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1.
BMC Genomics ; 22(1): 641, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34481466

RESUMO

BACKGROUND: Stroke can induce cardiac dysfunction in the absence of primary cardiac disease; however, the mechanisms underlying the interaction between the neurological deficits and the heart are poorly understood. The objective of this study was to investigate the effects of stroke on cardiac function and to identify the transcriptome characteristics of the heart. RESULTS: Stroke significantly decreased heart weight/tibia length ratio and cardiomyocyte cross-sectional areas and increased atrogin-1 and the E3 ubiquitin ligase MuRF-1, indicating myocardial atrophy in MCAO-induced mouse hearts. RNA sequencing of mRNA revealed 383 differentially expressed genes (DEGs) in MCAO myocardium, of which 221 were downregulated and 162 upregulated. Grouping of DEGs based on biological function and quantitative PCR validation indicated that suppressed immune response and collagen synthesis and altered activity of oxidoreductase, peptidase, and endopeptidase may be involved in MCAO-induced cardiomyopathy. The DEGs were mainly distributed in the membrane or extracellular region of cardiomyocytes and acted as potential mediators of stroke-induced cardiac dysregulation involved in cardiac atrophy. CONCLUSION: Stroke induced a unique transcriptome response in the myocardium and resulted in immediate cardiac atrophy and dysfunction.


Assuntos
Isquemia Encefálica , Cardiopatias , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/patologia , Cardiopatias/patologia , Camundongos , Atrofia Muscular , Miócitos Cardíacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Transcriptoma
2.
Ann Clin Lab Sci ; 51(4): 503-511, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452888

RESUMO

OBJECTIVE: To compare the e!cacy and functional outcomes of dl-3-n-Butylphthalide (NBP) and human urinary kallidinogenase (HUK) on ischemic stroke patients and to determine their effects on serum tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF). METHODS: A prospective study was conducted on 57 ischemic stroke patients. Functional outcomes were assessed by the National Institute Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the activities of daily living score (ADL), whereas TNF-α and VEGF expressions were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: TNF-α was significantly down-regulated in the NBP group and upregulated in the control group two weeks after treatment (p=0.017 and p=0.047, respectively). A significant difference in VEGF expressions was observed between the two groups (330.25±120.64 vs. 437.15±137.68, p=0.041) two weeks after treatment. Both groups showed significant improvement in NIHSS and ADL scores three months after treatment (p<0.001), with the NBP group exhibiting improvement in NIHSS scores as early as two weeks after treatment (p=0.008). The three-month NIHSS scores of the two groups were significantly lower than those of the control group (p=0.010 and p=0.008, respectively). Both the NBP and HUK groups showed a significant decline in mRS scores two weeks and three months after treatment (p<0.05). CONCLUSIONS: Both treatments are effective and can significantly promote recovery in stroke patients. Additionally, both options have similar effects in promoting long-term recovery, with NBP exerting a greater impact on serum VEGF and TNF-α expressions.


Assuntos
Benzofuranos/uso terapêutico , Biomarcadores/sangue , Isquemia Encefálica/patologia , AVC Isquêmico/patologia , Calicreínas/administração & dosagem , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/terapia , Estudos de Casos e Controles , Feminino , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/terapia , Calicreínas/urina , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Prognóstico , Adulto Jovem
3.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360581

RESUMO

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1ß, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.


Assuntos
Isquemia Encefálica/prevenção & controle , Sulfeto de Hidrogênio/metabolismo , Infarto da Artéria Cerebral Média/complicações , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Substâncias Protetoras/farmacologia , Tionas/farmacologia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sulfeto de Hidrogênio/análise , Masculino , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tionas/administração & dosagem
5.
Molecules ; 26(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34299399

RESUMO

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.


Assuntos
Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Lipídeos/análise , Triterpenos Pentacíclicos/farmacologia , Traumatismo por Reperfusão/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Lipidômica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
6.
Life Sci ; 283: 119842, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34298038

