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1.
Expert Opin Pharmacother ; 21(1): 97-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675255

RESUMO

Introduction: Bacterial meningitis (BM) is a medical emergency and its etiology varies according to the age group and geographic area. Studies have shown that brain damage, sequelae and neuropsychological deficits depend not only on the direct deleterious action of the pathogens, but also on the host defenses themselves.Areas covered: Corticosteroids (CS) were the first drugs used with the intent to limit the exaggerated host response. However, as steroid addition to antibiotics is frequently unsatisfactory, other measures have been suggested. In this study, the most important adjuvant therapies that are potentially useful to limit the neuropsychological damage of BM are discussed.Expert opinion: The pathophysiological mechanisms leading to the development of brain damage are not completely defined. Moreover, the efficacy of adjuvant therapies can vary according to the aetiologic cause of BM, and differences in immune system function of the host can play a relevant role in the expression of inflammation and related problems. It is likely that none of the measures with demonstrated efficacy in animal models can be translated into clinical practice in the next few years, suggesting that to reduce the total burden of BM, the increased use of vaccines seems to be the best solution.


Assuntos
Antibacterianos/uso terapêutico , Lesões Encefálicas/prevenção & controle , Meningites Bacterianas/tratamento farmacológico , Corticosteroides/uso terapêutico , Animais , Encéfalo/patologia , Humanos , Inflamação/tratamento farmacológico
2.
Orv Hetil ; 160(46): 1832-1839, 2019 Nov.
Artigo em Húngaro | MEDLINE | ID: mdl-31707820

RESUMO

Post-resuscitation brain injury forms the leading cause of death of patients after successful cardiopulmonary resuscitation that explains why post-resuscitation neuroprotection is the most important part of post-resuscitation therapy. The goals of the neuroprotection tools available today are preventing the evolution of primary and formation of secondary brain injury. We are going to summarize the neuroprotective possibilities that we can reach today. We will discuss the role of pharmacologic strategies including sedation, the modalities of upholding brain perfusion, the monitoring of proper hemodynamic variables and the practice of targeted temperature management. It is very important to avoid hypo- and hyperoxia, to keep normocapnia, normoglycemia and to control seizures during the management of post-cardiac arrest patients. There is still a lack of evidence to prove which pharmacologic agent may be effective in postresuscitation neuroprotection, however, there are some promising results regarding thiamine. Hemodynamic management guided by higher level hemodynamic monitoring may be beneficial in enhancing brain perfusion but more clinical studies are needed to investigate its usefulness. Targeted temperature management constitutes the main element of post-resuscitation neuroprotection, however, the details of its implementation raise several questions. Orv Hetil. 2019; 160(46): 1832-1839.


Assuntos
Lesões Encefálicas/prevenção & controle , Reanimação Cardiopulmonar/métodos , Parada Cardíaca/terapia , Hipotermia Induzida/métodos , Neuroproteção , Parada Cardíaca/complicações , Humanos , Fármacos Neuroprotetores/uso terapêutico
3.
Med Hypotheses ; 130: 109276, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383320

RESUMO

Cancer is the second cause of death worldwide, but current therapies are often insufficient or linked with toxicity. Initial evidence in scientific literature seems to support the role of non-pharmacological strategies, including hypoglycemia, in cancer treatment. The biological rationale for hypoglycemia-based treatment of cancer resides in the evidence that cancer cells predominantly utilize glucose as an energy source; notably, cancer cells seem to have damaged glycolysis regulation and few, defective mitochondria showing impaired oxidative phosphorylation. Preliminary data arising from both preclinical and human studies support the role of hypoglycemia in inducing apoptosis on cancer cells. In this paper, we describe how to induce and maintain severe hypoglycemia without causing damage to either the brain or the heart. Our hypothesis is that ExtraCorporeal Membrane Oxygenation (ECMO) and selective glucose perfusion of the carotid vessels are able to maintain severe hypoglycemia without causing cardiac or brain damage. This will allow physicians to study the effect of severe hypoglycemia on cancer cell apoptosis in vivo.


Assuntos
Lesões Encefálicas/prevenção & controle , Cardiopatias/prevenção & controle , Hipoglicemia/fisiopatologia , Neoplasias/terapia , Animais , Apoptose , Glicemia/análise , Encéfalo/metabolismo , Artérias Carótidas/fisiopatologia , Oxigenação por Membrana Extracorpórea , Glucose/metabolismo , Glicólise , Humanos , Mitocôndrias/metabolismo , Modelos Teóricos , Neoplasias/fisiopatologia , Fosforilação Oxidativa , Segurança do Paciente , Perfusão
4.
Mol Med Rep ; 20(2): 1837-1845, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257533

