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1.
Int J Mol Sci ; 20(20)2019 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-31635131

RESUMO

High salt (HS) dietary intake leads to impaired vascular endothelium-dependent responses to various physiological stimuli, some of which are mediated by arachidonic acid (AA) metabolites. Transgenic Tff3-/- gene knockout mice (Tff3-/-/C57BL/6N) have changes in lipid metabolism which may affect vascular function and outcomes of stroke. We aimed to study the effects of one week of HS diet (4% NaCl) on vascular function and stroke induced by transient occlusion of middle cerebral artery in Tff3-/- and wild type (WT/C57BL/6N) mice. Flow-induced dilation (FID) of carotid artery was reduced in WT-HS mice, but not affected in Tff3-/--HS mice. Nitric oxide (NO) mediated FID. NO production was decreased with HS diet. On the contrary, acetylcholine-induced dilation was significantly decreased in Tff3-/- mice on both diets and WT-HS mice. HS intake and Tff3 gene depletion affected the structural components of the vessels. Proteomic analysis revealed a significant effect of Tff3 gene deficiency on HS diet-induced changes in neuronal structural proteins and acute innate immune response proteins' expression and Tff3 depletion, but HS diet did not increase the stroke volume, which is related to proteome modification and upregulation of genes involved mainly in cellular antioxidative defense. In conclusion, Tff3 depletion seems to partially impair vascular function and worsen the outcomes of stroke, which is moderately affected by HS diet.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fator Trefoil-3/deficiência , Animais , Biomarcadores , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dieta , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Endotélio Vascular/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Proteoma , Fluxo Sanguíneo Regional , Fatores de Transcrição/metabolismo , Vasodilatação/efeitos dos fármacos
2.
J Clin Neurosci ; 70: 136-139, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31431403

RESUMO

Parkinson's disease (PD) has a variable spectrum of cognitive impairment. However, there are no clear evident-based management guidelines for PD with dementia (PDD). Alternative treatments for PDD are therefore required. We conducted this longitudinal study to evaluate the efficacy of nicergoline in treating PDD by analyzing changes in regional cerebral blood flow (rCBF) and neuropsychological tests before and after nicergoline administration. A total of nine PDD patients who received nicergoline therapy (PDD + N) and 14 PD patients who did not receive nicergoline therapy (PDD - N) underwent single photon emission computed tomography (SPECT) and clinical assessments at baseline and 12-month follow-up visits. The PDD + N received nicergoline at 30 mg twice per day. Changes in rCBF were compared between the groups, and correlation analysis was performed to determine possible relationship between rCBF and clinical characteristics. There were no significant differences in rCBF between the two groups at baseline. Although changes in cognitive test scores and the motor severity scale were not significantly different between baseline and the 12-month follow-up within groups, rCBF was lower in both the temporal and inferior frontal restricted areas in the PDD - N group than the PDD + N at the 12-month follow-up visit. In conclusions, nicergoline appears to delay the speed of deterioration of cognitive function in patients with PDD based on our observation of decreased rCBF in the temporal regions and inferior frontal regions of PDD - N patients compared to PDD + N patients after 12-month of nicergoline therapy. Therefore, we cautiously suggest that nicergoline administration in PDD patients may slow progression of cognitive impairment in affected brain regions.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Demência/etiologia , Nicergolina/uso terapêutico , Doença de Parkinson/complicações , Vasodilatadores/uso terapêutico , Idoso , Cognição/efeitos dos fármacos , Demência/tratamento farmacológico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/tratamento farmacológico
3.
Biosci Biotechnol Biochem ; 83(11): 1992-1999, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362597

RESUMO

The present study focused on the effect of paeonol, one of the main components of Guizhi Fuling Pill, on blood pressure, cerebral blood flow, and vascular endothelium injury in spontaneously hypertensive rats to provide theoretical basis for the treatment of hypertension. After treatment with paeonol, the mean arterial pressure (MAP) of LSHRT and HSHRT rats decreased gradually with the prolongation of treatment time. The systolic blood flow velocity (Vs), diastolic blood flow velocity (Vd) and mean blood flow velocity (Vm) were significantly increased after paeonol treatment (p < 0.05). Paeonol effectively improved the blood pressure and increased the cerebral blood flow velocity in spontaneously hypertensive rats. This may be related to the fact that paeonol reduced the blood viscosity and the oxidative stress and improved the antioxidant capacity. Moreover, paeonol protected vascular endothelial cells and reduced vascular endothelial injury in spontaneously hypertensive rats.


