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1.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207292

RESUMO

Aneurysmal rupture accounts for the majority of subarachnoid hemorrhage and is responsible for most cerebrovascular deaths with high mortality and morbidity. Initial hemorrhage severity and secondary brain injury due to early brain injury and delayed cerebral ischemia are the major determinants of outcomes after aneurysmal subarachnoid hemorrhage. Several therapies have been explored to prevent these secondary brain injury processes after aneurysmal subarachnoid hemorrhage with limited clinical success. Experimental and clinical studies have shown a neuroprotective role of certain anesthetics in cerebrovascular disorders including aneurysmal subarachnoid hemorrhage. The vast majority of aneurysmal subarachnoid hemorrhage patients require general anesthesia for surgical or endovascular repair of their aneurysm. Given the potential impact certain anesthetics have on secondary brain injury after SAH, appropriate selection of anesthetics may prove impactful on overall outcome of these patients. This narrative review focuses on the available evidence of anesthetics and their adjuvants in neurovascular protection in aneurysmal subarachnoid hemorrhage and discusses current impact on clinical care and future investigative directions.


Assuntos
Anestésicos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Aneurisma Intracraniano/complicações , Fármacos Neuroprotetores/uso terapêutico , Hemorragia Subaracnóidea/complicações , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/prevenção & controle , Humanos
2.
J Med Food ; 24(7): 686-696, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34280030

RESUMO

Nitraria tangutorun Bobr. has been used for thousands of years as a native folk medicine to alleviate dizziness and neurasthenia due to oxygen. In our previous study, natural antioxidant components (namely, NJBE) were isolated from industrial N. tangutorun Bobr. juice byproducts (NJBE) from the Qinghai-Tibet plateau. The current investigation assessed the effects of NJBE on ischemic stroke in mice and the potential mechanisms. C57BL/6 mice received NJBE (25, 50, or 100 mg/Kg) by gavage for 14 days and then stroke was induced by the middle cerebral artery occlusion (MCAO) model, followed by reperfusion for 72 h. The evaluation of brain infarct size, behavioral tests, and functional assessments was conducted to assess the effects of NJBE after MCAO. Our results suggested that NJBE significantly decreases infarct size, improves neurological deficits, as well as reduces the number of GFAP+ and Iba-1+ cells after MCAO. NJBE inhibited nitric oxide and malondialdehyde production in the ischemic brain. Meanwhile, it attenuated the expressions of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Also, NJBE significantly attenuated the expression levels of proinflammatory indicators, including TNF-α, IL-1ß, IL-6, and IL-12. This process was accompanied by the downregulation of TLR4, TRAF6, pIκB/pIκB, and MMP9 expression and the upregulation of claudin-5 expression. NJBE induced improvements in brain injury. The neuroprotective effect of NJBE provides evidence for its potential application in stroke treatment.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/genética , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo
3.
Ann Palliat Med ; 10(6): 6768-6778, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237977

RESUMO

BACKGROUND: Cerebral ischemic reperfusion injury (CI/RI) is a common cerebrovascular disease with high morbidity and disability that threatens human health. This study was conducted to explore the effects of dexmedetomidine (Dex) on the c-Jun N-terminal kinase (JNK) pathway in CI/RI, and to provide a theoretical basis for the recovery of brain function after cerebral ischemia. METHODS: Sprague Dawley (SD) rats (n=24) were randomly divided into Sham, Sham + Dex, Sham + yohimbine (Yoh) + Dex, Sham + SP600125, ischemic reperfusion (I/R), I/R + Dex, I/R + Yoh + Dex, and I/R + SP600125 groups, and a focal cerebral ischemia reperfusion rat model was established by linear thrombus. The neurological deficit score and infarct volume were measured. Wet/dry weight ratios were used to measure brain water content, and cerebral infarct volume was determined by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The cellular distribution of p-JNK and cleaved caspase-3 were examined using immunofluorescent staining (IF) and the total JNK and p-JNK were determined by Western blotting (WB). RESULTS: Compared with the Sham group, the rats in I/R, I/R + Dex, I/R + Yoh + Dex, and I/R + SP600125 groups developed hemiparesis of the left forelimb at different levels with a higher neurological deficit score, brain water content, infarct volume, and markedly upregulated expression of cleaved caspase-3, p-JNK (P<0.05). Compared with the I/R group, the neurological deficit score, brain water content, infarct volume, and expression of cleaved caspase-3, p-JNK were markedly decreased in I/R + Dex, I/R + Yoh + Dex, and I/R + SP600125 groups (P<0.05), and compared with the I/R + Dex group, the neurological deficit score, brain water content, infarct volume, and expression of cleaved caspase-3, p-JNK were markedly increased in the I/R + Yoh + Dex group (P<0.05). Double immunofluorescence staining showed there was a strong colocalization between p-JNK and the astroglial marker GFAP. CONCLUSIONS: The JNK signaling pathway is involved in CI/RI. Inhibition of the JNK pathway blocked caspase-3 activation which can decrease CI/RI. Dex can alleviate cerebral CI/RI in rats by increasing α2-adrenergic receptor and blocking JNK phosphorylation and activation of caspase-3.