RESUMO

Hypoxic preconditioning (HPC) is neuroprotective against ischaemic brain injury; however, the roles of potential anti­apoptotic signals in this process have not been assessed. To elucidate the molecular mechanisms involved in HPC­induced neuroprotection, the effects of HPC on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element­binding protein (CREB) signalling pathway and apoptosis in Sprague­Dawley pups (postnatal day 7) treated with propofol were investigated. Western blot and histological analyses demonstrated that HPC exerts multiple effects on the hippocampus, including the upregulation of cAMP and phosphorylation of CREB. These effects were partially blocked by intracerebroventricular injection of the protein kinase antagonist H89 (5 µmol/5 µl). Notably, the level of cleaved caspase­3 was significantly downregulated by treatment with the cAMP agonist Sp­cAMP (20 nmol/5 µl). The results indicate that propofol increased the level of cleaved caspase­3 and Bax by suppressing the activity of cAMP­dependent proteins and Bcl­2; thus, HPC prevents propofol from triggering apoptosis via the cAMP/PKA/CREB signalling pathway.


Assuntos
Lesões Encefálicas/terapia , Precondicionamento Isquêmico/métodos , Neurônios/metabolismo , Neuroproteção/genética , Animais , Animais Recém-Nascidos , Apoptose/genética , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , AMP Cíclico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Neurônios/patologia , Fosforilação/genética , Propofol/toxicidade , Ratos , Transdução de Sinais/genética , Lobo Temporal/metabolismo , Lobo Temporal/patologia
5.
Brain Struct Funct ; 224(7): 2281-2295, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278571

RESUMO

There is a widespread belief that neurogenesis exists in adult human brain, especially in the dentate gyrus, and it is to be maintained and, if possible, augmented with different stimuli including exercise and certain drugs. Here, we examine the evidence for adult human neurogenesis and note important limitations of the methodologies used to study it. A balanced review of the literature and evaluation of the data indicate that adult neurogenesis in human brain is improbable. In fact, in several high-quality recent studies in adult human brain, unlike in adult brains of other species, neurogenesis was not detectable. These findings suggest that the human brain requires a permanent set of neurons to maintain acquired knowledge for decades, which is essential for complex high cognitive functions unique to humans. Thus, stimulation and/or injection of neural stem cells into human brains may not only disrupt brain homeostatic systems, but also disturb normal neuronal circuits. We propose that the focus of research should be the preservation of brain neurons by prevention of damage, not replacement.


Assuntos
Diferenciação Celular/fisiologia , Transtornos Mentais/terapia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Lesões Encefálicas/prevenção & controle , Humanos
6.
Neurol India ; 67(3): 763-769, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347551

RESUMO

Background: White matter (WM) transgression is an unexplored concept in neuroendoscopy. Diffusion tensor image (DTI) tractography could be implemented as a planning and postoperative evaluation tool in functional disconnection procedures (FDPs), which are, currently, the subject of technological innovations. We intend to prove the usefulness of this planning method focused on the assessment of WM injury that is suitable for planning FDPs. Methods: Ten cranial magnetic resonance studies (20 sides) without pathological findings were processed. Fascicles were defined by two regions of interest (ROIs) using the fiber assignment method by the continuous tracking approach. Using three-dimensional (3D) simulation and DTI tractography, we created an 8-mm virtual endoscope and an uninjured inferior fronto-occipital fasciculus (IFOF) from two ROIs. The injured tract was generated using a third ROI built from the 3D model of the intersection of the oriented trajectory of the endoscope with the fascicle. Data and images were quantitatively and qualitatively analyzed. Results: The average percentage of the injured fibers was 32.0% (range: 12.4%-70%). The average intersected volume was 1.1 cm3 (range: 0.3-2.3 cm3). Qualitative analysis showed the inferior medial quadrant of the inferior fronto-occipital fasciculus (IFOF) as the most frequently injured region. No hemispherical asymmetry was found (P > 0.5). Conclusion: DTI tractography is a useful surgical planning tool that could be implemented in several endoscopic procedures. Together with a functional atlas, the presented technique provides a noninvasive method to assess the potential sequelae and thus to optimize the surgical route. The suggested method could be implemented to analyze pathological WM fascicles and to assess the surgical results of FDP such as hemispherotomy or amygdalohippocampectomy. More studies are needed to overcome the limitations of the tractography based information and to develop more anatomically and functionally reliable planning systems.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/prevenção & controle , Imagem de Tensor de Difusão , Neuroendoscopia/efeitos adversos , Lesões Encefálicas/etiologia , Humanos , Vias Neurais/diagnóstico por imagem , Vias Neurais/lesões , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Cuidados Pré-Operatórios , Período Pré-Operatório , Treinamento por Simulação , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/lesões
7.
Inflammation ; 42(5): 1830-1842, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230155