Assuntos
Acetofenonas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipertensão/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hemorreologia/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Cir Cir ; 87(5): 580-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448774

RESUMO

Monitoring of the neurocritical in the perioperatory is in constant evolution. There are essentially two ultrasonographic application of neuromonitoring: the diameter of the sheath of the optic nerve and transcranial Doppler. Ultrasound-guided neuromonitoring can detect stenosis or occlusion of intracranial arteries, monitor the evolution of patients with vasospasm after subarachnoid hemorrhage, detect cerebral embolism, evaluate the cerebral collateral system, determine brain death, calculate indirectly Intracranial pressure and cerebral perfusion and helps in clinical decisions and early therapeutic interventions in neurocritical care. The purpose of this review is to present the applications of ultrasonography to the head of the patient in neuromonitoring.


Assuntos
Transtornos Cerebrovasculares/diagnóstico por imagem , Monitorização Neurofisiológica Intraoperatória/métodos , Neuroimagem/métodos , Nervo Óptico/diagnóstico por imagem , Assistência Perioperatória/métodos , Ultrassonografia Doppler Transcraniana , Morte Encefálica/diagnóstico por imagem , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Circulação Cerebrovascular/efeitos dos fármacos , Tomada de Decisão Clínica , Humanos , Pressão Intracraniana , Órbita/diagnóstico por imagem , Fluxo Pulsátil , Hemorragia Subaracnóidea/diagnóstico por imagem , Vasoconstritores/farmacologia , Vasoespasmo Intracraniano/diagnóstico por imagem
5.
World Neurosurg ; 132: e834-e840, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31404696

RESUMO

BACKGROUND: Current guidelines recommend the administration of nimodipine for the prevention of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, nimodipine can lead to significant drops in mean arterial pressure and cerebral perfusion pressure. Catecholamines are then used to maintain them while nimodipine is reduced and/or held. There is no evidence that nimodipine retains its neuroprotective effect at lower doses. We aimed to investigate the role of nimodipine interruption in the setting of aSAH and its possible impact on the incidence of DCI. METHODS: We performed a retrospective analysis in patients with aSAH admitted to our center from January 2012 to October 2015. Nimodipine prophylaxis duration and dosage and the incidence of DCI were recorded. Bivariate correlation with Spearman's rho (ρ) and ordinal regression analyses were performed. RESULTS: A total of 170 patients were included in the study. Of these, 165 (97.1%) received nimodipine prophylaxis starting on day 0. Nimodipine was interrupted in 85 of 165 (51.5%), whereas dose was reduced in 47 of 165 (28.5%); full dose was received by only 33 of 165 (20%). DCI was observed in 85 of 170 (50%). Nimodipine interruption correlated in a statistically significant way with a greater incidence of DCI (ρ = 0.431, P < 0.001); receiving full doses of nimodipine showed a statistically significant inverse correlation to DCI (ρ = -0.273, P < 0.001). Ordinal regression analysis revealed nimodipine interruption as a statistically significant independent predictor of DCI (odds ratio 0.194; 95% confidence interval 0.079-0.474, P < 0.001). CONCLUSIONS: Our analysis reveals a greater incidence of DCI in patients with aSAH when nimodipine is interrupted.


