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1.
Am J Physiol Heart Circ Physiol ; 320(4): H1609-H1624, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33666506

RESUMO

This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor (AT1R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral arteries (MCA) of Sprague-Dawley rats. Eleven-week old, healthy male Sprague-Dawley rats on a standard diet were given the AT1R blocker losartan (1 mg/mL) in drinking water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade of AT1R attenuated FID and acetylcholine-induced dilation was compared with control group. Nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) and cyclooxygenase inhibitor indomethacin (Indo) significantly reduced FID in control group. The attenuated FID in losartan group was further reduced by Indo only at Δ100 mmHg, whereas l-NAME had no effect. In losartan group, Tempol (a superoxide scavenger) restored dilatation, whereas Tempol + l-NAME together significantly reduced FID compared with restored dilatation with Tempol alone. Direct fluorescence measurements of NO and reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly reduced vascular NO levels with AT1R blockade compared with control group, whereas in flow condition increased the NO and ROS production in losartan group and had no effect in the control group. In losartan group, Tempol decreased ROS production in both no-flow and flow conditions. AT1R blockade elicited increased serum concentrations of ANG II, 8-iso-PGF2α, and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results suggest that in small isolated cerebral arteries: 1) AT1 receptor maintains dilations in physiological conditions; 2) AT1R blockade leads to increased vascular and systemic oxidative stress, which underlies impaired FID.NEW & NOTEWORTHY The AT1R blockade impaired the endothelium-dependent, both flow- and acetylcholine-induced dilations of MCA by decreasing vascular NO production and increasing the level of vascular and systemic oxidative stress, whereas it mildly influenced the vascular wall inflammatory phenotype, but had no effect on the systemic inflammatory response. Our data provide functional and molecular evidence for an important role of AT1 receptor activation in physiological conditions, suggesting that AT1 receptors have multiple biological functions.


Assuntos
Circulação Cerebrovascular , Endotélio Vascular/metabolismo , Leucócitos/metabolismo , Mecanotransdução Celular , Artéria Cerebral Média/metabolismo , Estresse Oxidativo , Receptor Tipo 1 de Angiotensina/metabolismo , Vasodilatação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Artéria Cerebral Média/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
2.
Medicine (Baltimore) ; 100(8): e24811, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663100

RESUMO

BACKGROUND: We performed a randomized clinical trial protocol to assess the effectiveness of edaravone for acute stroke. We hypothesized that edaravone is beneficial in improving neurological impairment resulting from acute stroke. METHOD: The protocol was reviewed and approved by the Research Ethics Board of Affiliated Hospital of Chengde Medical University (0092-2394), each participant signed a written consent before participating, and SPIRIT guidelines were followed throughout. The inclusion criteria for patients were as follows: diagnosed as acute stroke (ischemic stroke or intracerebral hemorrhage) by head CT or MRI within 72 hours; age greater than 18; motor function disorder; Glasgow Coma Scale greater than 12. Patients with the following symptoms were excluded: concurrent serious complications, such as coma, drug allergy, mental disorder, and other severe organic lesions in the brain. Sixty patients were finally included in the study. The control group accepted conventional treatment, while the treatment group received edaravone treatment on top of the conventional treatment of the control group. After treatment, the differences in functional movement, living ability score, neurological score, treatment effect, and adverse reaction of these 2 groups were tested and compared. DISCUSSION: As aging worsens, the incidence of acute stroke continues to increase. Brain damage will induce the production of oxygen radicals, which can damage the cytomembrane of brain cells and finally damage the nervous system and cause cerebral injury as well as the cerebral edema. Edaravone is an antioxidant and oxygen radical scavenger that can inhibit lipid peroxidation during the scavenging of oxygen free radicals. Besides, it can also elicit anti-inflammatory protective effects for nerve cells, increase cerebral blood flow volume, prevent the aggravation of cerebral hypoperfusion toward necrosis, reduce nerve damage, and improve neurological functions and prognosis. This is the first randomized controlled trial to assess the efficacy of edaravone for treating acute stroke. High quality, large sample size, multicenter randomized trials are still required. TRIAL REGISTRATION: researchregistry6492.


