolismo
4.
Acta Neurochir Suppl ; 127: 105-119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407071

RESUMO

The protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, which is a branch of the unfolded protein response, participates in a range of pathophysiological processes of neurological diseases. However, few studies have investigated the role of the PERK in intracerebral hemorrhage (ICH). The present study evaluated the role of the PERK pathway during the early phase of ICH-induced secondary brain injury (SBI) and its potential mechanisms. An autologous whole blood ICH model was established in rats, and cultured primary cortical neurons were treated with oxyhemoglobin to mimic ICH in vitro. We found that levels of phosphorylated alpha subunit of eukaryotic translation initiation factor 2 (p-eIF2α) and activating transcription factor 4 (ATF4) increased significantly and peaked at 12 h during the early phase of the ICH. To further elucidate the role of the PERK pathway, we assessed the effects of the PERK inhibitor, GSK2606414, and the eIF2α dephosphorylation antagonist, salubrinal, at 12 h after ICH both in vivo and in vitro. Inhibition of PERK with GSK2606414 suppressed the protein levels of p-eIF2α and ATF4, resulting in increase of transcriptional activator CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12, which promoted apoptosis and reduced neuronal survival. Treatment with salubrinal yielded opposite results, which suggested that activation of the PERK pathway could promote neuronal survival and reduce apoptosis. In conclusion, the present study has demonstrated the neuroprotective effects of the PERK pathway during the early phase of ICH-induced SBI. These findings highlight the potential value of PERK pathway as a therapeutic target for ICH.


Assuntos
Lesões Encefálicas , Hemorragia Cerebral , RNA , eIF-2 Quinase , Animais , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Fator de Iniciação 2 em Eucariotos , Ratos , eIF-2 Quinase/metabolismo
5.
Biochemistry (Mosc) ; 84(11): 1306-1328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760920

RESUMO

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients' individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.


Assuntos
Lesões Encefálicas/patologia , Hipocampo/metabolismo , Animais , Lesões Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Estresse Oxidativo , Sistema Hipófise-Suprarrenal , Receptores de Esteroides/metabolismo
6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 500-505, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642226

RESUMO

OBJECTIVE: To evaluate the expression of translocator protein (TSPO) in brain tissue within 72 h after subarachnoid hemorrhage (SAH) in mice. METHODS: Forty-four C57BL/6J mice were randomly divided into two groups, 17 in the Sham group and 27 in the SAH group. SAH mice model was performed by endovascular perforation as previously described with slight modifications. Sham group mice were performed by the same method but without piercing the blood vessels. Before and 6 h, 24 h, 48 h, 72 h after modeling, the two groups were scored with modified Garcia score for neurological function. At 6 h, 24 h, 48 h, 72 h after modeling, the mice were sacrificed. Sham group mice were sacrificed at 24 h after modeling. The expression of TSPO in brain tissue was evaluated by Western blot, positron emission tomography-computed tomography (PET-CT) and immunofluorescence staining. Fluorescent double staining was used to assess the relationship of TSPO and microglia. RESULTS: The neurological function scores of the SAH group mice decreased with time and then increased. The expression of TSPO in the brain tissue increased first and then decreased with time, and there was a negative correlation between them (r=-0.615 6, P < 0.01). PET-CT showed that the tracer intake of mouse brain tissue after SAH was higher than that of Sham group, and the difference was statistically significant (P < 0.05). Immunofluorescence staining showed that TSPO increased in the parietal cortex and basal cortex of the SAH group. And fluorescent double staining suggested that TSPO colocalized with Iba-1 which was a specific marker of microglia. CONCLUSIONS: In the early brain injury after SAH, the expression of TSPO in brain is widely increased, and the expression level increases first and then decreases. TSPO could participate in the activation of microglia and regulate the occurrence and development of brain injury after SAH.


