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1.
Life Sci ; 263: 118556, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038375

RESUMO

AIMS: White matter injury (WMI) is the main form of brain injury in preterm neonate survivors, and perinatal inflammation is implicated in the pathogenesis of WMI. It has been demonstrated that dexmedetomidine, an anesthetic adjuvant, possesses neuroprotective effects in both preclinical and clinical trials. The present study was conducted to explore whether dexmedetomidine could protect against neurobehavioral impairments and myelination deficits caused by lipopolysaccharide (LPS) exposure in the early postnatal rat brain. MAIN METHODS: LPS (2 mg/kg) was intraperitoneally (i.p.) injected in Sprague-Dawley rat pups on postnatal day 2 (P2). Dexmedetomidine (25 µg/kg) or vehicle was given i.p. immediately after LPS injection. STAT3 and p-STAT3 expression were detected by western blot in rat brain 24 h after drug administration. Immunostaining for GFAP to was performed to evaluate astrocytic response at 24 h post-LPS and P14. Neurobehavioral tests (the righting reflex, negative geotaxis, and wire hanging maneuver tests) were performed from P5 to P10. Histological analysis of myelin content was accessed by immunohistochemistry for CNPase and MBP at P14. KEY FINDINGS: Our results showed that treatment with dexmedetomidine significantly ameliorated LPS-induced neurobehavioral abnormalities and myelin damage, which is accompanied by suppression of STAT3 activation and reactive astrogliosis. SIGNIFICANCE: Dexmedetomidine can alleviate neurobehavioral impairments and myelination deficits after LPS exposure in early postnatal rats, probably by mitigating STAT3-mediated reactive astrogliosis. Our results suggest that dexmedetomidine might be a promising agent to treat brain injury in neonates.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Dexmedetomidina/farmacologia , Gliose/prevenção & controle , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Fármacos Neuroprotetores/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Feminino , Gliose/induzido quimicamente , Gliose/metabolismo , Gliose/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
2.
Life Sci ; 263: 118547, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038380

RESUMO

AIMS: Brain injuries based on their causes are divided into two categories, TBI and NTBI. TBI is caused by damages such as head injury, but non-physical injury causes NTBI. Prolactin is one of the blood factors that increase during brain injury. It has been assumed to play a regenerative role in post-injury recovery. MATERIALS AND METHODS: In this review, various valid papers from electronic sources (including Web of Science, Scopus, PubMed, SID, Google Scholar, and ISI databases) used, which in them the protective effect of prolactin on brain injury investigated. KEY FINDINGS: Inflammation following brain injury with the production of pro-inflammatory cytokines in the affected area can even lead to excitotoxicity and cell death in the damaged area. Medical brain damage treatments are long-term, and can have several side effects. Therefore, it is better to consider medication treatments that have fewer side effects and greater efficacy. Research suggests that prolactin has numerous regenerative effects on brain injury, and prevents cell death. Prolactin is one of the hormones produced in the body; therefore it has fewer side effects and may be more effective because it increases during brain injury. SIGNIFICANCE: Prolactin can be used peripherally and centrally, and exerts its neuro regenerative effects against further damage post-TBI and NTBI.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Inflamação/prevenção & controle , Prolactina/uso terapêutico , Animais , Lesões Encefálicas/patologia , Citocinas/metabolismo , Humanos , Inflamação/metabolismo
3.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 31(5): 231-248, sept.-oct. 2020. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-195156