RESUMO

AIMS: Ischemic stroke occurs when there is a sudden blockage of cerebral blood flow. This condition is a major cause of mortality, especially in low-income countries, and its incidence is dramatically increasing. Therapeutic strategies against stroke are therefore required. The present study explored the effects of dihydrocapsaicin on neuronal loss, brain infarct volume, and antioxidants in a rat model of permanent occlusion of the right middle cerebral artery (Rt.MCAO). MAIN METHODS: Male Wistar rats received dihydrocapsaicin intraperitoneally for 7 days after permanent occlusion of their right middle cerebral artery (Rt.MCAO). Then, the brain infarct volume, neuronal density, and antioxidant and anti-apoptotic activities in the cortex and hippocampus were determined at the end of the study. KEY FINDING: Dihydrocapsaicin treatment was found to significantly improve neuronal density, decrease infarct volume, reduce MDA elevation, improve CAT and SOD activities, decrease the density ratio of Bax and caspase-3, and increase the density ratio of Bcl-XL to ß-actin in the cerebral cortex and hippocampus. SIGNIFICANCE: The present study suggests that dihydrocapsaicin effectively mitigates cerebral ischemia-induced pathological changes in vivo, partly via antioxidant and anti-apoptotic pathways.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Isquemia Encefálica , Capsaicina/análogos & derivados , Hipocampo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Capsaicina/farmacologia , Caspase 3/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
7.
Pediatr Infect Dis J ; 40(9): e340-e343, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288632

RESUMO

AIM: To describe a term newborn with acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and multisystem involvement including seizures associated to ischemic lesions in the brain. BACKGROUND: Coronavirus disease 2019 (COVID-19) is predominantly a respiratory infection, but it may affect many other systems. Most pediatric COVID-19 cases range from asymptomatic to mild-moderate disease. There are no specific clinical signs described for neonatal COVID-19 infections. In children, severe central nervous system compromise has been rarely reported. CASE DESCRIPTION: We describe a 17-day-old newborn who acquired a SARS-CoV-2 infection in a family meeting that was admitted for fever, seizures and lethargy and in whom consumption coagulopathy, ischemic lesions in the brain and cardiac involvement were documented. CONCLUSIONS: SARS-CoV-2 neonatal infection can be associated with multi-organic involvement. In our patient, significant central nervous system compromise associated to ischemic lesions and laboratory findings of consumption coagulopathy were found. CLINICAL SIGNIFICANCE: Although neonatal SARS-CoV-2 infections are infrequent, they can be associated with multi-organic involvement. Neonatologists and pediatricians should be aware of this unusual way of presentation of COVID-19 in newborn infants.


Assuntos
Isquemia Encefálica/virologia , COVID-19/complicações , Doenças do Recém-Nascido/virologia , SARS-CoV-2/isolamento & purificação , Aciclovir/uso terapêutico , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Encéfalo/diagnóstico por imagem , Isquemia Encefálica/patologia , COVID-19/tratamento farmacológico , COVID-19/patologia , Ceftriaxona/uso terapêutico , Febre , Lobo Frontal/irrigação sanguínea , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/patologia , Letargia , Imageamento por Ressonância Magnética , Masculino , Nasofaringe/virologia , Convulsões
8.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299128

RESUMO

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Carnosina/farmacologia , Infarto da Artéria Cerebral Média/complicações , Metaloproteinase 2 da Matriz/química , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Feminino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
9.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208178

RESUMO

The heat shock protein (HSP) 70 is considered the main hallmark in preclinical studies to stain the peri-infarct region defined area penumbra in preclinical models of brain ischemia. This protein is also considered as a potential disease modifier, which may improve the outcome of ischemic damage. In fact, the molecule HSP70 acts as a chaperonine being able to impact at several level the homeostasis of neurons. Despite being used routinely to stain area penumbra in light microscopy, the subcellular placement of this protein within area penumbra neurons, to our knowledge, remains undefined. This is key mostly when considering studies aimed at deciphering the functional role of this protein as a determinant of neuronal survival. The general subcellular placement of HSP70 was grossly reported in studies using confocal microscopy, although no direct visualization of this molecule at electron microscopy was carried out. The present study aims to provide a direct evidence of HSP70 within various subcellular compartments. In detail, by using ultrastructural morphometry to quantify HSP70 stoichiometrically detected by immuno-gold within specific organelles we could compare the compartmentalization of the molecule within area penumbra compared with control brain areas. The study indicates that two cell compartments in control conditions own a high density of HSP70, cytosolic vacuoles and mitochondria. In these organelles, HSP70 is present in amount exceeding several-fold the presence in the cytosol. Remarkably, within area penumbra a loss of such a specific polarization is documented. This leads to the depletion of HSP70 from mitochondria and mostly cell vacuoles. Such an effect is expected to lead to significant variations in the ability of HSP70 to exert its physiological roles. The present findings, beyond defining the neuronal compartmentalization of HSP70 within area penumbra may lead to a better comprehension of its beneficial/detrimental role in promoting neuronal survival.