Assuntos
Lesões Encefálicas/metabolismo , Microglia/metabolismo , Receptores de GABA/metabolismo , Hemorragia Subaracnóidea/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Distribuição Aleatória
7.
Life Sci ; 235: 116821, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476306

RESUMO

AIMS: This study aims to examine the effects of electroacupuncture (EA) pretreatment on brain injury after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) and its underlying mechanisms. MATERIALS AND METHODS: Adult male C57BL/6 mice were subjected to 6 min of cardiac arrest induced with a potassium chloride infusion and resuscitated by chest compressions and an epinephrine infusion. During the 3 days prior to CA/CRP, mice received EA pretreatment (1 mA, 2 Hz; daily session of 30 min) at the Baihui acupoint (GV20) once daily. Stimulation at a nonacupoint served as a control. In mechanistic studies, mice received the AKT inhibitor LY294002 or endothelial nitric oxide synthase (eNOS) inhibitor L-NIO 30 min before EA pretreatment. A neurological assessment was conducted 24 h after CA/CRP, followed by animal sacrifice and evaluation of physiological brain damage. KEY FINDINGS: CA/CPR resulted in severe brain injury as evidenced by neurological deficits and increased neuronal apoptosis, oxidative stress and the proinflammatory cytokines TNF-α and IL-6. EA pretreatment at the GV20 acupoint but not at a nonacupoint attenuated the neurological deficits and the pathological changes induced by CA/CPR. LY294002 or L-NIO eliminated the neuroprotective effects of the EA pretreatment. SIGNIFICANCE: This study showed that EA pretreatment at the GV20 acupoint can protect the brain from damage associated with globalized ischemia followed by reperfusion and that these protective effects occur via the AKT/eNOS signaling pathway.


Assuntos
Lesões Encefálicas/terapia , Reanimação Cardiopulmonar/efeitos adversos , Modelos Animais de Doenças , Eletroacupuntura/métodos , Parada Cardíaca/complicações , Fármacos Neuroprotetores , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética
8.
Nat Commun ; 10(1): 3983, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484925

RESUMO

Hypoxic ischemia (HI) is an acute brain threat across all age groups. Therapeutic hypothermia ameliorates resulting injury in neonates but its side effects prevent routine use in adults. Hypothermia up-regulates a small protein subset that includes RNA-binding motif protein 3 (RBM3), which is neuroprotective under stressful conditions. Here we show how RBM3 stimulates neuronal differentiation and inhibits HI-induced apoptosis in the two areas of persistent adult neurogenesis, the subventricular zone (SVZ) and the subgranular zone (SGZ), while promoting neural stem/progenitor cell (NSPC) proliferation after HI injury only in the SGZ. RBM3 interacts with IGF2 mRNA binding protein 2 (IMP2), elevates its expression and thereby stimulates IGF2 release in SGZ but not SVZ-NSPCs. In summary, we describe niche-dependent regulation of neurogenesis after adult HI injury via the novel RBM3-IMP2-IGF2 signaling pathway.


Assuntos
Lesões Encefálicas/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Animais Recém-Nascidos , Lesões Encefálicas/genética , Células Cultivadas , Células HEK293 , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Humanos , Hipóxia-Isquemia Encefálica/genética , Fator de Crescimento Insulin-Like II/genética , Ventrículos Laterais/citologia , Ventrículos Laterais/crescimento & desenvolvimento , Ventrículos Laterais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Neurogênese/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Nicho de Células-Tronco
9.
Biomed Pharmacother ; 118: 108940, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31382130