RESUMO

ANTECEDENTES Y OBJETIVOS: La lesión axonal traumática es considerada la principal causa de las alteraciones cognitivas y neuropsicológica de los pacientes tras traumatismo craneoencefálico (TCE). Además, existen algunas evidencias sobre la evolución dinámica de la lesión axonal traumática. La secuencia de RM Tensor de difusión (DTI, diffusion tensor imaging) se considera una técnica útil para la caracterización de la lesión axonal traumática, pero son escasos los estudios que hayan evaluado los cambios longitudinales de las características del DTI y su relación con la evolución de los pacientes. MATERIALES Y MÉTODOS: Ciento dieciocho pacientes con TCE moderado y grave fueron estudiados mediante RM-DTI en la fase subaguda precoz (<60 días) y otros estudios sucesivos a los 6 y/o 12 meses tras TCE. Se ha medido la anisotropía fraccionada, difusión axial y radial en las 3 porciones del cuerpo calloso (rodilla, cuerpo y esplenio) y se han comparado con los valores de un grupo control. Además, se ha determinado la situación clínica de los pacientes mediante la Glasgow Outcome Scale Extended al alta hospitalaria, 6 y 12 meses tras TCE. Para el análisis longitudinal de las características del DTI y su correlación con la evolución de los pacientes se han empleado pruebas no paramétricas y un análisis de regresión ordinal. RESULTADOS: A pesar de haber detectado cambios dinámicos en las características del DTI en las 3 porciones del cuerpo calloso, los pacientes continuaron mostrando valores de anisotropía fraccionada y difusión axial significativamente inferiores y valores de difusión radial mayores en comparación con los controles al final del periodo de estudio. También hemos encontrado diferencias en el patrón de cambio del DTI entre subgrupos de pacientes que presentaron evolución favorable. CONCLUSIONES: El perfil temporal del cambio en las características del DTI parece proporcionar información importante sobre la recuperación clínica de los pacientes tras TCE


BACKGROUND AND OBJECTIVES: Traumatic axonal injury is the main cause of the cognitive and neuropsychological situation of patients after head trauma (TBI). Additionally, there are some evidences about the dynamic evolution of traumatic axonal injury. Although the diffusion tensor MRI (DTI) sequence is considered a useful technique for modifying the extent of the traumatic axonal injury, few studies have evaluated the longitudinal changes in the characteristics of the DTI and its relation to evolution of patients. MATERIALS AND METHODS: We performed a prospective observational study in 118 patients with moderate to severe TBI. The study included clinical outcome assessment based on the Glasgow Outcome Scale Extended and serial DTI studies in the early subacute setting (< 60 days) and 6 and 12 months after injury. Fractional anisotropy, axial and radial diffusivities were measured in the 3 portions of corpus callosum (genu, body, splenium) at each time point and compared to normalized values from an age-matched control group. Longitudinal fractional anisotropy analysis and its correlation with patient improvement was also done by non-parametric testing and ordinal regression analysis. RESULTS: Although dynamic changes in DTI characteristics have been detected in the 3 portions of corpus callosum, patients continue to show lower fractional anisotropy and axial diffusivities values and higher radial diffusivities values compared to controls at the end of the period of study. We have also found differences in the pattern of DTI metrics change between subgroups of patients according with their favorable outcome CONCLUSIONS: The temporal profile of the change in DTI characteristics seems to provide important information about the clinical recovery of patients after TBI


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Cérebro/patologia , Lesões Encefálicas/patologia , Imagem de Tensor de Difusão/métodos , Índice de Gravidade de Doença , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Prognóstico , Cérebro/fisiopatologia , Lesões Encefálicas/fisiopatologia
4.
PLoS One ; 15(10): e0240122, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017422