Assuntos
Isquemia Encefálica/metabolismo , Citosol/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Vacúolos/metabolismo , Animais , Isquemia Encefálica/patologia , Morte Celular/fisiologia , Citosol/patologia , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Varredura , Mitocôndrias/patologia , Neurônios/patologia , Vacúolos/patologia
10.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34200045

RESUMO

Ischemic stroke is a disturbance in cerebral blood flow caused by brain tissue ischemia and hypoxia. We optimized a multifactorial in vitro model of acute ischemic stroke using rat primary neural cultures. This model was exploited to investigate the pro-viable activity of cell-penetrating peptides: arginine-rich Tat(49-57)-NH2 (R49KKRRQRRR57-amide) and its less basic analogue, PTD4 (Y47ARAAARQARA57-amide). Our model included glucose deprivation, oxidative stress, lactic acidosis, and excitotoxicity. Neurotoxicity of these peptides was excluded below a concentration of 50 µm, and PTD4-induced pro-survival was more pronounced. Circular dichroism spectroscopy and molecular dynamics (MD) calculations proved potential contribution of the peptide conformational properties to neuroprotection: in MD, Tat(49-57)-NH2 adopted a random coil and polyproline type II helical structure, whereas PTD4 adopted a helical structure. In an aqueous environment, the peptides mostly adopted a random coil conformation (PTD4) or a polyproline type II helical (Tat(49-57)-NH2) structure. In 30% TFE, PTD4 showed a tendency to adopt a helical structure. Overall, the pro-viable activity of PTD4 was not correlated with the arginine content but rather with the peptide's ability to adopt a helical structure in the membrane-mimicking environment, which enhances its cell membrane permeability. PTD4 may act as a leader sequence in novel drugs for the treatment of acute ischemic stroke.


Assuntos
Isquemia Encefálica/prevenção & controle , Peptídeos Penetradores de Células/farmacologia , Modelos Animais de Doenças , AVC Isquêmico/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Permeabilidade da Membrana Celular , Feminino , AVC Isquêmico/etiologia , AVC Isquêmico/patologia , Ratos , Ratos Wistar
11.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201112

RESUMO

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.


Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Isquemia Encefálica/prevenção & controle , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteoma/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Transcriptoma/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , RNA-Seq , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
12.
Theranostics ; 11(14): 6746-6765, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093851

RESUMO

Postsynaptic density protein-95 (PSD-95) is a multidomain protein critical to the assembly of signaling complexes at excitatory synapses, required for neuronal survival and function. However, calpain-processing challenges PSD-95 function after overactivation of excitatory glutamate receptors (excitotoxicity) in stroke, a leading cause of death, disability and dementia in need of efficient pharmacological treatments. A promising strategy is neuroprotection of the infarct penumbra, a potentially recoverable area, by promotion of survival signaling. Interference of PSD-95 processing induced by excitotoxicity might thus be a therapeutic target for stroke and other excitotoxicity-associated pathologies. Methods: The nature and stability of PSD-95 calpain-fragments was analyzed using in vitro assays or excitotoxic conditions induced in rat primary neuronal cultures or a mouse model of stroke. We then sequenced PSD-95 cleavage-sites and rationally designed three cell-penetrating peptides (CPPs) containing these sequences. The peptides effects on PSD-95 stability and neuronal viability were investigated in the cultured neurons, subjected to acute or chronic excitotoxicity. We also analyzed the effect of one of these peptides in the mouse model of stroke by measuring infarct size and evaluating motor coordination and balance. Results: Calpain cleaves three interdomain linker regions in PSD-95 and produces stable fragments corresponding to previously described PSD-95 supramodules (PDZ1-2 and P-S-G) as well as a truncated form SH3-GK. Peptide TP95414, containing the cleavage site in the PDZ3-SH3 linker, is able to interfere PSD-95 downregulation and reduces neuronal death by excitotoxicity. Additionally, TP95414 is delivered to mice cortex and, in a severe model of permanent ischemia, significantly improves the neurological outcome after brain damage. Conclusions: Interference of excitotoxicity-induced PSD-95-processing with specific CPPs constitutes a novel and promising therapeutic approach for stroke treatment.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Neurônios/efeitos dos fármacos , Neuroproteção , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Calpaína/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/química , Proteína 4 Homóloga a Disks-Large/genética , Regulação para Baixo , Agonistas de Aminoácidos Excitatórios/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transtornos dos Movimentos/tratamento farmacológico , N-Metilaspartato/farmacologia , Neurônios/metabolismo , Neurônios/patologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
13.
Toxicol Appl Pharmacol ; 426: 115635, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174262