RESUMO

Type 2 diabetes (T2D) appears to be a significant risk factor for brain injury. Glutaredoxin 2 (GRX2) belongs to the oxidoreductase family and plays an essential role in regulating various cellular processes. However, the pathogenic role of GRX2 in high fat diet (HFD)-induced brain injury is poorly understood. In the study, the loss-of-function approach was used to explore the effects of GRX2 on brain injury in HFD-challenged mice. The results indicated that HFD treatment resulted in significant increases in the change of body weight, insulin resistance and serum lipid deposition, which were markedly exaggerated by the loss of GRX2. Moreover, HFD-caused cognitive dysfunction was further promoted in GRX2 knockout mice. Histological analysis suggested that HFD administration led to the hippocampus damage, which was potentiated by GRX2 deficiency. In addition, GRX deletion enhanced HFD-induced inflammatory response in hippocampus of mice. Furthermore, GRX2 knockout markedly enhanced HFD-triggered insulin resistance in hippocampus of mice through down-regulating the protein levels of p-insulin receptor substrate 1 (IRS1) (Y632) and p-AKT (S473). The phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) suppressed by HFD administration was further reduced by GRX2 ablation. Moreover, HFD-induced oxidative stress and mitochondrial dysfunction were significantly aggravated in hippocampus of GRX2-knockout mice, which were largely dependent on the modulation of GSK-3ß signaling. These results above demonstrated that GRX2 was responsible for HFD-induced brain injury by enhancing insulin resistance, inflammation, oxidative stress and mitochondrial impairment via the meditation of GSK-3ß.


Assuntos
Lesões Encefálicas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glutarredoxinas/deficiência , Glicogênio Sintase Quinase 3 beta/metabolismo , Resistência à Insulina , Mitocôndrias/metabolismo , Animais , Astrócitos/metabolismo , Comportamento Animal/fisiologia , Lesões Encefálicas/etiologia , Células Cultivadas , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Glicogênio Sintase Quinase 3 beta/genética , Inflamação , Potencial da Membrana Mitocondrial/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo
10.
Mol Med Rep ; 20(4): 3363-3370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432127

RESUMO

The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid ß protein alloform 1­40 (Aß1­40) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aß1­40 co­injection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by co­injection of APOE4 + Aß1­40. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcription­quantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubule­associated protein tau and glycogen synthase kinase 3ß (GSK3ß). APOE4 and Aß1­40 co­aggregation decreased the short­term spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aß1­40 co­aggregation­induced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aß1­40 co­aggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3ß protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3ß phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aß1­40 co­aggregation in model rats.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Lesões Encefálicas/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Desacetilase 6 de Histona/biossíntese , Inibidores de Histona Desacetilases/farmacologia , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Colina O-Acetiltransferase/biossíntese , Hipocampo/patologia , Hipocampo/fisiopatologia , Desacetilase 6 de Histona/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/fisiopatologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
11.
Mol Med Rep ; 20(4): 3395-3405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432130

RESUMO

Cerebral ischemic injury is a major cause of death and long­term disability worldwide that leads to neurological and behavioral deficits, and for which successful treatments are still lacking. Ras homolog family member A (RhoA) and Rho­associated coiled­coil containing protein kinase (ROCK) are associated with the growth of neurons and the movement of neuronal growth cones. RhoA/ROCK inhibitors have been demonstrated to promote the recovery of motor function following nerve injury, but the underlying mechanism requires further investigation. The present study aimed to investigate the effects of the ROCK inhibitor Y­27632 on middle cerebral artery occlusion (MCAO)­induced cerebral ischemic injury. Rats were randomly assigned to the Control, Y­27632, MCAO + Vehicle or MCAO + Y­27632 group. Firstly, infarct volume, cognitive ability and cerebral injury were assessed. Secondly, indicators of cerebral inflammation, oxidative stress and apoptosis were evaluated. Finally, the expression of recombinant glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (AIF1) in the brain were measured to assess the activation of astrocytes and microglia, respectively. The results showed that Y­27632 effectively increased the survival rate and behavioral performance of rats, and attenuated the cerebral injury, oxidative stress and cerebral inflammation levels following MCAO. The disturbance in hippocampal neurons caused by MCAO was also alleviated following treatment with Y­27632. Neuronal apoptosis was also decreased following Y­27632 treatment, as demonstrated by the TUNEL assay and the expression levels of Caspases­3, 8 and 9 and Bax/Bcl­2 ratio. The levels of GFAP and AIF1 were increased by MCAO and further promoted by Y­27632, indicating the activation of astrocytes and microglia. In conclusion, the present study offered evidence of a protective effect of Y­27632 administration on cerebral ischemia/reperfusion induced behavioral and hippocampal damage by activating astrocytes and microglia.