Assuntos
Isquemia Encefálica , Dexmedetomidina , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Dexmedetomidina/uso terapêutico , Sistema de Sinalização das MAP Quinases , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico
4.
Nutrients ; 13(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201106

RESUMO

Ischemic stroke (IS) is still among the leading causes of death and disability worldwide. The pathogenic mechanisms beyond its development are several and are complex and this is the main reason why a functional therapy is still missed. The beneficial effects of natural compounds against cardiovascular diseases and IS have been investigated for a long time. In this article, we reviewed the association between the most studied polyphenols and stroke protection in terms of prevention, effect on acute phase, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbens on ischemic mechanisms leading to stroke. We analyzed the principal animal models used to evaluate the impact of these micronutrients to cerebral blood flow and to molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We reported the most significant clinical trials demonstrated as the persistent use of polyphenols is clinically relevant in terms of the reduction of vascular risk factors for IS, such as Atrial Fibrillation. Interestingly, different kinds of polyphenols provide brain protection by activating different pathways and mechanisms, like inducing antithrombotic effect, such as Honokiol. For this reason, we discussed an appropriate integrative use of them as a possible therapeutic alternative against stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Polifenóis/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Humanos , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Reabilitação do Acidente Vascular Cerebral
5.
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
6.
Artigo em Russo | MEDLINE | ID: mdl-34184475

RESUMO

OBJECTIVE: To assess the efficacy and safety of prospecta in the treatment of moderate cognitive impairment in the early recovery period of ischemic stroke. MATERIAL AND METHODS: The study included 275 patients (mean age 64.0±8.1 years) with a history of single ischemic stroke from 3 to 6 months, with moderate cognitive impairment, and moderate activity in everyday life, who were randomized in two groups. During the screening phase, the severity of cognitive impairment was assessed with the Mini-Mental State Examination and Montreal Cognitive Assessment scales; the level of activity in everyday life was evaluated with the Barthel Scale; and quality of life was assessed with the Stroke Specific Quality of Life Scale. Patients took 2 tablets of prospecta or placebo 2 times a day for 24 weeks. The follow-up period was 4 weeks. The primary endpoint of the study was the proportion of patients with improvement in cognitive function (+1 or more on the MoCA test) after 24 weeks of treatment. The occurrence and type of adverse events (AEs), their severity, relationship to the drug, outcome, changes in vital signs, and the proportion of patients with clinically significant abnormality in laboratory tests were analyzed to assess the safety. RESULTS: A clinically significant improvement in cognitive function was obtained in 91.9% of patients in the prospecta group vs 82.,1% in the placebo group, (p=0.02). There were 57 AEs in 37 (27.4%) Prospecta group patients and 53 AEs in 39 (27.9%) Placebo group participants (p=1.00). No AEs were certainly associated with taking the medication. No clinically significant changes in vital signs or abnormal laboratory results were detected during the study. CONCLUSION: Prospecta is an effective and safe treatment option for patients with moderate cognitive impairment in the early recovery period of ischemic stroke.