Assuntos
Edaravone/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Atividades Cotidianas , Circulação Cerebrovascular/efeitos dos fármacos , Edaravone/farmacologia , Feminino , Depuradores de Radicais Livres/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Life Sci ; 272: 119234, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607158

RESUMO

Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3ß/ß-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/metabolismo , Ginkgolídeos/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , China , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Catenina/metabolismo
4.
Magn Reson Imaging ; 75: 134-140, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127411

RESUMO

OBJECTIVE: Alfaxalone has been used increasingly in biomedical research and veterinary medicine of large animals in recent years. However, its effects on the cerebral blood flow (CBF) physiology and intrinsic neuronal activity of anesthetized brains remain poorly understood. METHODS: Four healthy adult rhesus monkeys were anesthetized initially with alfaxalone (0.125 mg/kg/min) or ketamine (1.6 mg/kg/min) for 50 min, then administrated with 0.8% isoflurane for 60 min. Heart rates, breathing beats, and blood pressures were continuously monitored. CBF data were collected using pseudo-continuous arterial spin-labeling (pCASL) MRI technique and rsfMRI data were collected using single-shot EPI sequence for each anesthetic. RESULTS: Both the heart rates and mean arterial pressure (MAP) remained more stable during alfaxalone infusion than those during ketamine administration. Alfaxalone reduced CBF substantially compared to ketamine anesthesia (grey matter, 65 ± 22 vs. 179 ± 38 ml/100g/min, p<0.001; white matter, 14 ± 7 vs. 26 ± 6 ml/100g/min, p < 0.05); In addition, CBF increase was seen in all selected cortical and subcortical regions of alfaxalone-pretreated monkey brains during isoflurane exposure, very different from the findings in isoflurane-exposed monkeys pretreated with ketamine. Also, alfaxalone showed suppression effects on functional connectivity of the monkey brain similar to ketamine. CONCLUSION: Alfaxalone showed strong suppression effects on CBF of the monkey brain.The residual effect of alfaxalone on CBF of isoflurane-exposed brains was evident and monotonous in all the examined brain regions when used as induction agent for inhalational anesthesia. In particular, alfaxalone showed similar suppression effect on intrinsic neuronal activity of the brain in comparison with ketamine. These findings suggest alfaxalone can be a good alternative to veterinary anesthesia in neuroimaging examination of large animal models. However, its effects on CBF and functional connectivity should be considered.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Ketamina/farmacologia , Pregnanodionas/farmacologia , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/farmacologia , Animais , Encéfalo/irrigação sanguínea , Frequência Cardíaca/efeitos dos fármacos , Isoflurano/administração & dosagem , Isoflurano/farmacologia , Macaca mulatta , Masculino , Pregnanodionas/administração & dosagem
5.
Medicine (Baltimore) ; 99(50): e23414, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327266

RESUMO

Our study aimed to investigate the effect of intravenous thrombolysis with alteplase and edaravone on cerebral hemodynamics and T lymphocyte level in patients harboring acute cerebral infarction.There involved a total of 118 patients with acute cerebral infarction from November 2017 to May 2019 in our hospital were randomly divided into 2 groups: the observation group (59 patients were treated with intravenous thrombolysis with alteplase combined with edaravone) and the control group (59 patients were treated with intravenous thrombolysis of alteplase). The clinical effect, neurological function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index of the 2 groups were observed and compared.Before the treatment, there were no significant differences in neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes between the 2 groups (P > .05). After the treatment, the neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes of the 2 groups were significantly improved. In addition, the observation group exerted greater beneficial effect in terms of the clinical effect, neurologic function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index than those of the control group (P < .05).The intravenous thrombolysis with alteplase and edaravone is effective in the treatment of acute cerebral infarction, which also provides better results in terms of improving the clinical efficacy and prognosis of patients and might be an alternative option for clinical practice.