Assuntos
Isquemia Encefálica/epidemiologia , Isquemia Encefálica/etiologia , Catecolaminas/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Nimodipina/administração & dosagem , Nimodipina/uso terapêutico , Hemorragia Subaracnóidea/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Arterial/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Nimodipina/efeitos adversos , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 98(27): e16175, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277122

RESUMO

BACKGROUND: Chronic cerebral circulation insufficiency (CCCI) is a common clinical cerebrovascular disease, especially among middle-aged and elderly patients, which seriously endangers their quality of life and physical and mental health. At present, Oral traditional Chinese patent medicine (OTCPM) is widely used in the treatment of CCCI in China, but its actual efficacy and safety lack of evidence-based evidence. Therefore, we will screen out the most effective OTCPM through a systematic review and network meta-analysis to provide a reliable theoretical basis for clinical decisions. METHODS: We will search electronic databases to collect relevant RCT studies from inception to October 2019. Those electronic databases include PubMed, Cochrane Library, Web of Science, EMBASE, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. Only randomized clinical trials (RCTs) concerned any OTCPM treatments for CCCI will be collected. The included studies will no restrictions on language or publication year. There were no publication year or language for the included literature. Risk bias tools will assess the quality of the included literature. A Bayesian NMA will be performed to combine the direct and indirect comparisons of TCPMs interventions. The surface under the cumulative ranking curve (SUCRA) will be drawn to display the hierarchy of each TCPMs treatment. All statistical analyses will be implemented using R v3.5.2. and GeMTC v1.4.3.We will publish this systematic review in academic journals. Since this literature review will not involve directly contacting patients, ethical approval and informed consent are not required. TRIAL REGISTRATION NUMBER: CRD42019123878.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Administração Oral , Humanos , Medicina Tradicional Chinesa , Metanálise como Assunto , Meta-Análise em Rede , Revisão Sistemática como Assunto
7.
Medicina (Kaunas) ; 55(7)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319603

RESUMO

Background and objectives: To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Materials and methods: The study was performed on male mice of the BALB/c line (acute toxicity was assessed) and male rats of the Wistar line, which were modeled chronic traumatic encephalopathy by the method of free fall of the load (weight 150 g from a 50 cm height). The injury to rats was reproduced once a day for 7 days. Further, cognitive functions, changes in sensorimotor deficiency, cerebral blood flow, neuron-specific enolase(NSE), S100ß, glial fibrillary acidic protein (GFAP) (in blood serum) and ß-amyloid, adenosine triphosphate (ATP) (in brain tissue supernatant) were evaluated. Mitochondrial respiration was also measured. Choline alfoscerate (100 mg/kg) was used as a reference drug. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats. In addition, against the administration of test-object marked increase in the concentration of ATP, the velocity of cerebral blood flow was 4.2 times (p < 0.05) and 35.6% (p < 0.05), respectively, as well as reduced concentration and GFAP,NSE, S100ß, ß-amyloid and sensorimotor deficit at 2.7 (p < 0.05) times; 2 times (p < 0.05); 2.4 times (p < 0.05); of 30.4% (p < 0.05 and 46.5% (p < 0.05), respectively. The LD50 (per os) for the test-object was 4973.56 ± 573.72 mg/kg. Conclusion: Based on the obtained data, high therapeutic efficacy and low systemic toxicity of the application are assumed 4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide in chronic traumatic encephalopathy.


Assuntos
Encefalopatia Traumática Crônica/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Pirimidinas/uso terapêutico , Animais , Circulação Cerebrovascular/efeitos dos fármacos , Encefalopatia Traumática Crônica/fisiopatologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Curva ROC , Ultrassonografia Doppler/métodos
8.
Int Rev Neurobiol ; 146: 1-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349924

RESUMO

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86±0.24°C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.