Assuntos
Isquemia Encefálica , Disfunção Cognitiva , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
7.
Artigo em Russo | MEDLINE | ID: mdl-34184483

RESUMO

OBJECTIVE: Systematization of the array of publications on cytidyldiphosphocholine (CDP-choline). MATERIAL AND METHODS: Systematic computer analysis of all currently available publications on CDP-choline (1750 publications in PUBMED) using the topological theory of big data analysis. RESULTS: CDP-choline is essential for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. The article describes the effects of CDP-choline on acetylcholinergic and other types of neurotransmission, anti-inflammatory, neuroprotective and neurotrophic effects of CDP-choline. Also, the paper presents the effects of the molecule on lipid metabolism and gene expression within the post-genomic paradigm (in particular, an increase in the expression of nicotinic and muscarinic acetylcholine receptors). The results of fundamental and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. CONCLUSION: The pharmacological effects of CDP-choline are mediated through multiple molecular mechanisms that contribute to the nootropic action of this molecule.


Assuntos
Isquemia Encefálica , Transtornos Cognitivos , Nootrópicos , Isquemia Encefálica/tratamento farmacológico , Cognição , Transtornos Cognitivos/tratamento farmacológico , Citidina Difosfato Colina/farmacologia , Citidina Difosfato Colina/uso terapêutico , Humanos , Nootrópicos/uso terapêutico
8.
Aging (Albany NY) ; 13(12): 16804-16815, 2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34176787

RESUMO

This study was designed to understand the pivotal anti-cerebral ischemia/reperfusion injury (CIRI) targets and pathways of calycosin through network pharmacology and molecular docking analyses. In this study, bioinformatics tools were employed to characterize and identify the pharmacological functions and mechanisms of calycosin for CIRI management. The network pharmacology data identified potential, merged CIRI-associated targets of calycosin including tumor protein p53 (TP53), protein kinase B (AKT1), vascular endothelial growth factor A (VEGFA), interleukin 6, tumor necrosis factor (TNF), and mitogen-activated protein kinase 1 (MAPK1). Molecular docking analysis indicated the binding efficacy of calycosin with three of the targets, namely TP53, AKT1, and VEGFA. The biological processes of calycosin for the treatment of CIRI are mainly involved in the improvement of endothelial cell proliferation and growth, inflammatory development, and cellular metabolism. In addition, the anti-CIRI actions of calycosin were primarily through suppression of the toll-like receptor, PI3K-AKT, TNF, MAPK, and VEGF signaling pathways. Taken together, the current bioinformatic findings revealed pivotal targets, biological functions, and pharmacological mechanisms of calycosin for the treatment of CIRI. In conclusion, calycosin, a functional phytoestrogen, can be potentially used for the treatment of CIRI in future clinical trials.


Assuntos
Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isoflavonas/uso terapêutico , Terapia de Alvo Molecular , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Algoritmos , Análise por Conglomerados , Humanos , Simulação de Acoplamento Molecular , Transdução de Sinais
9.
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
10.
Clinics (Sao Paulo) ; 76: e2728, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34133479