Assuntos
Infarto Cerebral/tratamento farmacológico , Edaravone/administração & dosagem , Fibrinolíticos/administração & dosagem , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Doença Aguda , Administração Intravenosa , Adulto , Idoso , Circulação Cerebrovascular/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
6.
Medicine (Baltimore) ; 99(46): e21717, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181634

RESUMO

OBJECTIVE: To compare the effects of milrinone, sodium nitroprusside (SNP), and nitroglycerin (NTG) on induced hypotension, cerebral perfusion, and postoperative cognitive function in elderly patients undergoing spine surgery. METHODS: Sixty patients >60 years scheduled for lumbar fusion surgery were assigned to receive milrinone (group M), SNP (group S), or NTG (group N). The administration of the study drug was initiated immediately after perivertebral muscle retraction and was stopped after completion of interbody fusion. Target blood pressure was a decrease of 30% in systolic blood pressure from baseline or mean blood pressure of 60 to 65 mm Hg. The regional cerebral venous oxygen saturation (rSVO2), as a measure of cerebral perfusion, and the change in perioperative Mini-Mental State Examination (MMSE) score, as a measure of postoperative cognitive function, were assessed. RESULTS: During the administration of the study drug, the overall and lowest intraoperative rSVO2 values were significantly higher (P = .01 and P = .01, respectively), and the duration of rSVO2 <60% was shorter in group M than in the other groups (P = .03). In group M, intraoperative rSVO2 was not different from the basal value, whereas in groups S and N, rSVO2 was significantly lower than the basal value during the administration of the study drug, but then returned to the basal value after terminating the study drug. Basal MMSE scores were comparable among the 3 groups. The MMSE score on postoperative day 5 was higher in group M than the other groups. CONCLUSIONS: Milrinone used to induce hypotension resulted in better intraoperative cerebral perfusion and postoperative cognitive function compared to SNP and nitroglycerin.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Milrinona/uso terapêutico , Idoso , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Cognição/fisiologia , Feminino , Humanos , Região Lombossacral/cirurgia , Masculino , Milrinona/farmacologia , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Período Pós-Operatório , Estudos Prospectivos , República da Coreia
7.
Medicine (Baltimore) ; 99(38): e22004, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957318

RESUMO

BACKGROUND: Mannitol and hypertonic saline (HTS) are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their efficacy on the ICP has not been evaluated rigorously. OBJECTIVE: To evaluate the efficacy of repeated bolus dosing of HTS and mannitol in similar osmotic burdens to treat intracranial hypertension (ICH) in patients with severe TBI. METHODS: The authors used an alternating treatment protocol to evaluate the efficacy of HTS with that of mannitol given for ICH episodes in patients treated for severe TBI at their hospital during 2017 to 2019. Doses of similar osmotic burdens (20% mannitol, 2 ml/kg, or 10% HTS, 0.63 ml/kg, administered as a bolus via a central venous catheter, infused over 15 minutes) were given alternately to the individual patient with severe TBI during ICH episodes. The choice of osmotic agents for the treatment of the initial ICH episode was determined on a randomized basis; osmotic agents were alternated for every subsequent ICH episode in each individual patient. intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were continuously monitored between the beginning of each osmotherapy and the return of ICP to 20 mm Hg. The duration of the effect of ICP reduction (between the beginning of osmotherapy and the return of ICP to 20 mm Hg), the maximum reduction of ICP and its time was recorded after each dose. Serum sodium and plasma osmolality were measured before, 0.5 hours and 3 hours after each dose. Adverse effects such as central pontine myelinolysis (CPM), severe fluctuations of serum sodium and plasma osmolality were assessed to evaluate the safety of repeated dosing of HTS and mannitol. RESULTS: Eighty three patients with severe TBI were assessed, including 437 ICH episodes, receiving 236 doses of HTS and 221 doses of mannitol totally. There was no significant difference between equimolar HTS and mannitol boluses on the magnitude of ICP reduction, the duration of effect, and the time to lowest ICP achieved (P > .05). The proportion of efficacious boluses was higher for HTS than for mannitol (P = .016), as was the increase in serum sodium (P = .038). The serum osmolality increased immediately after osmotherapy with a significant difference (P = .017). No cases of CPM were detected. CONCLUSION: Repeat bolus dosing of 10% HTS and 20% mannitol appears to be significantly and similarly effective for treating ICH in patients with severe TBI. The proportion of efficacious doses of HTS on ICP reduction may be higher than mannitol.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Diuréticos Osmóticos/uso terapêutico , Hipertensão Intracraniana/tratamento farmacológico , Hipertensão Intracraniana/etiologia , Manitol/uso terapêutico , Solução Salina Hipertônica/uso terapêutico , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Diuréticos Osmóticos/administração & dosagem , Diuréticos Osmóticos/efeitos adversos , Feminino , Humanos , Pressão Intracraniana/efeitos dos fármacos , Masculino , Manitol/administração & dosagem , Manitol/efeitos adversos , Pessoa de Meia-Idade , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/efeitos adversos , Índices de Gravidade do Trauma
8.
PLoS One ; 15(9): e0238224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881886

RESUMO

OBJECTIVE: We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p≤ 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling. METHODS: Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls. RESULTS: Following L-Arg, there was restoration of serum Arg (76-230 µM) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg. CONCLUSION: Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state. CLASSIFICATION OF EVIDENCE: This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus. CLINICAL TRIALS.GOV (NIH): NCT01603446.