RESUMO

OBJECTIVES: More and more evidence suggests oxidative stress and inflammation contribute importantly to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and secondary brain injury. Recent evidence indicates Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes. This study examines the effects of an activator of Nfr2, RTA 408, on SAH-induced cerebral vasospasm and possible mechanism underlying its effect in a two-hemorrhage rodent model of SAH. METHODS: We randomly assigned 60 Sprague-Dawley male rats (350 to 420g) to five groups twelve rats each: one control group (no SAH), one untreated SAH only group and three RTA-408 treatment groups (SAH+ RTA 408 0.5 mg/kg/day, SAH+RTA 408 1 mg/kg/day and a SAH+RTA 408 1.5 mg/kg/day). The treatment groups were administered RTA 408 by intraperitoneal injection thirty min following first induction of SAH for seven days starting with first hemorrhage. Cerebral vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of Nrf2, NF-κB and iNOS in basilar artery and expressions of Nrf2, HO-1, NQO1 and Cleaved caspase-3 were evaluated. Tissue TNF-alpha was assessed by ELISA using the protein sampled from the dentate gyrus, cerebral cortex, and hippocampus. RESULTS: Prior to perfusion fixation, there were no significant physiological differences among the control and treated groups. RTA 408 treatment attenuated the morphological changes caused by cerebral vasospasm. It mitigated SAH-induced suppression of Nrf2 and increased expression of NF-κB and iNOS in the basilar artery. In dentate gyrus, it reversed SAH-decreases in Nrf2, HO-1, NQO-1 and cleaved caspase-3 and RTA 408 1.5 mg/kg/day reversed SAH increases in TNF-alpha. CONCLUSION: It was concluded that RTA 408 reversal vasospasm was achieved via increases in Nrf2 and decreases in NF-κB and iNOS. It exerted a neuron-protection effect by decreasing the apoptosis-related protein cleaved caspase-3 and decreasing the information cytokine TNF-alpha expression, which it achieved by increasing HO-1 and NQO-1 protein found downstream from Nrf2 and Nrf2. We believe that RTA 408 can potentially be used to manage of cerebral vasospasm and secondary brain injury following SAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/agonistas , Hemorragia Subaracnóidea/complicações , Triterpenos/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Masculino , Fator 2 Relacionado a NF-E2/análise , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/patologia , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/patologia
5.
Nat Commun ; 11(1): 4524, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913280

RESUMO

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.


Assuntos
Lesões Encefálicas/fisiopatologia , Gliose/fisiopatologia , Sistema Glinfático/fisiologia , Meninges/fisiopatologia , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Gliose/etiologia , Gliose/patologia , Gliose/prevenção & controle , Sistema Glinfático/patologia , Humanos , Masculino , Meninges/patologia , Camundongos , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/uso terapêutico
6.
Sci Rep ; 10(1): 13179, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764697

RESUMO

The survival and function of brain cells requires uninterrupted ATP synthesis. Different brain structures subserve distinct neurological functions, and therefore have different energy production/consumption requirements. Typically, mitochondrial function is assessed following their isolation from relatively large amounts of starting tissue, making it difficult to ascertain energy production/failure in small anatomical locations. In order to overcome this limitation, we have developed and optimized a method to measure mitochondrial function in brain tissue biopsy punches excised from anatomically defined brain structures, including white matter tracts. We describe the procedures for maintaining tissue viability prior to performing the biopsy punches, as well as provide guidance for optimizing punch size and the drug doses needed to assess various aspects of mitochondrial respiration. We demonstrate that our method can be used to measure mitochondrial respiration in anatomically defined subfields within the rat hippocampus. Using this method, we present experimental results which show that a mild traumatic brain injury (mTBI, often referred to as concussion) causes differential mitochondrial responses within these hippocampal subfields and the corpus callosum, novel findings that would have been difficult to obtain using traditional mitochondrial isolation methods. Our method is easy to implement and will be of interest to researchers working in the field of brain bioenergetics and brain diseases.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/citologia , Técnicas Citológicas/métodos , Animais , Lesões Encefálicas/patologia , Respiração Celular , Hipocampo/patologia , Masculino , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-Dawley , Substância Branca/patologia
7.
Sci Rep ; 10(1): 13333, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770013

RESUMO

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS.


Assuntos
Lesões Encefálicas/patologia , Encéfalo/patologia , Inflamação/patologia , Esclerose Múltipla/patologia , Retina/patologia , Doenças Retinianas/patologia , Adulto , Axônios/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neurite Óptica/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos
8.
Sci Rep ; 10(1): 10833, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616806

RESUMO

Therapeutic hypothermia (HT) is standard care for term infants with hypoxic-ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we report a meta-analysis of data from every experiment in a single laboratory, including pilot data, examining the effect of HT in the Vannucci model. Across 21 experiments using 106 litters, median (95% CI) hemispheric area loss was 50.1% (46.0-51.9%; n = 305) in the normothermia group, and 41.3% (35.1-44.9%; n = 317) in the HT group, with a bimodal injury distribution. Median neuroprotection by HT was 17.6% (6.8-28.3%), including in severe injury, but was highly-variable across experiments. Neuroprotection was significant in females (p < 0.001), with a non-significant benefit in males (p = 0.07). Animals representing the median injury in each group within each litter (n = 277, 44.5%) were also analysed using formal neuropathology, which showed neuroprotection by HT throughout the brain, particularly in females. Our results suggest an inherent variability and sex-dependence of the neuroprotective response to HT, with the majority of studies in the Vannucci model vastly underpowered to detect true treatment effects due to the distribution of injury.