RESUMO

OBJECTIVES: To investigate the safety and efficacy of combined tirofiban-ozagrel therapy for treating progressive stroke patients out of thrombolytic therapy time window. METHODS: This prospective, double-blind, randomized controlled study included 337 patients who had experienced an acute ischemic stroke between November 2017 and December 2018. All patients were randomized into three groups: 1) the tirofiban/ozagrel group (n=113), 2) the tirofiban group (n=110), and 3) the ozagrel group (n=114). The platelet aggregation (PAG), thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FIB) levels in the patients from these groups were evaluated before starting treatment and then, at 24h, 7 days, and 14 days after treatment. The National Institutes of Health Stroke Scale (NIHSS) scores were evaluated before treatment and then, 24h, 1 week, 2 weeks, and 4 weeks after treatment. The Barthel Index (BI) score was used to measure safety, and the modified Rankin scale (mRS) was used to evaluate disability following 3 months of treatment. The risk factors affecting clinical outcomes were analyzed using logistic multivariate regression. RESULTS: The mean NIHSS score for all the patients was 13.17±3.13 before treatment, and no significant difference between the basic clinical parameters of the three patient groups was found. Following treatment, both PAG and FIB were significantly reduced compared with the baseline (p<0.05). The levels of PAG and FIB in the tirofiban/ozagrel group were significantly lower than those in the tirofiban and ozagrel groups at 24h and 7 days after treatment (p<0.05). The NIHSS score decreased significantly in all treatment groups (p<0.05). The tirofiban/ozagrel NIHSS scores were significantly lower than that of the tirofiban and ozagrel groups at 24h, 1 week, and 2 weeks post initiation (p<0.05 for all). There were no significant differences in the BI and mRS scores or the intracranial hemorrhage rates; further, age, sex, Trial of ORG 10172 in acute stroke treatment (TOAST) type, baseline NIHSS and 24-h NIHSS scores, baseline thrombus-related factors, and treatment methods were shown to not be independent risk factors for clinical outcomes. CONCLUSION: The combination of tirofiban and ozagrel, as well as monotherapy with either tirofiban or ozagrel, transiently improves the neural function of patients and reduces platelet aggregation and fibrinogen formation in the first 4 weeks following a stroke event; additionally, none of these treatments increased the risk for hemorrhage in these progressive stroke patients over a 3-month period.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Isquemia Encefálica/tratamento farmacológico , Infarto Cerebral/tratamento farmacológico , Método Duplo-Cego , Humanos , Metacrilatos , Estudos Prospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Tirofibana/uso terapêutico , Resultado do Tratamento
11.
Wiad Lek ; 74(6): 1307-1311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159909

RESUMO

OBJECTIVE: The aim: To investigate changes in motor activity and indicators of the state of the hemostasis system in the acute period of ischemic stroke during systemic thrombolytic therapy and without its use. PATIENTS AND METHODS: Materials and methods: We examined 26 male and female patients with a clinical diagnosis of ischemic stroke, who were hospitalized on the first day of the disease to the neurological departments. Patients were divided into 2 groups: group 1-patients who underwent systemic thrombolytic therapy (sTLT) (n=11), group 2-patients who did not receive sTLT (n=15). To compare the coagulogram parameters, 12 healthy patients were examined (control group). Examination of patients was performed on the 1st and 14th day of the disease (clinical examination, assessment of motor activity, coagulation test). Stroke severity was determined by the overall score of the National Institutes of Health Stroke Scale. RESULTS: Results: The average age of patients in group 1 - 60.1±8.2 years old, in group 2 -61.3±5.5 years old. The number of points on the NIHSS scale in group 1 was 8.8±1.13 on 1st day and 3.7±0.79 on 14th day (p<0.05), in group 2 -5.7±0,94 on the 1st day and 3.1±0.93 on the 14th day(p<0.05). The results of the study of the coagulogram indicate a significantly higher level of soluble fibrin-monomer complexes on the 1st day on the 14th day of the ischemic stroke. CONCLUSION: Conclusions: In the acute period of ischemic stroke changes in the hemostasis system reflected the direction of the selected therapy. The use of systematic thrombolytic therapy in ischemic stroke led to a more severe decrease in stroke severity on the NIHSS scale, a significant increase in Barthel index.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Hemostasia , Humanos , Lactente , Masculino , Atividade Motora , Projetos Piloto , Estudos Prospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Resultado do Tratamento
12.
Aging (Albany NY) ; 13(12): 16105-16123, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34118791