Assuntos
Amidas/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas , Piridinas/farmacologia , Traumatismo por Reperfusão , Quinases Associadas a rho/antagonistas & inibidores , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
12.
Mol Med Rep ; 20(4): 3043-3054, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432179

RESUMO

The present study was designed to investigate the role of microRNA­451 (miRNA­451) on cerebral ischemia­reperfusion and to explore its possible mechanism. The expression of miRNA­451 was downregulated in rats with cerebral ischemia­reperfusion. In an in vitro model of cerebral ischemia­reperfusion, the downregulation of miRNA­451 increased inflammation, demonstrated by increased levels of tumor necrosis factor α, interleukin (IL)­1b, IL­6 and IL­18. However, the upregulation of miRNA­451 expression decreased inflammation in the same in vitro model of cerebral ischemia­reperfusion. In addition, it was found that the downregulation of miRNA­451 induced the expression of Toll­like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor­κB (NF­κB)/p65. Moreover, the administration of a MyD88 inhibitor, ST 2825, reduced the expression of MyD88 and NF­κB/p65 in the in vitro model of cerebral ischemia­reperfusion, inhibiting the effects of miRNA­451 upregulation on inflammation. A TLR4 inhibitor, TAK­242, was used to reduce the expression of TLR4 in the in vitro model of cerebral ischemia­reperfusion. TAK­242 suppressed the effects of miRNA­451 downregulation on inflammation. The present study suggested that miRNA­451 regulated cerebral ischemia­reperfusion­induced inflammation, which is mediated through the TLR4/MyD88/NF­κB signaling pathway.


Assuntos
Lesões Encefálicas/metabolismo , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Lesões Encefálicas/patologia , Citocinas/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Traumatismo por Reperfusão/patologia , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores
13.
Analyst ; 144(20): 5965-5970, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31464302

RESUMO

Hydrogen peroxide (H2O2) plays crucial roles in immunological processes and has been revealed to be closely linked to the hypoxic-ischemic process. Thus, it is important to develop a reliable method for monitoring H2O2 in hypoxic-ischemic brain injury (HIBI). To achieve this, we report on a rationally designed fluorene-based ratiometric two-photon fluorescent probe for H2O2, i.e., FH2O2. The probe and fluorophore were tested under either one- or two-photon modes, respectively. After reacting with H2O2, the relative emission intensity ratio at wavelengths of 390-465 (Fblue) and 500-550 nm (Fyellow) of FH2O2 had a 6.5-fold increase (Fyellow/Fblue) within 40 min, and the maximal two-photon active cross-section value was detected as 66 GM at a wavelength of 750 nm. The probe exhibited high selectivity, low cytotoxicity, high sensitivity with a detection limit of 0.57 µM, and adequate photostability. After confirming satisfactory sensing performance of the probe in vitro, we were able to monitor H2O2in situ in mice with HIBI via two-photon microscopy, which could provide a potential method for clinical diagnosis during the neonatal HIBI process.


Assuntos
Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Corantes Fluorescentes/química , Peróxido de Hidrogênio/metabolismo , Imagem Molecular/métodos , Fótons , Animais , Células HeLa , Humanos
14.
Ann Biomed Eng ; 47(9): 1873-1888, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31372858