RESUMO

Salidroside, an active constituent of Rhodiola rosea, is neuroprotective after transient middle cerebral artery occlusion (tMCAO). However, its effects in other experimental stroke models are less understood. Here, we investigated the effect of daily intraperitoneal injections of salidroside in rats after permanent MCAO (pMCAO). Cerebral infarct volumes at 1 day after pMCAO were significantly reduced by treatment with 100 mg/kg/day salidroside, but not by 25 or 50 mg/kg/day, and this benefit of salidroside increased significantly over at least 7 days of treatment, when it was also accompanied by decreased neurological deficit scores. These observations led us to investigate the underlying mechanism of action of salidroside. 100 mg/kg salidroside for 1 day increased NeuN, Nrf2, and its downstream mediator HO-1, while it reduced nuclear NFκB p50, IL-6, and TNFα. Brusatol, a Nrf2 inhibitor, blocked the actions of salidroside on Nrf2, NFκB p50, IL-6, and TNFα. Salidroside also increased the ratio of p-PKB/PKB at 1 day after pMCAO even in the presence of brusatol. LY294002, a PI3K inhibitor, prevented all these effects of salidroside, including those on NeuN, p-PKB/PKB, Nrf2, HO-1, and pro-inflammatory mediators. In contrast, salidroside had no significant effect on the level of cerebral complement C3 after pMCAO, or on the activity of C3 as measured by the expression of cerebral Egr1. Our findings therefore suggest that salidroside reduces neuroinflammation and neural damage by regulating the PI3K/PKB/Nrf2/NFκB signaling pathway after pMCAO, and that this neuroprotective effect does not involve modulation of complement C3 activity.


Assuntos
Lesões Encefálicas/prevenção & controle , Complemento C3/metabolismo , Glucosídeos/farmacologia , Inflamação/prevenção & controle , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Isquemia Encefálica/prevenção & controle , Glucosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção/efeitos dos fármacos , Fenóis/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Ratos
8.
Khirurgiia (Mosk) ; (5): 57-63, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31169820

RESUMO

AIM: To study the effectiveness of intraoperative administration of Cytoflavine for the prevention of ischemic brain injury during cerebral aneurysm (CA) clipping with temporary occlusion of the leading artery under general anesthesia. MATERIAL AND METHODS: The prospective cohort single-center study included 40 patients with CA ( the main group - 27 patients with intraoperative administration of cytoflavine; the comparison group -13 patients without use of cytoflavine), who underwent aneurism clipping with temporary occlusion of the afferent artery. We assesed the intraoperative state of the brain, the time of awakening and extubation of patients after surgery, neurological deficit and local ischemic changes in the area of surgery according to the CT of the brain in the early postoperative period, resuscitation bed-day and the relationship of these indicators with the duration of temporary occlusion of the afferent artery in the selected groups of patients. RESULTS: In intergroup comparison, patients of the main group treated with intraoperative cytoflavin showed a reduction in the time of awakening (p=0.013) and the time of extubation (p=0.01) both with temporary occlusion of the afferent artery and in patients without temporary occlusion (p<0.05). The duration of resuscitation bed-day decreased in the main group of patients receiving intraoperatively cytoflavine (p=0.01), as well as in patients in the comparison group without temporary occlusion (p<0.05). CONCLUSION: Temporary occlusion of the afferent artery with short intervals of vessel occlusion in combination with intraoperative intravenous administration of cytoflavine expands the tolerability to artery occlusion in patients operated in the 'cold' period, reduces the possibility of neurological deficit, reduces the recovery period and resuscitation bed-day after surgical clipping CA.


Assuntos
Lesões Encefálicas/prevenção & controle , Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Aneurisma Intracraniano/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Procedimentos Neurocirúrgicos/efeitos adversos , Niacinamida/administração & dosagem , Succinatos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Lesões Encefálicas/etiologia , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/cirurgia , Isquemia Encefálica/etiologia , Isquemia Encefálica/cirurgia , Combinação de Medicamentos , Mononucleotídeo de Flavina/farmacologia , Humanos , Inosina Difosfato/farmacologia , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/cirurgia , Cuidados Intraoperatórios , Fármacos Neuroprotetores/farmacologia , Procedimentos Neurocirúrgicos/métodos , Niacinamida/farmacologia , Estudos Prospectivos , Succinatos/farmacologia , Técnicas de Sutura
9.
J Pharmacol Sci ; 140(2): 193-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31235271

RESUMO

We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion.