Assuntos
5-Hidroxitriptofano/efeitos adversos , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/patologia , Circulação Cerebrovascular/efeitos dos fármacos , 5-Hidroxitriptofano/antagonistas & inibidores , Albuminas/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/induzido quimicamente , Ciproeptadina/farmacologia , Diazepam/farmacologia , Fenclonina/farmacologia , Indometacina/farmacologia , Ketanserina/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Serotonina/sangue , Serotonina/metabolismo , Vimblastina/farmacologia
9.
J Stroke Cerebrovasc Dis ; 28(10): 104276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350168

RESUMO

BACKGROUND: We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 hour and reperfusion for 2 hours with or without PF-4708671 (S6K1 inhibitor, 75 mg/kg, 15 minutes after blockade). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small vessel (20-60 µm diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O2 saturation (23 of 80 veins with O2 saturation below 45%). PF-4708671 did not significantly alter cerebral blood flow or O2 consumption. However, it significantly reduced the number of small veins with low O2 saturations in the reperfused region (6 of 80 veins with O2 saturation below 45%). This was associated with a significantly reduced cortical infarct size after S6K1 inhibition (12.9 ± .8% control versus 6.6 ± .3% PF-4708671). CONCLUSION: This suggests that S6K1 inhibition is important for cell survival and that it reduces the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Piperazinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
10.
Hypertension ; 74(2): 413-420, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31203725

RESUMO

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Nifedipino/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Países Baixos , Nifedipino/uso terapêutico , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Ultrassonografia Doppler/métodos
11.
Molecules ; 24(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207980

RESUMO

Chuanxiong Rhizoma and Cyperi Rhizoma (CRCR), an ancient and classic formula comprised of Chuanxiong Rhizoma and Cyperi Rhizoma in a weight ratio of 1:2, has long been used for curing migraine. This study aimed to explore their anti-migraine effect and active constituents. A nitroglycerin (NTG)-induced migraine model in rats was established to evaluate pharmacological effects. Cerebral blood flow was detected by a laser Doppler perfusion monitor. The levels of endothelin-1 (ET-1), γ-aminobutyric acid (GABA), nitric oxide synthase (NOS), nitric oxide (NO), 5-hydroxytryptamine (5-HT), 5-hydoxyindoleacetic acid (5-HIAA), calcitonin gene-related peptide (CGRP) and ß-endorphin (ß-EP) were quantified with enzyme-linked immunosorbent assay. CGRP and c-Fos mRNA expression were quantified with quantitative real-time polymerase chain reaction. A UPLC-MS/MS method was developed and validated for the simultaneous quantification of active constituents in rat serum and cerebral cortex. CRCR significantly increased cerebral blood flow, decreased the levels of ET-1, GABA and NOS, and increased the levels of 5-HT, 5-HIAA and ß-EP in NTG-induced migraine rats. CGRP levels and CGRP mRNA expression, as well as c-Fos mRNA expression in the brainstem were markedly down-regulated with the treatment of CRCR. After oral administration of CRCR, ferulic acid (FA), senkyunolide A (SA), 3-n-butylphthalide (NBP), Z-ligustilide (LIG), Z-3-butylidenephthalide (BDPH), cyperotundone (CYT), nookatone (NKT) and α-cyperone (CYP) were qualified in rat serum and cerebral cortex. The above results suggested that CRCR showed powerfully therapeutic effects on migraine via increasing the cerebral blood flow, decreasing the expression of CGRP and c-Fos mRNA, and regulating the releasing of ET-1, GABA, NOS, 5-HT, 5-HIAA, CGRP and ß-EP in the serum and brainstem, consequently relieving neurogenic inflammation. The active constituents in CRCR for treating migraine were FA, SA, NBP, LIG, BDPH, CYT, NKT and CYP. These findings contributed for the further use of CRCR as a combinational and complementary phytomedicine for migraine treatment.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Rizoma/química , Espectrometria de Massas em Tandem , Animais , Biomarcadores , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Córtex Cerebral/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/isolamento & purificação , Regulação da Expressão Gênica , Modelos Animais , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Ratos , Reprodutibilidade dos Testes
12.
J Stroke Cerebrovasc Dis ; 28(7): 1987-1992, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31036341

