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1.
Neurochirurgie ; 66(3): 150-154, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278699

RESUMO

OBJECTIVE: Several parameters are known to predict the survival of glioblastoma (GB), including extent of resection and MGMT promotor methylation. Staining for glial fibrillary acidic protein (GFAP) is a common component of routine histological work-up, but its clinical utility in GB is unclear. The aim of the present study was to analyze the predictive value of quantitative GFAP measurements for survival of patients with GB. METHODS: All subjects in our institutional database of patients with primary GB who underwent surgery between 2011 and 2014 with examination of immunohistochemical staining of GFAP were included. Percentage GFAP staining was measured in 5% increments (5-100%). Univariate and multivariate analyses were performed between GFAP values and survival data. Clinically relevant cut-offs for GFAP staining were identified by receiver operating characteristic (ROC) curves. RESULTS: The final cohort consisted of 272GB patients with available quantitative GFAP measurements (mean age, 62 (±11.1) years, 117 females [43%]). Overall survival was 11.4 months (±8.6). Median GFAP value was 70% (range, 5-100%). The ROC curve showed the clinically relevant cut-off for GFAP at 75% (area under the curve: 0.691). Accordingly, GB patients with GFAP≥75% presented poorer survival on Kaplan-Meier survival estimation (P=0.021). Multivariate analysis adjusted for age, extent of resection, preoperative Karnofsky performance status scale, IDH1 mutation and MGMT methylation status confirmed the independent predictive value of GFAP≥75% for overall survival (P=0.032). Finally, patients with GFAP≥75% showed significantly poorer long-term survival than those with GFAP<75%: 5.8% vs. 15.2% (P=0.0183) and 0.8% vs. 8% (P=0.0076) for 2- and 3-year survival, respectively. CONCLUSION: Quantitative immunohistochemical assessment of GFAP staining could provide a novel biomarker for overall and especially long-term survival of patients with GB. Prospective multi-center validation of the prognostic value of GFAP for GB survival is needed.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Glioblastoma/genética , Glioblastoma/patologia , Idoso , Biomarcadores , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/biossíntese , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Metilação , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Proteínas Supressoras de Tumor/metabolismo
2.
Medicine (Baltimore) ; 98(46): e17957, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725655

RESUMO

BACKGROUND: Although surgical field visualization is important in functional endoscopic sinus surgery (FESS), the complications associated with controlled hypotension for surgery should be considered. Intraoperative hypotension is associated with postoperative stroke, leading to subsequent hypoxia with potential neurologic injury. We investigated the effect of propofol and desflurane anesthesia on S-100ß and glial fibrillary acidic protein (GFAP) levels which are early biomarkers for cerebral ischemic change during controlled hypotension for FESS. METHODS: For controlled hypotension during FESS, anesthesia was maintained with propofol/remifentanil in propofol group (n = 30) and with desflurane/remifentanil in desflurane group (n = 30). For S-100ß and GFAP assay, blood samples were taken at base, 20 and 60 minutes after achieving the target range of mean arterial pressure, and at 60 minutes after surgery. RESULTS: The base levels of S-100ß were 98.04 ±â€Š78.57 and 112.61 ±â€Š66.38 pg/mL in the propofol and desflurane groups, respectively. The base levels of GFAP were 0.997 ±â€Š0.486 and 0.898 ±â€Š0.472 ng/mL in the propofol and desflurane groups, respectively. The S-100ß and GFAP levels were significantly increased in the study period compared to the base levels in both groups (P ≤ .001). There was no significant difference at each time point between the 2 groups. CONCLUSION: On comparing the effects of propofol and desflurane anesthesia for controlled hypotension on the levels of S-100ß and GFAP, we noted that there was no significant difference in S-100ß and GFAP levels between the 2 study groups. CLINICAL TRIAL REGISTRATION: Available at: http://cris.nih.go.kr, KCT0002698.


Assuntos
Proteína Glial Fibrilar Ácida/sangue , Hipotensão Controlada/métodos , Propofol/uso terapêutico , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Sinusite/cirurgia , Adulto , Anestésicos Intravenosos , Pressão Arterial/efeitos dos fármacos , Dióxido de Carbono/sangue , Doença Crônica , Desflurano/administração & dosagem , Desflurano/efeitos adversos , Desflurano/uso terapêutico , Endoscopia , Feminino , Proteína Glial Fibrilar Ácida/biossíntese , Humanos , Hipotensão Controlada/efeitos adversos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Propofol/efeitos adversos , Estudos Prospectivos , Remifentanil/administração & dosagem , Subunidade beta da Proteína Ligante de Cálcio S100/biossíntese , Fatores de Tempo
3.
Ecotoxicol Environ Saf ; 182: 109407, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279280