RESUMO

Diabetic patients are more vulnerable to cerebral ischemia-reperfusion (CIR) injury and have a worse prognosis and higher mortality after ischemic stroke than non-diabetic counterparts. Melatonin can exert neuroprotective effects against CIR injury in nondiabetic animal models. However, its effects on diabetic CIR injury and the underlying mechanisms remain unclarified. Herein, we found that melatonin administration improved neurological deficit, cerebral infarct volume, brain edema, and cell viability, reduced mitochondrial swelling, reactive oxygen species generation, and cytoplasmic cytochrome C release, and increased mitochondrial antioxidant enzymes activities, adenosine triphosphate production, and mitochondrial membrane potential in both streptozotocin-induced diabetic mice and high glucose-treated HT22 cells. Importantly, melatonin also activated protein kinase B (Akt) and sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) signaling and upregulated mitochondrial biogenesis-related transcription factors. However, these effects were largely attenuated by LY294002 (a specific Akt signaling blocker) administration. Additionally, 3-TYP (a selective SIRT3 inhibitor) and SIRT3 siRNA inhibited the above protective effects of melatonin as well as the upregulation of SIRT3 and the decrease of SOD2 acetylation but did not affect the p-Akt/Akt ratio. Overall, we demonstrate that melatonin can alleviate CIR injury in diabetic mice by activating Akt-SIRT3-SOD2 signaling and subsequently improving mitochondrial damage.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Melatonina/uso terapêutico , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Edema Encefálico/complicações , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Isquemia Encefálica/complicações , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Diabetes Mellitus Experimental/complicações , Glucose/toxicidade , Masculino , Melatonina/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Morfolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos
13.
Sci Transl Med ; 13(597)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108252

RESUMO

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Humanos , Macaca mulatta , Camundongos , Peptídeos , Roedores , Acidente Vascular Cerebral/tratamento farmacológico
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.
Rev Med Chil ; 149(1): 128-131, 2021 Jan.
Artigo em Espanhol | MEDLINE | ID: mdl-34106144

RESUMO

We report a 78-year-old man with a basal Rankin score of 2 points, last seen 10 hours before in good conditions, who arrived at the emergency department with left hemiparesis, hypoesthesia, and spacial neglect. Neuroimaging was compatible with stroke in the territory of the right middle cerebral artery. Due to the evolution time of the stroke, usual thrombolysis was contraindicated. Therefore, a thrombolysis with Tenecteplase was used with reversal of symptoms without symptomatic bleeding and with recovery of baseline functionality.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Tenecteplase/uso terapêutico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
16.
Ann Palliat Med ; 10(5): 5706-5713, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34107714

RESUMO

BACKGROUND: At present, the treatment of acute ischaemic stroke (AIS) by aticepase (rt-PA) in emergency veins has become the main treatment mode in hospital, but the research on early hemorrhage complications in patients with emergency thrombolysis is rarely reported. This research aims to study the earlier warning index of early hemorrhage complications in patients with emergency thrombolysis. METHODS: A retrospective analysis was performed on the clinical data of rt-PA intravenous thrombolysis-treated AIS patients in the advanced stroke center of the emergency department of a tertiary grade hospital from January 2018 to May 2020. Patients were divided into a hemorrhage group and non-hemorrhage group according to the hemorrhage situation within 24 hours after thrombolytic therapy. The differences between the 2 groups in terms of pre-thrombolysis risk factors were analyzed. Logistic regression analysis was used to analyze the independent risk factors associated with post-thrombolysis hemorrhage. RESULTS: After intravenous thrombolysis, the hemorrhage group had 91 cases and the non-hemorrhage group had 146 cases. Logistic regression analysis showed that atrial fibrillation, systolic blood pressure before thrombolysis, platelet count, and antiplatelet drugs were independent risk factors for hemorrhage after intravenous thrombolysis (P<0.05). CONCLUSIONS: Patients with AIS have a higher incidence of hemorrhage after intravenous thrombolysis. Atrial fibrillation, systolic blood pressure before thrombolysis, platelet count, and antiplatelet drugs were independent risk factors for hemorrhage after intravenous thrombolysis. These independent risk factors can provide a basis for clinical nurses to evaluate hemorrhage risk in AIS patients after intravenous thrombolysis.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/tratamento farmacológico , Serviço Hospitalar de Emergência , Fibrinolíticos/efeitos adversos , Hemorragia , Humanos , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
17.
Mol Biol (Mosk) ; 55(3): 402-411, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34097675