Assuntos
Lesões Encefálicas/terapia , Modelos Animais de Doenças , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/terapia , Laboratórios/estatística & dados numéricos , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Feminino , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , Metanálise como Assunto , Ratos , Ratos Wistar , Fatores Sexuais
9.
J Virol ; 94(19)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669339

RESUMO

Brain injury occurs within days in simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) infection, and some recovery may occur within weeks. Inflammation and oxidative stress associate with such injury, but what drives recovery is unknown. Chronic HIV infection associates with reduced brain frontal cortex expression of the antioxidant/anti-inflammatory enzyme heme oxygenase-1 (HO-1) and increased neuroinflammation in individuals with cognitive impairment. We hypothesized that acute regional brain injury and recovery associate with differences in regional brain HO-1 expression. Using SIV-infected rhesus macaques, we analyzed multiple brain regions through acute and chronic infection (90 days postinfection [dpi]) and quantified viral (SIV gag RNA), synaptic (PSD-95; synaptophysin), axonal (neurofilament/neurofilament light chain [NFL]), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]) markers. PSD-95 was reduced in the brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except the brainstem recovered. Unchanged NFL was consistent with no acute axonal injury. SIV RNA expression was highest in the brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during the synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in the brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than the brainstem. Within the brainstem, the high SIV load and inflammation, along with reduction of HO-2, may impair recovery. In other brain regions, stable HO-2 expression, with or without increasing HO-1, may promote recovery. Our data support roles for heme oxygenase isoforms in modulating recovery from synaptic injury in SIV infection and suggest their therapeutic targeting for promoting neuronal recovery.IMPORTANCE Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy.


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Vírus da Imunodeficiência Símia/imunologia , Animais , Anti-Inflamatórios , Encéfalo/patologia , Encéfalo/virologia , Lesões Encefálicas/patologia , Lesões Encefálicas/virologia , Modelos Animais de Doenças , Feminino , Infecções por HIV , Heme Oxigenase-1/metabolismo , Inflamação , Macaca mulatta , Masculino , Estresse Oxidativo , Isoformas de Proteínas , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/patogenicidade
10.
Sci Rep ; 10(1): 8949, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488168

RESUMO

Traumatic brain injury (TBI) is often accompanied by gastrointestinal and metabolic disruptions. These systemic manifestations suggest possible involvement of the gut microbiota in head injury outcomes. Although gut dysbiosis after single, severe TBI has been documented, the majority of head injuries are mild, such as those that occur in athletes and military personnel exposed to repetitive head impacts. Therefore, it is important to determine if repetitive, mild TBI (rmTBI) will also disrupt the gut microbiota. Male mice were exposed to mild head impacts daily for 20 days and assessed for cognitive behavior, neuropathology and disruptions in the gut microbiota at 0, 45 or 90 days after injury. Deficits in recognition memory were evident at the late post-injury points. Brains show an early increase in microglial activation at the 0-day time point that persisted until 90 days post-injury. This was compounded by substantial increases in astrocyte reactivity and phosphorylated tau at the 90-day time point. In contrast, changes in the microbial community were minor and transient, and very few differences were observed in mice exposed to rmTBI compared to controls. While the progressive emergence of white matter damage and cognitive alterations after rmTBI resembles the alterations observed in athletes and military personnel exposed to rmTBI, these changes could not be linked to systematic modifications in the gut microbiota.