Assuntos
Benzimidazóis/administração & dosagem , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Bloqueadores dos Canais de Cálcio/administração & dosagem , Ciclopropanos/administração & dosagem , Infarto da Artéria Cerebral Média/complicações , Naftalenos/administração & dosagem , Traumatismo por Reperfusão/complicações , Animais , Benzimidazóis/metabolismo , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo T/fisiologia , Ciclopropanos/metabolismo , Infusões Intraventriculares , Infusões Parenterais , Masculino , Camundongos Endogâmicos , Naftalenos/metabolismo , Fatores de Tempo
10.
Neuroscience ; 410: 239-253, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121260

RESUMO

Excitotoxicity plays an important role in the pathogenesis of developing brain injury. The neuropeptide secretoneurin (SN) has neuroprotective potential. The aim of this study was to investigate SN plasma concentrations following excitotoxicity and to evaluate the effect of SN as therapeutic strategy in excitotoxic newborn brain injury. Baseline SN plasma concentrations were established in healthy animals. To evaluate the effect of an excitotoxic insult on SN levels, mice pups were subjected to an intracranial injection of ibotenic acid and SN plasma concentrations were measured thereafter. To assess SN's neuroprotective potential, a subgroup of animals was randomly assigned to the following groups: i) "single treatment": vehicle 1× phosphate-buffered saline (PBS), SN 0.25 µg/g body weight (bw), SN 2.5 µg/g bw or SN 12.5 µg/g bw in a single dose 1 h after insult; ii) "acute repetitive treatment": vehicle 1× PBS or SN 0.25 µg/g bw every 24 h starting 1 h after insult; iii) "delayed repetitive treatment": vehicle 1× PBS or SN 0.25 µg/g bw every 24 h starting 60 h after insult. Animals subjected to excitotoxic injury showed significantly lower SN plasma concentrations 6 and 120 h after insult in comparison to healthy controls. Administration of SN did not positively affect lesion size, apoptotic cell death, microglial cell activation or cell proliferation. To conclude, endogenous SN plasma levels are lower in newborn mice subjected to an excitotoxic insult than in healthy controls. Supplementation with SN in various treatment regimens is not neuroprotective in the experimental animal model of excitotoxic newborn brain injury.


Assuntos
Lesões Encefálicas/sangue , Lesões Encefálicas/prevenção & controle , Ácido Ibotênico/toxicidade , Neuropeptídeos/sangue , Neuropeptídeos/uso terapêutico , Neurotoxinas/toxicidade , Secretogranina II/sangue , Secretogranina II/uso terapêutico , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Lesões Encefálicas/induzido quimicamente , Camundongos , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Distribuição Aleatória
12.
JAMA ; 321(17): 1677-1685, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063573

RESUMO

Importance: Therapeutic hypothermia may increase survival with good neurologic outcome after cardiac arrest. Trans-nasal evaporative cooling is a method used to induce cooling, primarily of the brain, during cardiopulmonary resuscitation (ie, intra-arrest). Objective: To determine whether prehospital trans-nasal evaporative intra-arrest cooling improves survival with good neurologic outcome compared with cooling initiated after hospital arrival. Design, Setting, and Participants: The PRINCESS trial was an investigator-initiated, randomized, clinical, international multicenter study with blinded assessment of the outcome, performed by emergency medical services in 7 European countries from July 2010 to January 2018, with final follow-up on April 29, 2018. In total, 677 patients with bystander-witnessed out-of-hospital cardiac arrest were enrolled. Interventions: Patients were randomly assigned to receive trans-nasal evaporative intra-arrest cooling (n = 343) or standard care (n = 334). Patients admitted to the hospital in both groups received systemic therapeutic hypothermia at 32°C to 34°C for 24 hours. Main Outcomes and Measures: The primary outcome was survival with good neurologic outcome, defined as Cerebral Performance Category (CPC) 1-2, at 90 days. Secondary outcomes were survival at 90 days and time to reach core body temperature less than 34°C. Results: Among the 677 randomized patients (median age, 65 years; 172 [25%] women), 671 completed the trial. Median time to core temperature less than 34°C was 105 minutes in the intervention group vs 182 minutes in the control group (P < .001). The number of patients with CPC 1-2 at 90 days was 56 of 337 (16.6%) in the intervention cooling group vs 45 of 334 (13.5%) in the control group (difference, 3.1% [95% CI, -2.3% to 8.5%]; relative risk [RR], 1.23 [95% CI, 0.86-1.72]; P = .25). In the intervention group, 60 of 337 patients (17.8%) were alive at 90 days vs 52 of 334 (15.6%) in the control group (difference, 2.2% [95% CI, -3.4% to 7.9%]; RR, 1.14 [95% CI, 0.81-1.57]; P = .44). Minor nosebleed was the most common device-related adverse event, reported in 45 of 337 patients (13%) in the intervention group. The adverse event rate within 7 days was similar between groups. Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, trans-nasal evaporative intra-arrest cooling compared with usual care did not result in a statistically significant improvement in survival with good neurologic outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01400373.