RESUMO

Due to its nootropic, neuroprotective, and immunomodulatory effects, the peptide Semax is utilized in the treatment of ischemic stroke. Our earlier RNA-Seq analysis of the transcriptome in an ischemic model of transient occlusion of the middle cerebral artery showed an increase in the mRNA levels of many proinflammatory genes, and the suppression of their induction by Semax. However, for many relevant genes, including Il1a, Il1b, Il6 and Tnfa, the levels of their expression were too low for detailed quantitative evaluation. Here we utilize qRT-PCR to analyze the effects of the Semax peptide on the expression of weakly expressed mRNAs encoding several proinflammatory mediators, and show that exposure to Semax leads to a statistically significant decrease in the Il1a, Il1b, Il6, Ccl3, and Cxcl2 mRNAs, which compensates for the increase in the transcription of these genes induced by ischemia-reperfusion. We conclude that the observed protective effect of Semax in the model of stroke may be due to its anti-inflammatory effects. We also discuss the limitations of the RNA-Seq when applied to quantifying less abundant transcripts as compared to the real-time RT-PCR method.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Preparações Farmacêuticas , Hormônio Adrenocorticotrópico/análogos & derivados , Animais , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia , Fragmentos de Peptídeos , RNA Mensageiro/genética , Ratos , Ratos Wistar
18.
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
19.
BMC Neurol ; 21(1): 220, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107911

RESUMO

BACKGROUND: For acute ischaemic stroke patients, it is uncertain whether intravenous thrombolysis combined with statins might increase the therapeutic effect. Additionally, using high-intensity statins after thrombolysis may increase the risk of bleeding in patients. Asian stroke patients often take low-dose statins. It is speculated that reducing the dose of statins may improve the risk of bleeding. METHODS: Data from consecutive acute ischaemic stroke patients with intravenous thrombolysis were prospectively collected. Efficacy outcomes included NIHSS (National Institutes of Health Stroke Scale) score improvement at 7 days after admission and mRS (Modified Rankin Scale) improvement at 90 days. Safety outcomes included haemorrhage events (intracerebral haemorrhage and gastrointestinal haemorrhage) in the hospital and death events within 2 years. RESULTS: The study finally included 215 patients. The statin group had a higher percentage of NIHSS improvement at 7 days (p < 0.001) and a higher percentage of a favourable functional outcome (FFO, mRS < = 2) (p < 0.001) at 90 days. The statin group had a lower percentage of intracerebral haemorrhage (p < 0.001) and gastrointestinal haemorrhage (p = 0.003) in the hospital and a lower percentage of death events (p < 0.001) within 2 years. Logistic regression indicated that statin use was significantly related to NIHSS improvement (OR = 4.697, p < 0.001), a lower percentage of intracerebral haemorrhage (OR = 0.372, p = 0.049) and gastrointestinal haemorrhage (OR = 0.023, p = 0.016), and a lower percentage of death events (OR = 0.072, p < 0.001). CONCLUSION: For acute ischaemic stroke patients after intravenous thrombolysis, the use of low-dose statins was related to NIHSS improvement at 7 days and inversely related to haemorrhage events in the hospital and death events within 2 years, especially for moderate stroke or noncardioembolic stroke patients.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/etiologia , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
20.
Neurol Sci ; 42(7): 2713-2719, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33945037

RESUMO

Human serum albumin has shown remarkable efficacy in rodent models of ischemic stroke, while results from relevant clinical research on albumin therapy remain controversial. We conducted a meta-analysis of published studies to quantitatively analyze the neurofunctional outcomes of patients with ischemic stroke treated with albumin. PubMed, Embase, and Cochrane Library were searched in July 2020. A total of four studies and 1611 patients were included. The aggregated results indicated that there were 635 patients with good neurological outcomes, among which 321 patients were in the albumin group (39.8%) and 314 patients in the control group (39.1%), showing no statistically significant difference between the albumin and control groups (OR = 1.04, 95% CI 0.85-1.27). The results suggest that albumin therapy at the acute stage of ischemic stroke has no beneficial effect on the long-term neurological function of patients with ischemic stroke. Considering pulmonary edema and other complications are more likely to occur in such patients after albumin infusion, the administration of albumin therapy for acute ischemic stroke should be done with utmost caution.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Albuminas , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Humanos , Acidente Vascular Cerebral/tratamento farmacológico
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