RESUMO

BACKGROUND: Mechanical thrombectomy is the standard of care for patients with large vessel occlusion (LVO) presenting with severe symptoms; however, little is known about the best treatment for patients with LVO and mild symptoms. The absence of good collaterals has been associated with a worse outcome in patients with LVO. In this study, we aim to assess the use of collateral score to identify patients with LVO and mild symptoms that might benefit from mechanical thrombectomy (MT). METHODS: A retrospective review of prospectively collected data on patients presenting with mild ischemic stroke (National Institute of Health Stroke Scale [NIHSS] <6) and anterior circulation LVO between September 2015 and July 2017 was performed. Collected data included baseline demographics, NIHSS on admission, Alberta Stroke Program Early CT Score (ASPECTS), location of occlusion, collateral score using Tan scoring system, final infarct volume, and 90-day modified Rankin Scale (mRS). Patients who underwent MT were excluded from this analysis. Two multivariable models were used to assess outcomes. A gamma distributed generalized linear regression model with a log link was used to examine the impact on final infarct volume. To predict the odds of a positive 90-day outcome we estimated a logistic regression. RESULTS: Forty-one patients were identified. Mean age was 67.7-years with 56.1% males. Median NIHSS on admission was 3. The most common vessels involved were the middle cerebral artery (26), internal carotid artery (14), and anterior cerebral artery (1). Twelve patients received intravenous alteplase. Median ASPECTS score was 9, median collateral score was 2.3. Median infarct volume was 10.7 mL. A good functional outcome (mRS 0-2) at 90 days was achieved in 86.4% of patients. There was a negative relationship between collateral score and final infarct volume (-.3134, P = .046). Multivariable regression results showed that with a one-point increase in NIHSS on admission there was a 25% increase in final infarct volume. Higher infarct volume was associated with lower odds of achieving good functional outcome (mRS 0-2) (odds ratio .96, P = .049 [95% confidence interval .918-.999). CONCLUSIONS: Most patients with anterior circulation LVO and low NIHSS achieve good long-term functional outcome, however, approximately 15% had significant disability. The absence of collaterals correlates with a larger final infarct volume and a worse long-term functional outcome. Collateral score might be a useful tool in identifying patients with LVO and low NIHSS who might benefit from MT.


Assuntos
Infarto Encefálico/fisiopatologia , Circulação Cerebrovascular , Circulação Colateral , Doenças Arteriais Intracranianas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/tratamento farmacológico , Angiografia Cerebral/métodos , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Angiografia por Tomografia Computadorizada , Avaliação da Deficiência , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Doenças Arteriais Intracranianas/diagnóstico por imagem , Doenças Arteriais Intracranianas/tratamento farmacológico , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Terapia Trombolítica , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
13.
Curr Opin Anaesthesiol ; 32(5): 585-591, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31145199

RESUMO

PURPOSE OF REVIEW: Stroke is the second leading cause of death and the third leading cause of disability worldwide. Treatment is time limited and delays cost lives. This review discusses modern stroke management, during a time when treatments and guidelines are rapidly evolving. RECENT FINDINGS: Stroke thrombectomy has become the therapy of choice for large vessel occlusion (LVO) strokes. Perfusion imaging techniques, both computed tomography (CT) and MRI, now allow treatment beyond a set time window in specific patients. Both general anaesthesia and conscious sedation are options for patients undergoing stroke thrombectomy. SUMMARY: An individualized approach to the patient's anaesthetic management is optimal, and depends on close communication with the neurointerventionalist regarding patient and procedure-specific variables. No specific anaesthetic agent is preferred. Guiding principles are minimization of time delay, and maintenance of cerebral perfusion pressure.