Assuntos
Lesões Encefálicas/prevenção & controle , Serviços Médicos de Emergência , Hipotermia Induzida/métodos , Parada Cardíaca Extra-Hospitalar/terapia , Idoso , Encéfalo/fisiopatologia , Lesões Encefálicas/etiologia , Reanimação Cardiopulmonar/métodos , Epistaxe/etiologia , Feminino , Humanos , Hipotermia Induzida/efeitos adversos , Hipotermia Induzida/instrumentação , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/complicações , Parada Cardíaca Extra-Hospitalar/mortalidade , Tamanho da Amostra , Método Simples-Cego , Taxa de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento
13.
J Thorac Cardiovasc Surg ; 157(6): 2406-2413.e2, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981520

RESUMO

OBJECTIVE: There is considerable variability in anticoagulation use in neonates with transposition of the great arteries (TGA) and single ventricle physiology (SVP) for secondary stroke prevention and primary cardiovascular indications. Leveraging cross-center differences in anticoagulation use, we compared the risk of new postoperative brain injury in neonates with TGA and SVP treated with anticoagulation relative to untreated neonates. METHODS: Two-center observational cohort study of 118 term-born neonates with TGA (n = 83) and SVP (n = 35), undergoing cardiopulmonary bypass surgery and pre- and postoperative brain magnetic resonance imaging. Anticoagulation and antiplatelet therapy details were obtained. Magnetic resonance images were scored for stroke, white matter injury, and hemorrhage. New postoperative injury was compared between neonates with and without anticoagulation for the 2-center cohort, and subsequently stratified by cardiac lesion type and anticoagulation indication. RESULTS: Thirty-six out of 118 neonates (29%) received anticoagulation: 11 (30%) for preoperative stroke, 20 (56%) for preoperative peripheral/intracardiac thrombus, and 5 (14%) for Blalock-Taussig shunt. Five out of 36 neonates (14%) treated with anticoagulation also received antiplatelet therapy. Although no differences were identified for the 2-center cohort or for neonates with TGA separately, significantly more new postoperative parenchymal brain injury (P = .04), particularly stroke, was found in SVP neonates with compared to without anticoagulation (31% vs 5%). In neonates who experienced preoperative stroke, new subdural hemorrhage (36% vs 0%) was more frequent in neonates treated with anticoagulation therapy compared with those without anticoagulation therapy. CONCLUSIONS: In our cohort of neonates with TGA and SVP, anticoagulation for preoperative stroke, preoperative thrombus, and/or Blalock-Taussig shunt did not have the anticipated benefit of preventing new perioperative brain injury. These findings indicate the critical need for rigorous randomized trials on the safety and effectiveness of anticoagulation therapy in this population.


Assuntos
Anticoagulantes/uso terapêutico , Lesões Encefálicas/prevenção & controle , Cardiopatias Congênitas/cirurgia , Encéfalo/diagnóstico por imagem , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Ponte Cardiopulmonar/efeitos adversos , Ponte Cardiopulmonar/métodos , Feminino , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Estudos Prospectivos , Transposição dos Grandes Vasos/cirurgia , /cirurgia
14.
J Int Med Res ; 47(4): 1677-1684, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30966831

RESUMO

OBJECTIVE: To study the brain protective effect of dexmedetomidine (DEX) during surgery in paediatric patients with congenital heart disease (CHD). METHODS: This randomized single-blind controlled study enrolled paediatric patients aged 0-3 years with CHD who underwent surgery and randomized them into two groups: one group received DEX and the control group received 0.9% NaCl during anaesthesia. Demographic data, heart rate (HR), mean arterial pressure (MAP) and central venous pressure (CVP) were recorded. Levels of neuron specific enolase (NES) and S-100ß protein were determined using enzyme-linked immunosorbent assays. RESULTS: The study enrolled 80 paediatric patients with CHD. Compared with the control group, HR, MAP and CVP were significantly lower in the DEX group at all time-points except for T0. At all time-points except for T0, the levels of jugular venous oxygen saturation in the DEX group were significantly higher compared with the control group. At all time-points except for T0, the levels of arterial venous difference and cerebral extraction of oxygen were significantly lower in the DEX group compared with the control group. Levels of NES and S-100ß protein in the DEX group were significantly lower compared with the control group at all time-points except for T0. CONCLUSION: DEX treatment during surgery for CHD improved oxygen metabolism in brain tissues and reduced the levels of NES and S-100ß protein.


Assuntos
Lesões Encefálicas/prevenção & controle , Encéfalo/efeitos dos fármacos , Dexmedetomidina/uso terapêutico , Cardiopatias Congênitas/cirurgia , Hipnóticos e Sedativos/uso terapêutico , Tratamentos com Preservação do Órgão , Substâncias Protetoras/uso terapêutico , Pré-Escolar , Feminino , Seguimentos , Cardiopatias Congênitas/tratamento farmacológico , Humanos , Masculino , Monitorização Intraoperatória , Prognóstico , Método Simples-Cego
15.
Neurochem Res ; 44(7): 1678-1689, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982205