RESUMO

Aflatoxin B1 poses the greatest risk among the mycotoxins to target-organisms particularly human, however, no studies addressed the neurotoxicity of chronic exposure of aflatoxin. The oral dose level 1/600th of LD50 for 30, 60, and 90 days was used for three aflatoxin groups, respective to negative and vehicle control groups. Activity levels of brain antioxidants viz: superoxide dismutase, catalase, glutathione, and glutathione peroxidase significantly decreased in the three experimental durations in time-dependent trend, in contrast, lipid peroxidation showed a significant increase compared to controls. Significantly, chronic-dependent increase trend was noticed in the AF60 and AF90 group for acid phosphatase (16.1%, 35.2%), alkaline phosphatase (32.1%, 50.8%), aspartate aminotransferase (38.7%, 120.0%) and lactate dehydrogenase (30.6%, 42.1%) activities, respectively. However, a significant 23.7% decrease in the brain creatine kinase activity following 90 days of AFB1administration. Chronic administration of aflatoxin also causes alterations in activities of protein carbonyl with a maximum increase (twofold) after 90 days. Further, histopathological and immunohistochemical results confirmed time-related vasodilation, necrosis and astrocytes gliosis by high glial fibrillary acidic protein immunostaining in response to AFB1. These findings infer that long-term exposure to AFB1 results in several pathophysiological circumstances in a duration-dependent manner concerning neurodegeneration especially Alzheimer's disease.


Assuntos
Aflatoxina B1/toxicidade , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Poluentes Ambientais/toxicidade , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Astrócitos/imunologia , Astrócitos/patologia , Encéfalo/patologia , Relação Dose-Resposta a Droga , Proteína Glial Fibrilar Ácida/biossíntese , Imuno-Histoquímica , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ratos , Ratos Wistar , Fatores de Tempo , Testes de Toxicidade Crônica
4.
Neurol Res ; 41(7): 633-643, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31002029

RESUMO

Objective: Animal models of chronic pain have demonstrated that glial cells are promising target for development of analgesic drugs. However, preclinical studies on glial response under chronic pain conditions vary depending on the cellular markers, the species used, the experimental design and model. Therefore, we investigate the expression profile of GFAP and Iba-1 during the behavioral manifestation of sensory disorder in inflammatory and neuropathic pain models. Methods: the expression profile of fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) were quantitated in the spinal dorsal horn of Balb/C mice submitted to six models of chronic pain. Protein analysis was performed by western blot and the results colligated with pain-related behavior. Results: Using the same method to quantitate proteins we observed that while GFAP is upregulated after axotomy, partial nerve injury and cutaneous inflammation, its expression is not changed during muscle inflammation, non-inflammatory muscle pain, and in a viral-associated pain. Differently, Iba-1 is downregulated after axotomy but upregulated after partial lesion of peripheral nerve as well as after virus inoculation and during non-inflammatory muscle pain. Cutaneous and muscle inflammation induced no change in Iba-1 expression in the dorsal horn.In spite of a marked time-dependent variation in protein expression, mechanical allodynia was present at any time of all the models investigated. Discussion: Under distinct pain conditions, GFAP and Iba-1 expression is dependent on the origin of the stimulus, disease progression and tissue affected. Moreover, their expression and is not necessarily associated to the behavior manifestation of pain.


Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Dor Crônica/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Inflamação/metabolismo , Proteínas dos Microfilamentos/biossíntese , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Camundongos , Músculos/fisiopatologia , Nervo Isquiático/lesões , Pele/fisiopatologia , Regulação para Cima
5.
Int J Neurosci ; 129(9): 896-903, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30806135

RESUMO

Aim: Thalidomide is one of the first line therapies in cancer pain management. Previous study has shown that thalidomide decreases the expression of tumor necrosis factor alpha in the mouse spinal cord. However, the exact cellular and molecular mechanism underlying the effect of thalidomide remains unclear. Here, we investigated the effect of thalidomide on the expression level of NF-κB as well as glial fibrillary acidic protein (GFAP) in the spinal cord astrocyte in a mice model. Materials and methods: MC57G fibrosarcoma cells were intramedullary injected into the right femurs of C57/BL mice to induce behaviors related to bone cancer pain. Postoperative thalidomide was administered intraperitoneally to the mice at dose of 100 mg/kg/day for 7 days. The effect of thalidomide on pain hypersensitivity was checked by behavioral testing. The expression levels of NF-κB and GFAP in spinal cord were evaluated by using Western blotting and Immunohistochemistry. Results: Compared with the controls, the tumor-bearing mice showed substantial pain-related behaviors. Furthermore, the expression levels of both NF-κB and GFAP increased significantly in the spinal cord astrocytes of the tumor-bearing mice. Treating the tumor-bearing mice with thalidomide results in a dramatic reduction in pain behaviors and a significant decrease of NF-κB and GFAP expressions. Conclusions: Thalidomide alleviates the pain behaviors probably by down-regulating the expression of NF-κB and GFAP.