Assuntos
Anestesia Geral/métodos , Sedação Consciente/métodos , Procedimentos Endovasculares/efeitos adversos , Trombose Intracraniana/complicações , Acidente Vascular Cerebral/cirurgia , Trombectomia/efeitos adversos , Anestesia Geral/efeitos adversos , Anestésicos/efeitos adversos , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Circulação Cerebrovascular/efeitos dos fármacos , Sedação Consciente/efeitos adversos , Procedimentos Endovasculares/métodos , Medicina Baseada em Evidências/métodos , Humanos , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/cirurgia , Imagem por Ressonância Magnética , Acidente Vascular Cerebral/etiologia , Trombectomia/métodos , Fatores de Tempo , Tempo para o Tratamento , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
J Stroke Cerebrovasc Dis ; 28(7): 1993-2002, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029568

RESUMO

BACKGROUND: Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-ß accumulation, neuroinflammation, and oxidative stress. The pathological impact of chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood. METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical analysis, and immunofluorescent histochemistry. RESULTS: In the present study, chronic cerebral hypoperfusion, which is commonly found in aged Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from 5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular amyloid-ß plaque and intracellular oligomer formations, and amyloid angiopathy at 12 months. Severe upregulations of oxidative markers and inflammatory markers were found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment (20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and reduced the above amyloid-ß pathology and neuronal loss, alleviated neuroinflammation and oxidative stress. CONCLUSIONS: The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's disease with chronic cerebral hypoperfusion.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/administração & dosagem , Encéfalo/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Cistina/administração & dosagem , Glutamina/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Ascórbico/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/fisiopatologia , Doença Crônica , Cognição/efeitos dos fármacos , Cistina/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Glutamina/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Mutação , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide
15.
Adv Mater ; 31(21): e1808361, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957932

RESUMO

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Sirolimo/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/metabolismo , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Humanos , Micelas , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/química , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
16.
Arterioscler Thromb Vasc Biol ; 39(4): 593-602, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816798

RESUMO

There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment. In this focused review, we discuss the contribution of 2 major vasoactive pathways to cerebrovascular dysfunction and cognitive impairment in an effort to identify early intervention strategies.


Assuntos
Circulação Cerebrovascular , Transtornos Cognitivos/fisiopatologia , Cognição/fisiologia , Endotelinas/fisiologia , Sistema Renina-Angiotensina/fisiologia , Doença de Alzheimer/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/fisiologia , Previsões , Humanos , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Receptores de Endotelina/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos
17.
Trials ; 20(1): 164, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871594

RESUMO

BACKGROUND: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. METHODS: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume. DISCUSSION: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest. TRIAL REGISTRATION: Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.


Assuntos
Bosentana/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Bélgica , Bosentana/efeitos adversos , Método Duplo-Cego , Antagonistas dos Receptores de Endotelina/efeitos adversos , Humanos , Imagem por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Estudo de Prova de Conceito , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
18.
Nitric Oxide ; 87: 60-72, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877024

RESUMO

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is a key regulator of cerebral blood flow (CBF) dynamics. Mice with eNOS deficiency (eNOS-/-) display age-related increases in amyloid beta in the brain and memory deficits, implicating eNOS dysfunction in the neuropathogenesis and/or development of Alzheimer's disease (AD). The present study systematically investigated behavioural, CBF and brain arginine metabolic profile changes in male and female wildtype (WT) and eNOS-/- mice at 14 months of age. eNOS-/- mice displayed altered behaviour in the Y-maze and open field tests. A real-time microcirculation imager revealed a significant sex difference in the basal CBF and significantly increased perfusion response to whisker stimulations in the Barrel cortex in both male and female eNOS-/- mice relative to their sex-matched WT controls. The treatment of 7-nitroindazole blocked the increased perfusion response to whisker stimulations in eNOS-/- mice. Neurochemically, the most intriguing changes were markedly reduced glutamine levels in both male and female eNOS-/- mice in the frontal cortex, hippocampus, parahippocampal region and cerebellum. These findings demonstrate altered behavioural function, neurovascular coupling and brain arginine metabolism (glutamine in particular) under the condition of eNOS deficiency, which further supports the role of eNOS dysfunction in the AD neuropathogenesis.