Assuntos
Arginina/uso terapêutico , Circulação Cerebrovascular/fisiologia , Síndrome MELAS/tratamento farmacológico , Acoplamento Neurovascular/fisiologia , Administração Oral , Adolescente , Arginina/sangue , Arginina/farmacologia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Dióxido de Carbono/sangue , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Acoplamento Neurovascular/efeitos dos fármacos , Ornitina/sangue , Oxigênio/sangue , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Córtex Visual/efeitos dos fármacos , Adulto Jovem
9.
J Stroke Cerebrovasc Dis ; 29(10): 105168, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912520

RESUMO

BACKGROUND AND PURPOSE: Isolated Sulcal Effacement (ISE) is focal cortical swelling without obscuration of cortical gray-white junction. The available information on its role in acute stroke patients treated with intravenous (IV) tissue plasminogen activator (tPA) is limited. METHODS: ISE along with ASPECT and rLMC collateral score were determined in pre-treatment CT/CT angiography of 195 consecutive acute stroke patients treated with IV tPA "only". In addition, ISE-ASPECT score was created. Role of ISE on responsiveness to IV tPA, thrombolysis-associated hemorrhage and functional outcome were studied in 102 patients with CT-angiography-confirmed anterior system proximal vessel occlusion. RESULTS: ISE was observed in 12 patients (6.2% of all and 11.4% of those with occlusion of the carotid terminus, M1, or proximal M2) corresponding to excellent specificity (100%) but fair sensitivity (12%) for diagnosis of anterior cerebral circulation proximal artery occlusion. ISE ASPECT score was significantly correlated with rLMC score (p=0.023). Presence of ISE was linked to younger age, female gender, lower NIHSS, along with higher ASPECT and rLMC scores. Albeit not persisted after adjustment for collateral status and NIHSS, dramatic response to IV tPA along with excellent (23% vs. 8%, p<0.05), good (21% vs. 6%, p<0.05) and acceptable (19% vs. 4%, p<0.05) functional outcome were significantly higher in patients with ISE. CONCLUSIONS: As a plain CT marker of sufficient collateral status and increased cerebral blood volume, ISE indicates a better response to IV tPA. However, it should be noted that this relatively rare CT finding is highly specific for cerebral large vessel occlusions amenable neurothrombectomy.


Assuntos
Edema Encefálico/etiologia , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/fisiopatologia , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Bases de Dados Factuais , Avaliação da Deficiência , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/efeitos adversos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
Stroke ; 51(9): 2834-2843, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772681

RESUMO

BACKGROUND AND PURPOSE: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. METHODS: Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. RESULTS: In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm3, P<0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. CONCLUSIONS: Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.


Assuntos
Circulação Colateral/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Fibrinolíticos/farmacologia , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/patologia , Fluxometria por Laser-Doppler , Masculino , Meninges/irrigação sanguínea , Meninges/diagnóstico por imagem , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reperfusão
11.
Br J Anaesth ; 125(4): 539-547, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32718724