Assuntos
Concussão Encefálica/fisiopatologia , Cognição/fisiologia , Substância Branca/fisiopatologia , Animais , Bactérias/genética , Encéfalo/metabolismo , Concussão Encefálica/metabolismo , Concussão Encefálica/microbiologia , Lesões Encefálicas/patologia , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Disbiose/microbiologia , Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Substância Branca/metabolismo
11.
PLoS One ; 15(6): e0234082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479533

RESUMO

OBJECTIVES: To investigate whether cerebrospinal fluid levels of neuron-specific enolase (CSF-NSE) during the first 72 hours correlate with other tools used to assess ongoing brain damage, including clinical grading of hypoxic-ischemic encephalopathy (HIE), abnormal patterns in amplitude integrated electroencephalography (aEEG), and magnetic resonance imaging (MRI), as well as with the neurodevelopmental outcomes at two years of age. MATERIAL AND METHODS: Prospective observational study performed in two hospitals between 2009 and 2011. Forty-three infants diagnosed with HIE within 6 hours of life were included. HIE was severe in 20 infants, moderate in 12, and mild in 11. Infants with moderate-to-severe HIE received whole-body cooling. Both the HIE cohort and a control group of 59 infants with suspected infection underwent measurement of CSF-NSE concentrations at between 12 and 72 hours after birth. aEEG monitoring was started at admission and brain MRI was performed within the first 2 weeks. Neurodevelopment was assessed at 24 months. RESULTS: The HIE group showed higher levels of CSF-NSE than the control group: median 70 ng/ml (29; 205) vs 10.6 ng/ml (7.7; 12.9); p <0.001. Median levels of CSF-NSE in infants with severe, moderate, and mild HIE were 220.5 ng/ml (120.5; 368.8), 45.5 ng/ml (26, 75.3), and 26 ng/ml (18, 33), respectively. CSF-NSE levels correlated were significantly higher in infants with seizures, abnormal aEEG, or abnormal MRI, compared to those without abnormalities. Infants with an adverse outcome showed higher CSF-NSE levels than those with normal findings (p<0.001), and the most accurate CSF-NSE cutoff level for predicting adverse outcome in the whole cohort was 108 ng/ml and 50ng/ml in surviving infants. CONCLUSIONS: In the era of hypothermia, CSF-NSE concentrations provides valuable information as a clinical surrogate of the severity of hypoxic-ischemic brain damage, and this information may be predictive of abnormal outcome at two years of age.


Assuntos
Lesões Encefálicas/patologia , Hipotermia Induzida/efeitos adversos , Hipóxia-Isquemia Encefálica/diagnóstico , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Lesões Encefálicas/etiologia , Estudos de Casos e Controles , Eletroencefalografia , Feminino , Idade Gestacional , Humanos , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/terapia , Recém-Nascido , Listeria monocytogenes/patogenicidade , Imagem por Ressonância Magnética , Masculino , Estudos Prospectivos , Convulsões/complicações , Convulsões/diagnóstico , Índice de Gravidade de Doença
12.
J Neuropathol Exp Neurol ; 79(7): 791-799, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32447392

RESUMO

Cerebral radiation necrosis (CRN) is a delayed complication of radiosurgery that can result in severe neurological deficits. The biological changes leading to necrotic damage may identify therapeutic targets for this complication. Connexin43 expression associated with chronic inflammation may presage the development of CRN. A mouse model of delayed CRN was used. The left hemispheres of adult female mice were irradiated with single-fraction, high-dose radiation using a Leksell Gamma Knife. The brains were collected 1 and 4 days, and 1-3 weeks after the radiation. The expression of connexin43, interleukin-1ß (IL-1ß), GFAP, isolectin B-4, and fibrinogen was evaluated using immunohistochemical staining and image analysis. Compared with the baseline, the area of connexin43 and IL-1ß staining was increased in ipsilateral hemispheres 4 days after radiation. Over the following 3 weeks, the density of connexin43 gradually increased in parallel with progressive increases in GFAP, isolectin B-4, and fibrinogen labeling. The overexpression of connexin43 in parallel with IL-1ß spread into the affected brain regions first. Further intensified upregulation of connexin43 was associated with escalated astrocytosis, microgliosis, and blood-brain barrier breach. Connexin43-mediated inflammation may underlie radiation necrosis and further investigation of connexin43 hemichannel blockage is merited for the treatment of CRN.