RESUMO

Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality and disability rate. Mitochondria plays a crucial role in neuronal survival after ICH. This study first showed that activation of adiponectin receptor 1 (AdipoR1) by AdipoRon could attenuate mitochondrial dysfunction after ICH. In vivo, experimental ICH model was established by autologous blood injection in mice. AdipoRon was injected intraperitoneally (50 mg/kg). Immunofluorescence staining were performed to explicit the location of AdipoR1, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1a (PGC1α). The PI staining was used to quantify neuronal survival. The expression of AdipoR1 and its downstream signaling molecules were detected by Western blotting. In vitro, 10 µM oxyhemoglobin (OxyHb) was used to induce the neuronal injury in SH-SY5Y cells. Annexin V-FITC/PI staining was used to detect the neuronal apoptosis and necrosis. Mitochondrial membrane potential (Δψm) was measured by a JC-1 kit and mitochondrial mass was quantified by mitochondrial fluorescent probe. In vivo, PI staining showed that the administration of AdipoRon could reduce neuronal death at 72 h after ICH in mice. AdipoRon treatment enhanced ATP levels and reduced ROS levels in perihematoma tissues, and increased the protein expression of AdipoR1, P-AMPK, PGC1α, NRF1 and TFAM. In vitro, the JC-1 staining and Mito-tracker™ Green showed that AdipoRon significantly alleviated OxyHb-induced collapse of Δψm and enhanced mitochondrial mass. Moreover, flow cytometry analysis indicated that the neurons treated with AdipoRon showed low necrotic and apoptotic rate. AdipoRon alleviates mitochondrial dysfunction after intracerebral hemorrhage via the AdipoR1-AMPK-PGC1α pathway.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/prevenção & controle , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Necrose/tratamento farmacológico , Neurônios/patologia , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Adiponectina/metabolismo
16.
Neurotox Res ; 35(4): 809-822, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30850947

RESUMO

3-Methylglutaric acid (MGA) is an organic acid that accumulates in 3-methylglutaconic (MGTA) and 3-hydroxy-3-methylglutaric (HMGA) acidurias. Patients affected by these disorders present with neurological dysfunction that usually appears in the first years of life. In order to elucidate the pathomechanisms underlying the brain injury in these disorders, we evaluated the effects of MGA administration on redox homeostasis, mitochondrial respiratory chain activity, and biogenesis in the cerebral cortex of developing rats. Neural damage markers and signaling pathways involved in cell survival, and death were also measured after MGA administration. Furthermore, since the treatment for MGTA and HMGA is still limited, we tested whether a pre-treatment with the pan-peroxisome proliferator-activated receptor (PPAR) agonist bezafibrate could prevent the alterations caused by MGA. MGA provoked lipid peroxidation, increased heme oxygenase-1 content, and altered the activities of antioxidant enzymes, strongly suggestive of oxidative stress. MGA also impaired mitochondrial function and biogenesis by decreasing the activities of succinate dehydrogenase and various respiratory chain complexes, as well as the nuclear levels of PGC-1α and NT-PGC-1α, and cell content of Sirt1. AMPKα1 was further increased by MGA. Neural cell damage was also observed following the MGA administration, as verified by decreased Akt and synaptophysin content and reduced ERK phosphorylation, and by the increase of active caspase-3 and p38 and Tau phosphorylation. Importantly, bezafibrate prevented MGA-elicited toxic effects towards mitochondrial function, redox homeostasis, and neural cell injury, implying that this compound may be potentially used as an adjunct therapy for MGTA and HMGA and other disorders with mitochondrial dysfunction.


Assuntos
Bezafibrato/administração & dosagem , Lesões Encefálicas/metabolismo , Meglutol/análogos & derivados , Biogênese de Organelas , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/prevenção & controle , Caspase 3/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Meglutol/administração & dosagem , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Sinaptofisina/metabolismo , Proteínas tau/metabolismo
17.
Neuroscience ; 406: 369-375, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30910643

RESUMO

Early brain injury (EBI) mainly leads to the poor outcome of subarachnoid hemorrhage (SAH), with which inflammation is closely associated. It was reported that triggering receptor expressed on myeloid cells-1 (TREM-1), a critical inflammatory amplifier, increased in cerebrospinal fluid of SAH patients in our recent research. This study was conducted to examine the effects of TREM-1 inhibition on EBI after experimental SAH (eSAH). The endovascular perforation model of SAH was produced and 120 rats were randomly divided into four groups as sham, SAH + vehicle and SAH + LP17 (1.0 mg/kg and 3.5 mg/kg). The LP17, a selective inhibitor of TREM-1, or vehicle was administered by an intraperitoneal injection 1 h post-modeling. Western blot analysis for TREM-1, p38 mitogen-activated protein kinase (p38MAPK), matrix metalloproteinase-9 (MMP-9) and zonula occludens-1 (ZO-1) was conducted at 24 h post-modeling. EBI was assessed in terms of mortality, neuroscore, brain edema, blood-brain barrier (BBB) disruption in 24 and 72 h. The results showed that TREM-1 was induced in brain after eSAH. Both high dose (3.5 mg/kg) and low dose (1.0 mg/kg) of Lp17 significantly inhibited the induction of TREM-1, but only high dose of LP17 improved neuroscore, brain edema, and BBB disruption which are associated with downregulation of p38MAPK/MMP-9 and subsequent preservation of ZO-1. Overall, the current study provides new evidence that TREM-1 may participate in the pathogenesis of SAH-induced EBI via promoting p38MAPK/MMP-9 activation and ZO-1 degradation, while TREM-1 inhibition attenuated the EBI severity obviously, providing a novel approach for the treatment of EBI.