RESUMO

BACKGROUND: Patients undergoing cerebral bypass surgery are prone to cerebral hypoperfusion. Currently, arterial blood pressure is often increased with vasopressors to prevent cerebral ischaemia. However, this might cause vasoconstriction of the graft and cerebral vasculature and decrease perfusion. We hypothesised that cardiac output, rather than arterial blood pressure, is essential for adequate perfusion and aimed to determine whether dobutamine administration resulted in greater graft perfusion than phenylephrine administration. METHODS: This randomised crossover study included 10 adult patients undergoing cerebral bypass surgery. Intraoperatively, patients randomly and sequentially received dobutamine to increase cardiac index or phenylephrine to increase mean arterial pressure (MAP). An increase of >10% in cardiac index or >10% in MAP was targeted, respectively. Before both interventions, a reference phase was implemented. The primary outcome was the absolute difference in graft flow between the reference and intervention phase. We compared the absolute flow difference between each intervention and constructed a random-effect linear regression model to explore treatment and carry-over effects. RESULTS: Graft flow increased with a median of 4.1 (inter-quartile range [IQR], 1.7-12.0] ml min-1) after dobutamine administration and 3.6 [IQR, 1.3-7.8] ml min-1 after phenylephrine administration (difference -0.6 ml min-1; 95% confidence interval [CI], -14.5 to 5.3; P=0.441). There was no treatment effect (0.9 ml min-1; 95% CI, 0.0-20.1; P=0.944) and no carry-over effect. CONCLUSIONS: Both dobutamine and phenylephrine increased graft flow during cerebral bypass surgery, without a preference for one method over the other. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register, NL7077 (https://www.trialregister.nl/trial/7077).


Assuntos
Revascularização Cerebral/métodos , Circulação Cerebrovascular/efeitos dos fármacos , Dobutamina/farmacologia , Fenilefrina/farmacologia , Adulto , Pressão Arterial/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
PLoS One ; 15(7): e0235084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614837

RESUMO

Hemorrhagic shock is one of the leading causes of mortality and morbidity in pediatric trauma. Current treatment based on volume resuscitation is associated to adverse effects, and it has been proposed that vasopressors may be used in the pharmacological management of trauma. Terlipressin has demonstrated its usefulness in other pediatric critical care scenarios and its long half-life allows its use as a bolus in an outpatient critical settings. The aim of this study was to analyze whether the addition of a dose of terlipressin to the initial volume expansion produces an improvement in hemodynamic and cerebral perfusion at early stages of hemorrhagic shock in an infant animal model. We conducted an experimental randomized animal study with 1-month old pigs. After 30 minutes of hypotension (mean arterial blood pressure [MAP]<45 mmHg) induced by the withdrawal of blood over 30 min, animals were randomized to receive either normal saline (NS) 30 mL/kg (n = 8) or a bolus of 20 mcg/kg of terlipressin plus 30 mL/kg of normal saline (TP) (n = 8). Global hemodynamic and cerebral monitoring parameters, brain damage markers and histology samples were compared. After controlled bleeding, significant decreases were observed in MAP, cardiac index (CI), central venous pressure, global end-diastolic volume index (GEDI), left cardiac output index, SvO2, intracranial pressure, carotid blood flow, bispectral index (BIS), cerebral perfusion pressure (CPP) and increases in systemic vascular resistance index, heart rate and lactate. After treatment, MAP, GEDI, CI, CPP and BIS remained significantly higher in the TP group. The addition of a dose of terlipressin to initial fluid resuscitation was associated with hemodynamic improvement, intracranial pressure maintenance and better cerebral perfusion, which would mean protection from ischemic injury. Brain monitoring through BIS was able to detect changes caused by hemorrhagic shock and treatment.


Assuntos
Hemodinâmica/efeitos dos fármacos , Solução Salina/uso terapêutico , Choque Hemorrágico/terapia , Terlipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Animais , Animais Recém-Nascidos , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Hidratação , Masculino , Ressuscitação , Choque Hemorrágico/sangue , Choque Hemorrágico/fisiopatologia , Suínos
13.
Am J Obstet Gynecol ; 223(3): 441.e1-441.e8, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544404