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Conexina 43/biossíntese , Lesões por Radiação/metabolismo , Animais , Encéfalo/patologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Conexina 43/genética , Feminino , Expressão Gênica , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Necrose/metabolismo , Necrose/patologia , Lesões por Radiação/genética , Lesões por Radiação/patologia
13.
Sci Rep ; 10(1): 7718, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382007

RESUMO

We investigated the role of dynamic changes of serum levels S100B protein in brain injury and poor outcome of sepsis. This is a prospective cohort study designed to include 104 adult patients with sepsis who are admitted to ICU from Jan 2015 to Aug 2016. Sepsis was defined as sepsis 3.0. Patients with a GCS score of <15, or at least one positive CAM-ICU score were thought to have brain dysfunction. 59 patients were diagnosed with SAE and the rest 45 patients were diagnosed with non-SAE. Serum S100B was measured on day 1 and 3 after ICU admission. Primary outcomes included brain dysfunction and 28-day/180-day mortality. The SAE group showed a significantly higher APACHE II score, SOFA scores, length of ICU stay, 28-day and 180-day mortality, serum S100B levels on day 1 and day 3. S100B levels on day 1 of 0.226 µg/L were diagnostic for SAE with 80.0% specificity and 66.1% sensitivity, and the area under (AUC) the curve was 0.728, S100B levels on day 3 of 0.144 µg/L were diagnostic for SAE with 84.44% specificity and 69.49% sensitivity, and the AUC was 0.819. In addition, the AUC for S100B on day 3 for predicting 180-day mortality was larger than for S100B on day 1 (0.731 vs. 0.611). Multiple logistic regression analysis showed that S100B3 (p = 0.001) but not S100B1 (p = 0.927) were independently correlated with SAE. Kaplan-Meier survival analysis showed that patients with S100B levels higher than 0.144 µg/L had a lower probability of survival at day 180. There were more patients with encephalopathy and a higher 28-day or 180-day mortality in the ΔS100B + group than in the ΔS100B- group. Multiple logistic regression analysis showed that SAE and IL-6 on day 3 were independently correlated with S100B dynamic increase. These findings suggest that elevated serum S100B levels on day 3 and the dynamic changes of serum S100B levels from day three to one were more associated with brain dysfunction and mortality than that on day 1 in patients with sepsis.


Assuntos
Lesões Encefálicas/sangue , Interleucina-6/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Encefalopatia Associada a Sepse/sangue , Lesões Encefálicas/epidemiologia , Lesões Encefálicas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Encefalopatia Associada a Sepse/epidemiologia , Encefalopatia Associada a Sepse/patologia
14.
Sci Rep ; 10(1): 7815, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385407

RESUMO

A high-resolution, three-dimensional, optical imaging technique for the murine brain was developed to identify the effects of different therapeutic windows for preclinical brain research. This technique tracks the same cells over several weeks. We conducted a pilot study of a promising drug to treat diffuse axonal injury (DAI) caused by traumatic brain injury, using two different therapeutic windows, as a means to demonstrate the utility of this novel longitudinal imaging technique. DAI causes immediate, sporadic axon damage followed by progressive secondary axon damage. We administered minocycline for three days commencing one hour after injury in one treatment group and beginning 72 hours after injury in another group to demonstrate the method's ability to show how and when the therapeutic drug exerts protective and/or healing effects. Fewer varicosities developed in acutely treated mice while more varicosities resolved in mice with delayed treatment. For both treatments, the drug arrested development of new axonal damage by 30 days. In addition to evaluation of therapeutics for traumatic brain injury, this hybrid microlens imaging method should be useful to study other types of brain injury and neurodegeneration and cellular responses to treatment.


Assuntos
Axônios/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesão Axonal Difusa/tratamento farmacológico , Minociclina/farmacologia , Animais , Axônios/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Lesão Axonal Difusa/diagnóstico por imagem , Lesão Axonal Difusa/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Imagem Óptica
15.
Life Sci ; 255: 117815, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32442450