RESUMO

The beneficial role of prasugrel, a P2Y12 receptor blocker, in several neurointerventional procedures has been reviewed clinically. Beyond its antiplatelet capacity, the potential neuroprotective mechanisms of prasugrel are poorly addressed experimentally. Relevant to the imbalance between neuro-inflammation and neuroprotective pathways in cerebral ischemia/reperfusion (I/R), our study evaluated the anti-ischemic potential of prasugrel treatment through tackling novel targets. Male Wistar rats were allocated into 2 sets; set 1 (I/R 60 min/3 days) to assess the neurological deficits/biochemical impact of prasugrel and set 2 (I/R 60 min/5 days) for evaluating short memory/morphological/immunoreactive changes. Each set comprised 4 groups designated as sham, sham + prasugrel, I/R, and I/R + prasugrel. Post-administration of prasugrel for 3 and 5 days reduced neurological deficit scores and improved the spontaneous activity/short term spatial memory using the Y-maze paradigm. On the molecular level, prasugrel turned off SUMO2/3-inhibitory kappa (Iκ)Bα, Ubc9 and nuclear factor kappa (NF-κ)B. Besides, it inhibited malondialdehyde (MDA) and inactivated astrocytes by downregulating the glial fibrillary acidic protein (GFAP) hippocampal immune-expression. Conversely, it activated its target molecule cAMP, protein kinase (PK)A, and cAMP response element-binding protein (CREB) to enhance the brain-derived nuclear factor (BDNF) hippocampal content. Additionally, cAMP/PKA axis increased the hippocampal content of deacetylator silent information regulator 1 (SIRT1) and the micro RNA (miR)-22 gene expression. The crosstalk between these paths partakes in preserving hippocampal cellularity. Accordingly, prasugrel, regardless inhibiting platelets activity, modulated other cellular components; viz., SUMO2/3-IκBα/Ubc9/NF-κB, cAMP/PKA related trajectories, CREB/BDNF and SIRT1/miR-22 signaling, besides inhibiting GFAP and MDA to signify its anti-ischemic potential.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/sangue , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , MicroRNAs/sangue , Inibidor de NF-kappaB alfa/metabolismo , Fármacos Neuroprotetores/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Cloridrato de Prasugrel/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos Wistar , Sirtuína 1/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Memória Espacial/efeitos dos fármacos , Enzimas de Conjugação de Ubiquitina/metabolismo
14.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068564

RESUMO

Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/genética , AVC Isquêmico/tratamento farmacológico , Bicarbonatos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Dióxido de Carbono/metabolismo , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , AVC Isquêmico/genética , Sulfonamidas/uso terapêutico
15.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062911

RESUMO

Hypoxic-ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = -17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.


Assuntos
Asfixia Neonatal/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Ácido Cinurênico/análogos & derivados , Neurônios/metabolismo , Animais , Asfixia Neonatal/metabolismo , Asfixia Neonatal/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/diagnóstico por imagem , Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/diagnóstico por imagem , Região CA3 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Potenciais Evocados Visuais/efeitos dos fármacos , Humanos , Ácido Cinurênico/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Pesquisa Médica Translacional
16.
Int J Nanomedicine ; 16: 3661-3678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093011

RESUMO

Introduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen-glucose deprivation (OGD). Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed. Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes. Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.


Assuntos
Benzamidas/farmacologia , Carbamatos/farmacologia , Nanofibras/química , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Células Cultivadas , Endocanabinoides/metabolismo , Glucose/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Membranas Artificiais , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/metabolismo , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/química
17.
Nat Commun ; 12(1): 2590, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972513

RESUMO

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI95% [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Progressão da Doença , Fibrinolíticos/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo
18.
Phytomedicine ; 87: 153569, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33985878