RESUMO

A mechanics-based brain damage framework is used to model the abnormal accumulation of hyperphosphorylated p-tau associated with chronic traumatic encephalopathy within the brains of deceased National Football League (NFL) players studied at Boston University and to provide a framework for understanding the damage mechanisms. p-tau damage is formulated as the multiplicative decomposition of three independently evolving damage internal state variables (ISVs): nucleation related to number density, growth related to the average area, and coalescence related to the nearest neighbor distance. The ISVs evolve under different rates for three well known mechanical boundary conditions, which in themselves introduce three different rates making a total of nine scenarios, that we postulate are related to brain damage progression: (1) monotonic overloads, (2) cyclic fatigue which corresponds to repetitive impacts, and (3) creep which is correlated to damage accumulation over time. Different NFL player positions are described to capture the different types of damage progression. Skill position players, such as quarterbacks, are expected to exhibit a greater p-tau protein accumulation during low cycle fatigue (higher amplitude impacts with a lesser number), and linemen who exhibit a greater p-tau protein accumulation during high cycle fatigue (lower amplitude impacts with a greater number of impacts). This mechanics-based damage framework presents a foundation for developing a multiscale model for traumatic brain injury that combines mechanics with biology.


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Futebol Americano/lesões , Modelos Biológicos , Proteínas tau/metabolismo , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade
15.
J Neuroinflammation ; 16(1): 170, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429777

RESUMO

BACKGROUND: Lysophosphatidic acid receptor 1 (LPA1) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA1 might also be a therapeutic strategy for cerebral ischemia because LPA1 triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO). METHODS: To address the role of LPA1 in the ischemic brain damage, we used AM095, a selective LPA1 antagonist, as a pharmacological tool and lentivirus bearing a specific LPA1 shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA1 in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis. RESULTS: AM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1 day after tMCAO, which was reaffirmed by LPA1 shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3 days after tMCAO. LPA1 antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA1 antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-κB activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA1-driven proinflammatory responses appeared to occur in activated microglia because NF-κB activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA1 in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA1 activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA1 influenced PI3K/Akt and MAPKs; suppressing LPA1 activity decreased MAPK activation and increased Akt phosphorylation. CONCLUSION: This study demonstrates that LPA1 is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage.


Assuntos
Lesões Encefálicas/metabolismo , Ataque Isquêmico Transitório/metabolismo , Microglia/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Lesões Encefálicas/patologia , Ataque Isquêmico Transitório/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microglia/patologia
16.
Int J Mol Med ; 44(3): 813-822, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257456

RESUMO

The key to successful treatment of cerebral venous­sinus occlusion (CVO) is the rapid recanalization of the sinus following venous­sinus occlusion; however, rapid recanalization of the sinus may also cause secondary cerebral injury. The present study examined mechanical thrombectomy­related brain injury and the possible molecular mechanisms following CVO recanalization, and investigated the protective effect of glycyrrhizin (GL) in CVO recanalization. The cerebral venous sinus thrombosis (CVST) model was induced in rats using 40% FeCl3. Mechanical thrombectomy was performed at 6 h post­thrombosis. GL was administered to rats following thromboembolism. Neurological function and brain water content were measured prior to sacrifice of the rats. Serum malondialdehyde, superoxide dismutase and nitric­oxide synthase concentrations were measured. The expression levels of high­mobility group box 1 (HMGB1) and receptor of advanced glycation end products (RAGE) and its downstream inflammatory mediators were measured in serum and brain tissues. Rapid CVO recanalization caused brain injury, and the brain parenchymal damage and neurological deficits caused by CVO were not completely restored following recanalization. Similarly, following rapid recanalization in the venous sinus, the expression levels of HMGB1 and RAGE were lower than those in the CVST group, but remained significantly higher than those of the sham group. The combination of mechanical thrombectomy and GL improved cerebral infarction and cerebral edema in rats, and inhibited the extracellular transport of HMGB1, and the expression of downstream inflammatory factors and oxidative­stress products. The administration of exogenous recombinant HMGB1 reversed the neural protective effects of GL. In conclusion, mechanical thrombectomy subsequent to CVO in rats can cause brain injury following recanalization. HMGB1 and RAGE promote inflammation in the process of brain injury following recanalization. GL has a relatively reliable neuroprotective effect on brain injury by inhibiting HMGB1 and its downstream inflammatory factors, and decreasing oxidative stress.