RESUMO

BACKGROUND: Pregnant women with preeclampsia have been found to have elevated cerebral perfusion pressure and impaired cerebral autoregulation compared with normal pregnant women. Transcranial Doppler is a noninvasive technique used to estimate cerebral perfusion pressure. The effects of different antihypertensive medications on cerebral perfusion pressure in preeclampsia are unknown. OBJECTIVE: To compare the change in cerebral perfusion pressure before and after intravenous labetalol vs oral nifedipine in the setting of acute severe hypertension in pregnancy. STUDY DESIGN: This is a prospective cohort study of pregnant women between 24 and 42 weeks' gestation with severe hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg). Women who consented to the study and received either intravenous labetalol or oral nifedipine were included. Exclusion criteria included active labor or receipt of any antihypertensive medication within 2 hours of initial cerebral perfusion pressure measurement. Peripheral blood pressure and transcranial Doppler studies for middle cerebral artery hemodynamics were performed prior to the administration of antihypertensive medications and repeated 30 minutes after medication administration. RESULTS: A total of 16 women with acute severe hypertension were enrolled; 8 received intravenous labetalol and 8 received oral nifedipine. There were no significant differences between the labetalol and nifedipine groups in baseline characteristics such as maternal age, race and ethnicity, payment, hospital site, body mass index, nulliparity, gestational age, preexisting diabetes mellitus or chronic hypertension, fetal growth restriction, magnesium sulfate administration, and symptomatology (P>.05). When examined 30 minutes after the administration of either intravenous labetalol or oral nifedipine, there was a significantly greater decrease in systolic blood pressure (-9.8 mm Hg vs -39 mm Hg; P=.003), mean arterial pressure (-7.1 mm Hg vs -22.3 mm Hg; P=.02), and cerebral perfusion pressure (-2.5 mm Hg vs -27.7 mm Hg; P=.01) in the nifedipine group. There was no statistically significant decrease in diastolic blood pressure (-12.9 mm Hg vs -5.4 mm Hg; P=.15). The change in middle cerebral artery velocity by transcranial Doppler was compared between the groups and was not different (0.07 cm/s vs 0.16 cm/s; P=.64). CONCLUSION: Oral nifedipine resulted in a significant decrease in cerebral perfusion pressure, whereas labetalol did not, after administration for acute severe hypertension among women with preeclampsia. This decrease seems to be driven by a decrease in peripheral arterial blood pressure rather than a direct change in cerebral blood flow.


Assuntos
Anti-Hipertensivos/administração & dosagem , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Labetalol/administração & dosagem , Nifedipino/administração & dosagem , Administração Oral , Adulto , Anti-Hipertensivos/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Estudos de Coortes , Feminino , Humanos , Infusões Intravenosas , Labetalol/farmacologia , Nifedipino/farmacologia , Gravidez , Cuidado Pré-Natal , Estudos Prospectivos , Ultrassonografia Doppler Transcraniana
14.
Anesthesiology ; 133(2): 304-317, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32482999

RESUMO

BACKGROUND: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine. METHODS: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation. RESULTS: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 µmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] µmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 µmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] µmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups. CONCLUSIONS: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.


Assuntos
Anestesia/tendências , Neoplasias Encefálicas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Efedrina/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Fenilefrina/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Circulação Cerebrovascular/fisiologia , Método Duplo-Cego , Efedrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Fenilefrina/farmacologia , Estudos Prospectivos , Resultado do Tratamento , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
15.
J Vasc Res ; 57(4): 178-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434183

RESUMO

BACKGROUND: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. OBJECTIVE: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel (20-60 µm in 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 (43 of 80 veins with O2 saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O2 extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O2 saturations in the reperfused region (76 of 80 veins with O2 saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). CONCLUSION: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Lisofosfolipídeos/toxicidade , Microcirculação/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Traumatismo por Reperfusão/patologia , Animais , Morte Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Veias Cerebrais/efeitos dos fármacos , Veias Cerebrais/patologia , Veias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/fisiopatologia
16.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R33-R42, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401627

RESUMO

Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) (P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) (P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) (P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.


Assuntos
Circulação Cerebrovascular/fisiologia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/efeitos dos fármacos , Nitroglicerina/farmacologia , Análise de Onda de Pulso , Ultrassonografia Doppler em Cores , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Adulto Jovem
17.
AJNR Am J Neuroradiol ; 41(5): 785-791, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32299799