Assuntos
Lesões Encefálicas/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Hemorragia Subaracnóidea/metabolismo , Junções Íntimas/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Lesões Encefálicas/prevenção & controle , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/prevenção & controle , Junções Íntimas/efeitos dos fármacos , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
18.
J Perinat Med ; 47(4): 478-489, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30789826

RESUMO

Background Erythropoietin (EPO) appears to confer neuroprotection to the injured brain. Randomized clinical trials (RCTs) have demonstrated its safety in neonates with hypoxic-ischemic encephalopathy (HIE); however, the evidence is unclear. The objective of this study was to examine the role of EPO in perinatal HIE by a systematic review and meta-analysis. Methods Database search included Embase, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Central Register of Controlled Trials (CENTRAL). RCTs reporting a death, neurodevelopmental outcomes or brain injury were included. Two authors extracted the data independently from included studies and assessed the level of evidence (LOE). Results Six RCTs (EPO=5 and darbepoetin α=1) involving 454 neonates were included. A trend toward a lower risk of death was identified in infants treated with EPO [EPO with or without hypothermia: five RCTs, 368 participants, relative risk (RR) 0.74, 95% confidence interval (CI) 0.47-1.19, LOE-low; EPO without hypothermia: four RCTs, 318 participants, RR 0.89, 95% CI 0.49-1.32, LOE-low]. EPO treatment without hypothermia compared to placebo resulted in a reduced risk of cerebral palsy (two RCTs, 230 participants, RR 0.47, 95% CI 0.27-0.80, LOE-moderate) and moderate to severe cognitive impairment (two RCTs, 226 participants, RR 0.49, 95% CI 0.28-0.85, LOE-moderate). A reduced risk of brain injury was identified in EPO treated infants (EPO with or without hypothermia, two RCTs, 148 participants, RR 0.70, 95% CI 0.53-0.92, LOE-moderate). Conclusion EPO administration in neonates with perinatal HIE reduces the risk of brain injury, cerebral palsy and cognitive impairment. The evidence is limited to suggest its role as an adjuvant to hypothermia. Larger powered trials are underway to overcome this limitation.


Assuntos
Lesões Encefálicas/prevenção & controle , Eritropoetina/uso terapêutico , Hipóxia-Isquemia Encefálica/complicações , Transtornos do Neurodesenvolvimento/prevenção & controle , Lesões Encefálicas/etiologia , Humanos , Hipóxia-Isquemia Encefálica/mortalidade , Recém-Nascido , Recém-Nascido Prematuro , Transtornos do Neurodesenvolvimento/etiologia
19.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(1): 55-60, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30707870