Assuntos
Lesões Encefálicas/etiologia , Ácido Glicirrízico/farmacologia , Proteína HMGB1/genética , Fármacos Neuroprotetores/farmacologia , Receptor para Produtos Finais de Glicação Avançada/genética , Trombectomia , Animais , Biomarcadores , Biópsia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Expressão Gênica , Proteína HMGB1/metabolismo , Masculino , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Trombose dos Seios Intracranianos/complicações , Trombose dos Seios Intracranianos/terapia , Trombectomia/métodos
17.
Exp Neurol ; 321: 113015, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326353

RESUMO

Spared corticospinal tract (CST) and proprioceptive afferent (PA) axons sprout after injury and contribute to rewiring spinal circuits, affecting motor recovery. Loss of CST connections post-injury results in corticospinal signal loss and associated reduction in spinal activity. We investigated the role of activity loss and injury on CST and PA sprouting. To understand activity-dependence after injury, we compared CST and PA sprouting after motor cortex (MCX) inactivation, produced by chronic MCX muscimol microinfusion, with sprouting after a CST lesion produced by pyramidal tract section (PTx). Activity suppression, which does not produce a lesion, is sufficient to trigger CST axon outgrowth from the active side to cross the midline and to enter the inactivated side of the spinal cord, to the same extent as PTx. Activity loss was insufficient to drive significant CST gray matter axon elongation, an effect of PTx. Activity suppression triggered presynaptic site formation, but less than PTx. Activity loss triggered PA sprouting, as PTx. To understand injury-dependent sprouting further, we blocked microglial activation and associated inflammation after PTX by chronic minocycline administration after PTx. Minocycline inhibited myelin debris phagocytosis contralateral to PTx and abolished CST axon elongation, formation of presynaptic sites, and PA sprouting, but not CST axon outgrowth from the active side to cross the midline. Our findings suggest sprouting after injury has a strong activity dependence and that microglial activation after injury supports axonal elongation and presynaptic site formation. Combining spinal activity support and inflammation control is potentially more effective in promoting functional restoration than either alone.


Assuntos
Microglia/metabolismo , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Tratos Piramidais/lesões , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Masculino , Microglia/patologia , Neurônios/patologia , Neurônios Aferentes/metabolismo , Neurônios Aferentes/patologia , Tratos Piramidais/metabolismo , Tratos Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
18.
Biomed Pharmacother ; 117: 109102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228802

RESUMO

Ischemic stroke is a cerebrovascular disease with high morbidity, high mortality, and high disability, representing a serious threat to human life and health. Clinically, the extensive injury caused by ischemic stroke results from ischemia-reperfusion (I/R) injury thrombolytic treatment. However, there are few reports on the use of medications in the subacute stage of cerebral I/R. Baicalein (5,6,7-trihydroxyflavone) is a biologically active ingredient extracted from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the therapeutic effect of baicalein administered in the subacute phase of cerebral I/R injury in a rat model of ischemia induced by occlusion of the middle cerebral artery (MCA). Rats were treated daily with baicalein (200 mg/kg, i.g.) in the subacute phase (24 h after reperfusion) for 7 days. The results showed that baicalein significantly reduced neurobehavioral deficits and decreased brain infarct volume from 18.99% to 7.41%. Immunofluorescence analysis of the ischemic penumbra showed that baicalein significantly reduced expression of the M1 marker, cluster of differentiation (CD) 16 and CD86, and increased expression of the M2 marker, CD 163 and CD206, indicating that baicalein inhibited M1 transformation and promoted M2 transformation of microglia/macrophage to inhibit neuroinflammation. Moreover, baicalein suppressed NF-κB signaling by reducing IκBα phosphorylation and nuclear translocation of NF-κB/p65, which decreased the release of the pro-inflammatory factors IL-6, IL-18, and TNF-α. In addition, baicalein reduced phosphorylation of JNK, ERK and p38, which are involved modulation of microglia/macrophage M1/M2 polarization. Western blot analysis of apoptosis- and autophagy-related proteins showed that baicalein increased the Bcl-2/Bax ratio and reduced caspase-3 expression to decrease neuronal apoptosis and ameliorate neuronal loss. Baicalein also decreased the LC3-II/LC3-I ratio and promoted phosphorylation of the PI3K/Akt/mTOR signaling pathway which implied inhibition of autophagy. These observations suggest that baicalein exerts neuroprotective effects by reducing neuroinflammation, apoptosis and autophagy, and protects against cerebral I/R injury in the subacute phase in vivo.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Flavanonas/farmacologia , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Int J Neurosci ; 129(10): 1024-1038, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215278