RESUMO

BACKGROUND: Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4) on microglia have been found as important regulators in the inflammatory response during cerebral ischemia/reperfusion (I/R). In China, traditional Chinese medicine Salvia miltiorrhiza (danshen) and its some components are considered to be effective in rescuing cerebral I/R injury through clinical practice. HYPOTHESIS/PURPOSE: Here we examined the effect of Salvianolic acid A (SAA), a monomer compound in the water extract of Salvia miltiorrhiza, on TLR2/4 of microglia and its mediated inflammatory injury during cerebral I/R in vivo and in vitro. STUDY DESIGN: For exploring the effect of SAA on cerebral I/R and TLR2/4, classic middle cerebral artery occlusion (MCAO) model and oxygen glucose deprivation / reoxygenation (OGD/R) model of co-culture with primary hippocampal neurons and microglia in vitro were used. Signal pathway research and gene knockout have been applied to further explain its mechanism. METHODS: The evaluation indexes of I/R injury included infarct size, edema degree and pathology as well as primary hippocampal neurons and microglia culture, ELISA, western, RT-PCR, HE staining, immunofluorescence, flow cytometry, siRNA gene knockout were also employed. RESULTS: SAA significantly improved the degree of brain edema and ischemic area in I/R rats accompanied by decreases in levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α). Pathological staining revealed that SAA could reduce inflammatory cell infiltration and mcirogila activation after reperfusion. Both protein and gene expression of TLR2 and TLR4 in ischemic hemisphere were obviously inhibited by SAA treatment while changes were not found in the non-ischemic hemisphere. In order to further study its mechanism, OGD/R model was used to mimic inflammatory damage of ischemic tissue by co-culturing primary rat hippocampal neurons and microglial cells. It was found that SAA also inhibited the protein and gene expression of TLR2 and TLR4 after OGD/R injury in microglia. After TLR2/4 knockout, the inhibitory effect of SAA on IL-1ß and TNF-α levels in cell supernatant and neuron apoptosis were significantly weakened in each dose group. Moreover, expression levels of myeloid differentiation factor 88 (MyD88), NFκB, IL-1ß and IL-6 in TLR2/4 mediated inflammatory pathway were reduced with SAA treatment. CONCLUSION: SAA could significantly reduce the inflammatory response and injury in cerebral ischemia-reperfusion in vivo and in vitro, and its mechanism may be through the inhibition of TLR2/4 and its related signal pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ácidos Cafeicos/farmacologia , Lactatos/farmacologia , Microglia/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Isquemia Encefálica/patologia , Ácidos Cafeicos/uso terapêutico , Infarto da Artéria Cerebral Média , Inflamação/metabolismo , Lactatos/uso terapêutico , Masculino , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética
19.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947043

RESUMO

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.


Assuntos
Isquemia Encefálica/complicações , Paralisia Cerebral/etiologia , Modelos Animais de Doenças , Endotelina-1/toxicidade , Vasoconstritores/toxicidade , Animais , Animais Recém-Nascidos , Aprendizagem por Associação , Atrofia , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/patologia , Contagem de Células , Córtex Cerebral/patologia , Paralisia Cerebral/patologia , Transtornos Cognitivos/etiologia , Corpo Estriado/patologia , Endotelina-1/administração & dosagem , Inflamação , Injeções , Microglia/patologia , Transtornos dos Movimentos/etiologia , Neurônios/patologia , Transtornos da Percepção/etiologia , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Vasoconstritores/administração & dosagem , Substância Branca/patologia
20.
Life Sci ; 278: 119526, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33894268

RESUMO

AIMS: White matter damage is the main pathological feature of chronic cerebral hypoperfusion (CCH) and glial activation is crucial in this process. Physical exercise has protective effects on CCH, but the mechanism is unclear. Therefore, this study focuses on investigating the influence of physical exercise on activated astrocytes polarization and its role in CCH. MAIN METHODS: Rats were given wheel running 48 h after 2VO (2 vessel occlusion) surgery. The cognitive function was evaluated by Morris water maze and novel object recognition test. Inflammatory cytokines expressions were detected by ELISA. Astrocytes polarization was analyzed by immunofluorescence. Myelin debris clearance and remyelination were detected by immunofluorescence and transmission electron microscopy. KEY FINDINGS: Astrocytes were activated and mainly switched to A1 phenotype in rats 2 and 3 months after 2VO. Myelin debris deposition and limited remyelination can be observed at the corresponding time. Whereas physical exercise can improve the cognitive function of 2VO rats, downregulate the expression of inflammatory factors IL-1α, C1q and TNF, upregulate the release of TGFß, and promote activated astrocytes transformation from A1 to A2 phenotype. In addition, it can also enhance myelin debris removal and remyelination. SIGNIFICANCE: These findings suggest that the benefits of physical exercise on white matter repair and cognition improvement may be related to its regulation of astrocytes polarization, which contributes to myelin debris clearance and effective remyelination in CCH.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Bainha de Mielina/química , Neuroglia/metabolismo , Condicionamento Físico Animal , Substância Branca/patologia , Animais , Isquemia Encefálica/patologia , Cognição/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Inflamação , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Atividade Motora , Reconhecimento Visual de Modelos , Perfusão , Fenótipo , Ratos , Ratos Wistar , Remielinização
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