RESUMO

AIMS: The aim of this study was to investigate the molecular mechanism underlying preterm white matter injury (WMI) via the identification and functional analysis of differentially expressed long non-coding RNAs (lncRNAs) and mRNAs. MAIN METHODS: A neonatal rat model of preterm WMI was established by ligating the common carotid artery and hypoxia induction. RNA sequencing was performed to analyze gene expression profiles of brain samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analyses were performed to evaluate functions of target mRNAs. A co-expression network was generated to explore regulatory mechanisms. KEY FINDINGS: In total, 210 lncRNAs and 619 mRNAs were differentially expressed between the preterm WMI group and the sham group. Based on GO and KEGG analyses, enriched pathways included the apoptotic signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway, natural killer cell-mediated cytotoxicity pathway, and the autophagy pathway. SIGNIFICANCE: Differentially expressed lncRNAs and mRNAs in the brain tissues of preterm WMI model were identified, and the biological processes were closely associated with the development of preterm WMI, thus being considered potential targets for future studies.


Assuntos
Lesões Encefálicas/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Substância Branca/lesões , Animais , Animais Recém-Nascidos , Apoptose/genética , Lesões Encefálicas/genética , Modelos Animais de Doenças , Nascimento Prematuro/patologia , Ratos , Ratos Sprague-Dawley
16.
Proc Natl Acad Sci U S A ; 117(15): 8616-8623, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32229571

RESUMO

In the adult brain, vascular endothelial growth factor D (VEGFD) is required for structural integrity of dendrites and cognitive abilities. Alterations of dendritic architectures are hallmarks of many neurologic disorders, including stroke-induced damage caused by toxic extrasynaptic NMDA receptor (eNMDAR) signaling. Here we show that stimulation of eNMDARs causes a rapid shutoff of VEGFD expression, leading to a dramatic loss of dendritic structures. Using the mouse middle cerebral artery occlusion (MCAO) stroke model, we have established the therapeutic potential of recombinant mouse VEGFD delivered intraventricularly to preserve dendritic architecture, reduce stroke-induced brain damage, and facilitate functional recovery. An easy-to-use therapeutic intervention for stroke was developed that uses a new class of VEGFD-derived peptide mimetics and postinjury nose-to-brain delivery.


Assuntos
Lesões Encefálicas/prevenção & controle , Dendritos/fisiologia , Modelos Animais de Doenças , Mucosa Nasal/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Acidente Vascular Cerebral/complicações , Fator D de Crescimento do Endotélio Vascular/administração & dosagem , Administração Intranasal , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica
17.
J Clin Neurosci ; 75: 71-79, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32241644

RESUMO

Gunshot wounds (GSW) are one of the most lethal forms of head trauma. The lack of clear guidelines for civilian GSW complicates surgical management. We aimed to develop a decision-tree algorithm for mortality prediction and report long-term outcomes on survivors based on 15-year data from our level 1 trauma center. We retrospectively reviewed 96 consecutive patients who presented with cerebral GSWs between 2003 and 2018. Clinical information from our trauma database, EMR, and relevant imaging scans was reviewed. A decision-tree model was constructed based on variables showing significant differences between survivors and non-survivors. After excluding patients who died at arrival, 54 patients with radiologically confirmed intracranial injury were included. Compared to survivors (51.9%), non-survivors (48.1%) were significantly more likely to have perforating (entry and exit wound), as opposed to penetrating (entry wound only), injuries. Bi-hemispheric and posterior fossa involvement, cerebral herniation, and intraventricular hemorrhage were more commonly present in non-survivors. Based on the decision-tree, Glasgow Coma Scale (GCS) > 8 and penetrating, uni-hemispheric injury predicted survival. Among patients with GCS ≤ 8 and normal pupillary response, lack of 1) posterior fossa involvement, 2) cerebral herniation, 3) bi-hemispheric injury, and 4) intraventricular hemorrhage, were associated with survival. Favorable long-term outcomes (mean follow-up 34.4 months) were possible for survivors who required neurosurgery and stable patients who were conservatively managed. We applied clinical and radiological characteristics that predicted survival to construct a decision-tree to facilitate surgical decision-making for GSW. Further validation of the algorithm in a large patient setting is recommended.