RESUMO

BACKGROUND AND PURPOSE: Dynamic changes in cerebrovascular reactivity after acetazolamide administration vary markedly among patients with major cerebral arterial steno-occlusive disease. MR quantitative susceptibility mapping can dynamically quantify the cerebral magnetic susceptibility. The purpose of this study was to determine whether dynamic changes in susceptibility after administration of acetazolamide on 7T quantitative susceptibility mapping are associated with pre-existing states of CBV and the cerebral metabolic rate of oxygen in the cerebral hemispheres with major cerebral arterial steno-occlusive disease. MATERIALS AND METHODS: Sixty-five patients underwent 7T MR imaging at baseline and at 5, 10, 15, and 20 minutes after acetazolamide administration. Differences between the susceptibility of venous structures and surrounding brain tissue were calculated in the quantitative susceptibility mapping images. Susceptibility differences at 5, 10, 15, and 20 minutes after acetazolamide administration relative to baseline were calculated in 97 cerebral hemispheres with major cerebral arterial steno-occlusive disease. CBV and the cerebral metabolic rate of oxygen were also calculated using 15O-gas PET in the resting state. RESULTS: Dynamic changes of susceptibility after acetazolamide administration were classified into 3 patterns: abnormally increasing 5 or 10 minutes after acetazolamide administration; abnormally decreasing within 20 minutes after acetazolamide administration; and remaining unchanged after acetazolamide administration. CBV was significantly greater in the first pattern than in the latter 2. The cerebral metabolic rate of oxygen differed significantly in descending order from the first to middle to last pattern. CONCLUSIONS: Dynamic changes of susceptibility after acetazolamide administration on 7T MR quantitative susceptibility mapping are associated with pre-existing states of CBV and the cerebral metabolic rate of oxygen in major cerebral arterial steno-occlusive disease.


Assuntos
Acetazolamida/farmacologia , Doenças Arteriais Cerebrais/diagnóstico por imagem , Neuroimagem/métodos , Adulto , Idoso , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Tomografia por Emissão de Pósitrons
18.
Nutr Metab Cardiovasc Dis ; 30(4): 625-633, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32127335

RESUMO

BACKGROUND AND AIMS: Chronic conditions such as obesity, which contribute to endothelial dysfunction in older adults, can cause impairments in cerebrovascular perfusion, which is associated with accelerated cognitive decline. Supplementing the diet with bioactive nutrients that can enhance endothelial function, such as fish oil or curcumin, may help to counteract cerebrovascular dysfunction. METHODS AND RESULTS: A 16-week double-blind, randomized placebo-controlled trial was undertaken in 152 older sedentary overweight/obese adults (50-80 years, body mass index: 25-40 kg/m2) to investigate effects of fish oil (2000 mg docosahexaenoic acid + 400 mg eicosapentaenoic acid/day), curcumin (160 mg/day) or a combination of both on cerebrovascular function (measured by Transcranial Doppler ultrasound), systemic vascular function (blood pressure, heart rate and arterial compliance) and cardiometabolic (fasting glucose and blood lipids) and inflammatory (C-reactive protein) biomarkers. The primary outcome, cerebrovascular responsiveness to hypercapnia, was not affected by the interventions. However, cerebral artery stiffness was significantly reduced in males following fish oil supplementation (P = 0.007). Furthermore, fish oil reduced heart rate (P = 0.038) and serum triglycerides (P = 0.006) and increased HDL cholesterol (P = 0.002). Curcumin did not significantly affect these outcomes either alone or in combination with fish oil. CONCLUSION: Regular supplementation with fish oil but not curcumin improved biomarkers of cardiovascular and cerebrovascular function. The combined supplementation did not result in additional benefits. Further studies are warranted to identify an efficacious curcumin dose and to characterize (in terms of sex, BMI, cardiovascular and metabolic risk factors) populations whose cerebrovascular and cognitive functions might benefit from either intervention. CLINICAL TRIAL REGISTRATION: ACTRN12616000732482p.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Curcumina/administração & dosagem , Suplementos Nutricionais , Óleos de Peixe/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Obesidade/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Sistema Cardiovascular/fisiopatologia , Curcumina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Método Duplo-Cego , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Óleos de Peixe/efeitos adversos , Nível de Saúde , Humanos , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , New South Wales , Obesidade/diagnóstico , Obesidade/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
19.
Nat Commun ; 11(1): 1160, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127545

RESUMO

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Ocitocina/administração & dosagem , Administração Intranasal , Administração Intravenosa , Adulto , Tonsila do Cerebelo/irrigação sanguínea , Encéfalo/irrigação sanguínea , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética , Masculino , Nebulizadores e Vaporizadores , Ocitocina/sangue , Ocitocina/farmacocinética , Placebos , Adulto Jovem
20.
Lancet Diabetes Endocrinol ; 8(4): 325-336, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135131

RESUMO

Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Depressão/etiologia , Diabetes Mellitus Tipo 2/complicações , Microcirculação/efeitos dos fármacos , Acidente Vascular Cerebral/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
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