RESUMO

OBJECTIVE: To investigate the effect of III-type phosphatidylinositide 3 kinase (PI3K) pathway adjusting autophagy on brain damage mechanism after cardiopulmonary resuscitation (CPR) and hypothermia treatment. METHODS: The asphyxia induce cardiac arrest-CPR model was reproduced on healthy male Sprague-Dawley (SD) rats. Sixty rats after restoration of spontaneous circulation (ROSC) were randomly divided into normothermia group, therapeutic hypothermia group and PI3K inhibitor 3-methyl adenine (3-MA) pretreatment group, differentiated by 24 hours and 48 hours after ROSC. Each group had 10 rats at each time point. The anal temperature in the normothermia group was maintained at (37.0±0.2) centigrade, and the rats in the hypothermia group were given cooling treatment immediately after ROSC, and the target rectal temperature was 32-34 centigrade. In the 3-MA pretreatment group, 10 mmol/L 3-MA 5 µL was injected into the ventricle 20 minutes before asphyxia, and other groups were given the same amount of normal saline. Ten rats without CPR were included in Sham group only received anesthesia and catheterization. The rats were sacrificed at 24 hours and 48 hours after ROSC respectively, and the brain tissues were harvested, the brain water content (BWC) was measured by dry-wet weight method. Western Blot was used to determine the autophagy related proteins Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3), apoptosis related proteins Bcl-2 and caspase-3, and the III-type PI3K pathway proteins Vps34 and Atg14. Ultrastructural changes in brain tissue were observed with transmission electron microscope. Neurological deficit scores (NDS) was obtained in each group at 48 hours after ROSC. RESULTS: Compared with Sham group, the cortex at 24 hours after ROSC in normothermic group showed obvious edema, apoptosis and autophagy began to appear under transmission electron microscope, and the expressions of autophagy, apoptosis and III- type PI3K-related proteins in brain tissue were significantly increased in a time-dependent manner, and the neurological function at 48 hours after ROSC was significantly damaged. After hypothermia intervention, brain edema of rats was significantly reduced, no obvious apoptosis was found, but autophagy was increased, the expressions of autophagy-related proteins Vps34, Atg14 and III-type PI3K-related proteins Beclin-1 and LC3 at 48 hours after ROSC were further higher than those of normothermic group (Vps34/GAPDH: 0.25±0.03 vs. 0.15±0.04, Atg14/GAPDH: 0.12±0.03 vs. 0.05±0.04, Beclin-1/GAPDH: 0.060±0.002 vs. 0.018±0.002, LC3 -II/GAPDH: 0.160±0.010 vs. 0.050±0.010, all P < 0.05), the expressions of apoptosis related proteins Bcl-2 and caspase-3 were significantly lowered (Bcl-2/GAPDH: 0.05±0.03 vs. 0.20±0.04, caspase-3/GAPDH: 0.050±0.002 vs. 0.140±0.015, both P < 0.05), neurological function was significantly improved (NDS: 157±85 vs. 343±198, P < 0.05). Pretreatment with 3-MA inhibited the protective effect of hypothermia on brain tissues. The expressions of Vps34, Atg14, Beclin-1 and LC3 in brain tissues at 48 hours after ROSC in 3-MA pretreatment group was significantly lower than those in the hypothermia group (Vps34/GAPDH: 0.18±0.03 vs. 0.25±0.03, Atg14/GAPDH: 0.07±0.04 vs. 0.12±0.03, Beclin-1/GAPDH: 0.015±0.003 vs. 0.060±0.002, LC3-II/GAPDH: 0.045±0.030 vs. 0.160±0.010, all P < 0.05), the expressions of Bcl-2 and caspase-3 were significantly increased (Bcl-2/GAPDH: 0.15±0.04 vs. 0.05±0.03, caspase-3/GAPDH: 0.120±0.015 vs. 0.050±0.002, both P < 0.05), and NDS score was significantly increased (341±208 vs. 157±85, P < 0.05). CONCLUSIONS: Hypothermia treatment reduced brain edema and ameliorated brain function after CPR, which might be related to increase autophagy and inhibit apoptosis adjustment by activating III-type PI3K pathway.


Assuntos
Autofagia/fisiologia , Lesões Encefálicas/prevenção & controle , Hipotermia Induzida , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Reanimação Cardiopulmonar , Parada Cardíaca/terapia , Masculino , Ratos , Ratos Sprague-Dawley
20.
Neurotoxicology ; 71: 138-149, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639357

RESUMO

Status epilepticus (SE) during developmental periods can cause short- and long-term consequences to the brain. Brain damage induced by SE is associated to NMDA receptors (NMDAR)-mediated excitotoxicity. This study aimed to investigate whether blockade of GluN2B-containing NMDAR is neuroprotective against SE-induced neurodegeneration and neuroinflammation in young rats. Forty-eight Wistar rats (16 days of life) were injected with pilocarpine (60 mg/kg; i.p.) 12-18 h after LiCl (3 mEq/kg; i.p.). Fifteen minutes after pilocarpine administration, animals received i.p. injections of saline solution (0.9% NaCl; SE + SAL group), ketamine (a non-selective and noncompetitive NMDAR antagonist; 25 mg/kg; SE + KET), CI-1041 (a GluN2B-containing NMDAR antagonist; 10 mg/kg; SE + CI group) or CP-101,606 (a NMDAR antagonist with great selectivity for NMDAR composed by GluN1/GluN2B diheteromers; 10 mg/kg; SE + CP group). Seven days after SE, brains were removed for Fluoro-Jade C staining and Iba1/ED1 immunolabeling. GluN2B-containing NMDAR blockade by CI-1041 or CP-101,606 did not terminate LiCl-pilocarpine-induced seizures. SE + SAL group presented intense neurodegeneration and Iba1+/ED1+ double-labeling in hippocampus (CA1 and dentate gyrus; DG) and amygdala (MePV nucleus). Administration of CP-101,606 did not alter this pattern. However, GluN2B-containing NMDAR blockade by CI-1041 reduced neurodegeneration and Iba1+/ED1+ double-labeling in hippocampus and amygdala similar to the reduction observed for SE + KET group. Our results indicate that GluN2B-containing NMDAR are involved in SE-induced neurodegeneration and microglial recruitment and activation, and suggest that stopping epileptic activity is not a condition required to prevent short-term brain damage in young animals.


Assuntos
Lesões Encefálicas/prevenção & controle , Encéfalo/efeitos dos fármacos , Encefalite/prevenção & controle , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estado Epiléptico/complicações , Animais , Benzoxazóis/administração & dosagem , Encéfalo/patologia , Lesões Encefálicas/etiologia , Encefalite/etiologia , Feminino , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Piperidinas/administração & dosagem , Ratos Wistar
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