RESUMO

Aim: The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on the brain tissues oxidative damage and learning and memory impairment in the juvenile hypothyroid rats was evaluated. Main methods: Rats were classified as: ( 1 ) Control; (2) Propylthiouracil (PTU); (3) PTU-Pio 10 and (4) PTU-Pio 20. PTU was given in drinking water (0.05%) during 6 weeks. Pioglitazone (10 or 20 mg/kg) was daily injected intraperitoneally. Passive avoidance (PA) and Morris water maze (MMW) were conducted. Later, the animals were sacrificed and the brain tissues were removed for biochemical measurements. Key funding: The results indicated that in the MWM escape latency as well as traveled path increased in the PTU group as compared to the control group. Also, the time spent in the target quadrant in the probe test of MWM and step-through latency in the PA test were decreased in the PTU group as compared to the control group. Pioglitazone reversed all the negative behavioral effects of hypothyroidism. Administration of PTU attenuated thiol and superoxide dismutase (SOD), and catalase (CAT) activities in the brain tissues, whereas increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. PPARγ agonist improved thiol, SOD and CAT, while diminished MDA concentration. Significance: Our finding in the present study indicated that PPARγ agonist pioglitazone prevented the brain tissues from oxidative damage and learning and memory impairments in juvenile hypothyroid rats.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Hipotireoidismo/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona/farmacologia , Fatores Etários , Animais , Lesões Encefálicas/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipotireoidismo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Estresse Oxidativo/fisiologia , Pioglitazona/uso terapêutico , Ratos , Ratos Wistar , Resultado do Tratamento
20.
Med Sci Monit ; 25: 4723-4733, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237865

RESUMO

BACKGROUND Electroacupuncture (EA) has been commonly used to treat stroke in China. However, the underlying mechanism remains largely unknown. The present study investigated the neuroprotective effects of EA in middle cerebral artery occlusion (MCAO) rats and elucidated the possible anti-inflammatory mechanisms. MATERIAL AND METHODS In this study, modified neurological severity scoring (mNSS) was used to assess neurological deficits, and TTC staining and brain water content were measured to evaluate the degree of brain damage. HE staining, Nissl staining, and TUNEL staining were employed to evaluate apoptotic neuronal death. Molecular biological methods were used to measure the levels of miR-233, NLRP3, caspase-1, IL-1ß, and IL-18 in the peri-infarct cortex. RESULTS Our results showed that EA treatment significantly decreased the neurological deficit score and infarct volume of MCAO rats. The level of miR-223 was increased, while the levels of NLRP3, caspase-1, IL-1ß, and IL-18 were decreased in the peri-infarct cortex of EA-treated MCAO rats. However, the neuroprotective effect of EA was partially blocked by antagomir-223. CONCLUSIONS These data suggest that EA treatment can alleviate neuroinflammation by inhibiting the miR-223/NLRP3 pathway, thus playing a neuroprotective role in MCAO in rats.


Assuntos
Isquemia Encefálica/terapia , Eletroacupuntura/métodos , Infarto da Artéria Cerebral Média/terapia , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pontos de Acupuntura , Animais , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia
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