Assuntos
Algoritmos , Regras de Decisão Clínica , Árvores de Decisões , Ferimentos por Arma de Fogo/mortalidade , Adulto , Lesões Encefálicas/etiologia , Lesões Encefálicas/mortalidade , Lesões Encefálicas/patologia , Traumatismos Craniocerebrais/etiologia , Traumatismos Craniocerebrais/mortalidade , Traumatismos Craniocerebrais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Traumatologia , Ferimentos por Arma de Fogo/complicações , Ferimentos por Arma de Fogo/patologia
18.
J Neurosci ; 40(17): 3385-3407, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32241837

RESUMO

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.


Assuntos
Lesões Encefálicas/terapia , Vesículas Extracelulares , Células-Tronco Mesenquimais , Córtex Motor/patologia , Células Piramidais/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Feminino , Macaca mulatta , Masculino , Córtex Motor/fisiopatologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia
19.
World Neurosurg ; 139: e428-e438, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32311569

RESUMO

BACKGROUND: The caudate nucleus is a C-shaped structure that is located in the center of the brain and is divided into 3 parts: the head, body, and tail. METHODS: We detail the anatomic connections, relationships with other basal ganglia structures, and clinical implications of injury to the caudate nucleus. RESULTS: Anatomically, the most inferior transcapsular gray matter is the lentiform peduncle, which is the connection between the lentiform nucleus and caudate nucleus as well as the amygdala. The border between the tail and body of the caudate nucleus is the posterior insular point. The tail of the caudate nucleus is extraependymal in some parts and intraependymal in some parts of the roof of the temporal horn of the lateral ventricle. The tail of the caudate nucleus crosses the inferior limiting sulcus (temporal stem), and section of the tail during approaches to lesions involving the temporal stem may cause motor apraxia. The mean distance from the temporal limen point, which is the junction of the limen insula and inferior limiting sulcus, to the tail of the caudate nucleus in the temporal stem is 15.87 ± 3.10 mm. CONCLUSIONS: Understanding of the functional anatomy and connections of the distinct parts of the caudate nucleus is essential for deciding the extent of resection of lesions involving the caudate nucleus and the types of deficits that may be found postoperatively.


Assuntos
Núcleo Caudado/anatomia & histologia , Núcleo Caudado/cirurgia , Tonsila do Cerebelo/anatomia & histologia , Gânglios da Base/anatomia & histologia , Lesões Encefálicas/patologia , Cadáver , Núcleo Caudado/irrigação sanguínea , Córtex Cerebral/anatomia & histologia , Ventrículos Cerebrais/anatomia & histologia , Circulação Cerebrovascular , Substância Cinzenta/anatomia & histologia , Humanos , Vias Neurais , Procedimentos Neurocirúrgicos , Lobo Temporal/anatomia & histologia
20.
Int J Mol Sci ; 21(8)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295117

RESUMO

Lipid emulsion was recently shown to attenuate cell death caused by excitotoxic conditions in the heart. There are key similarities between neurons and cardiomyocytes, such as excitability and conductibility, which yield vulnerability to excitotoxic conditions. However, systematic investigations on the protective effects of lipid emulsion in the central nervous system are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of kainic acid-induced excitotoxicity through intrahippocampal microinjections. Kainic acid and/or lipid emulsion-injected rats were subjected to the passive avoidance test and elevated plus maze for behavioral assessment. Rats were sacrificed at 24 h and 72 h after kainic acid injections for molecular study, including immunoblotting and qPCR. Brains were also cryosectioned for morphological analysis through cresyl violet staining and Fluorojade-C staining. Anxiety and memory functions were significantly preserved in 1% lipid emulsion-treated rats. Lipid emulsion was dose-dependent on the protein expression of ß-catenin and the phosphorylation of GSK3-ß and Akt. Wnt1 mRNA expression was elevated in lipid emulsion-treated rats compared to the vehicle. Neurodegeneration was significantly reduced mainly in the CA1 region with increased cell survival. Our results suggest that lipid emulsion has neuroprotective effects against excitotoxic conditions in the brain and may provide new insight into its potential therapeutic utility.


Assuntos
Encéfalo/efeitos dos fármacos , Emulsões , Lipídeos/administração & dosagem , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Lesões Encefálicas/mortalidade , Lesões Encefálicas/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intralesionais , Memória , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos , Via de Sinalização Wnt
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