Assuntos
Arginina/metabolismo , Encéfalo/metabolismo , Acoplamento Neurovascular/fisiologia , Óxido Nítrico Sintase Tipo III/deficiência , Doença de Alzheimer/etiologia , Animais , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Inibidores Enzimáticos/farmacologia , Feminino , Indazóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética
19.
Circ Res ; 124(7): 1025-1044, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30920929

RESUMO

Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension has more recently been linked also to Alzheimer disease-the major cause of dementia in older people. Thus, although midlife hypertension is a risk factor for late-life dementia, hypertension may also promote the neurodegenerative pathology underlying Alzheimer disease. The mechanistic bases of these harmful effects remain to be established. Hypertension is well known to alter in the structure and function of cerebral blood vessels, but how these cerebrovascular effects lead to cognitive impairment and promote Alzheimer disease pathology is not well understood. Furthermore, critical questions also concern whether treatment of hypertension prevents cognitive impairment, the blood pressure threshold for treatment, and the antihypertensive agents to be used. Recent advances in neurovascular biology, epidemiology, brain imaging, and biomarker development have started to provide new insights into these critical issues. In this review, we will examine the progress made to date, and, after a critical evaluation of the evidence, we will highlight questions still outstanding and seek to provide a path forward for future studies.


Assuntos
Pressão Sanguínea , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Transtornos Cerebrovasculares/epidemiologia , Cognição , Disfunção Cognitiva/epidemiologia , Hipertensão/epidemiologia , Acoplamento Neurovascular , Animais , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/prevenção & controle , Transtornos Cerebrovasculares/psicologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertensão/psicologia , Acoplamento Neurovascular/efeitos dos fármacos , Prognóstico , Medição de Risco , Fatores de Risco
20.
Psychopharmacology (Berl) ; 236(7): 1985-1997, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30820633

RESUMO

RATIONALE: Anterior cingulate cortex (ACC) glutamatergic abnormalities are reported in treatment-resistant schizophrenia (TRS) and implicated in functional dysconnectivity and psychopathology. Preclinical evidence indicates riluzole reduces synaptic glutamate. However, it is unknown whether riluzole can modulate glutamate metabolite levels and associated functional connectivity in TRS. OBJECTIVES: To examine the relationship between glutamatergic function and cortical connectivity and determine if riluzole can modulate glutamate metabolite levels and cortical functional connectivity in TRS. METHODS: Nineteen TRS patients and 18 healthy volunteers (HV) underwent magnetic resonance imaging consisting of MR spectroscopy measuring ACC glutamate plus glutamine (Glx), fMRI measuring resting ACC-functional connectivity, and arterial spin labelling measuring regional cerebral blood flow (rCBF), and clinical measures. They then received 50 mg riluzole twice daily for 2 days when imaging was repeated. RESULTS: Baseline (pre-riluzole) Glx levels were correlated directly with negative symptom severity (r = 0.49; p = 0.03) and inversely with verbal learning in TRS (r = - 0.63; p = 0.002), but not HV (r = - 0.24; p = 0.41). Connectivity between the ACC and anterior prefrontal cortex (aPFC) was correlated with verbal learning in TRS (r = 0.49; p = 0.04), but not HV (r = 0.28; p = 0.33). There was a significant group × time interaction effect on Glx levels (p < 0.05) and on ACC connectivity to the aPFC (p < 0.05, FWE-corrected). Riluzole decreased Glx and increased ACC-aPFC connectivity in TRS relative to HV. Change in Glx correlated inversely with change in ACC-aPFC connectivity in TRS (r = - 0.52; p = 0.02) but not HV (r = 0.01; p = 0.98). Riluzole did not alter rCBF (p > 0.05), indicating absence of a non-specific blood flow effect. CONCLUSION: Results indicate glutamatergic function and cortical connectivity are linked to symptoms and cognitive measures and that it is possible to pharmacologically modulate them in TRS.


Assuntos
Ácido Glutâmico/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Riluzol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Riluzol/farmacologia , Esquizofrenia/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
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