Assuntos
Astrócitos/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Dor do Câncer/tratamento farmacológico , Proteína Glial Fibrilar Ácida/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Talidomida/uso terapêutico , Animais , Astrócitos/metabolismo , Neoplasias Ósseas/metabolismo , Dor do Câncer/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Expressão Gênica , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/biossíntese , NF-kappa B/genética , Distribuição Aleatória
6.
Glia ; 67(7): 1308-1319, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30801815

RESUMO

Enhanced glial fibrillary acidic protein (GFAP) expression occurs in most diseases of the central nervous system. Thus far, little is known about the effect that GFAP exerts on astrocyte cell signaling. In the present study, we observed that silencing GFAP expression in isolated astrocytes leads to enhanced CCL2 and CXCL10 release, whereas overexpression of GFAP in astrocytes results in a significantly reduced CXCL10 release in vitro. Additionally, we analyzed transgenic mice carrying a full-length copy of the wild-type human GFAP gene. We demonstrate that a persistent GFAP increase alters the astrocytic cell signaling profile, thereby protecting oligodendrocytes, myelin and, subsequently, axons from cuprizone-induced demyelination. Our study revealed that reduced CXCL10 mRNA was accompanied by reduced NF-κB expression in astrocytes. Furthermore, analysis of human tissue from a patient with Alexander disease showed NF-κB activation in astrocytes to be almost completely absent. Our findings indicate that regulation of GFAP expression in astrocytes is crucial for astrocyte signaling and function. Understanding the role of the cytoskeletal protein, GFAP is thus of importance as it is highly regulated in diseases of the central nervous system.


Assuntos
Astrócitos/metabolismo , Quimiocinas/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Adolescente , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Células Cultivadas , Quelantes/toxicidade , Doenças Desmielinizantes/genética , Feminino , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Humanos , Camundongos , Camundongos Transgênicos
7.
Int J Hematol ; 109(3): 309-318, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632058

RESUMO

Nestin-expressing stromal cells (NESCs) and Schwann cells in the bone marrow (BM) play crucial roles as a niche for normal hematopoietic stem cells in mice. It has been reported that both types of cells are decreased in myeloproliferative neoplasms in patients and also in a mouse model, whereas an increase in NESCs was reported in acute myeloid leukemia. It is thus of interest whether and how these BM stromal cells are structured in myelodysplastic syndromes (MDS). Here, we focused on NESCs and glial fibrillary acidic protein (GFAP)-expressing cells in the BM of MDS patients. We found a marked increase of NESCs in MDS with fibrosis (MDS-F) at a high frequency (9/19; 47.4%), but not in MDS without fibrosis (0/26; 0%). Intriguingly, in eight of the nine (88.9%) MDS-F cases with elevated NESCs, a majority of NESCs also expressed GFAP, with an additional increase in GFAP single-positive cells. Furthermore, in seven of them, we found a prominent structure characterized by neurofilament heavy chain staining surrounded by NESCs with GFAP expression. This structure may represent peripheral nerve axons surrounded by Schwann cells, and could be relevant to the pathophysiology of MDS-F.


Assuntos
Células da Medula Óssea/metabolismo , Síndromes Mielodisplásicas/metabolismo , Nestina/biossíntese , Mielofibrose Primária/metabolismo , Células de Schwann/metabolismo , Adulto , Animais , Células da Medula Óssea/patologia , Feminino , Proteína Glial Fibrilar Ácida/biossíntese , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Mielofibrose Primária/patologia , Células de Schwann/patologia
8.
J Cereb Blood Flow Metab ; 39(1): 74-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29160736

RESUMO

Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38 µM or 380 µM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de GABA/biossíntese , Recuperação de Função Fisiológica/efeitos dos fármacos , Serina/análogos & derivados , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/fisiopatologia , Relação Dose-Resposta a Droga , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Proteína Glial Fibrilar Ácida/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Desempenho Psicomotor/efeitos dos fármacos , Serina/farmacologia , Serina/uso terapêutico , Acidente Vascular Cerebral/fisiopatologia , Regulação para Cima/efeitos dos fármacos
9.
J Spinal Cord Med ; 42(3): 387-394, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30513271

RESUMO

OBJECTIVE: Inflammation and oxidative stress are implicated in pathogenesis of spinal cord injury (SCI). Trehalose, a nonreducing disaccharide, exhibits anti-inflammatory and antioxidant effects. The present study investigated the therapeutic efficacy of trehalose in the SCI model. DESIGN AND SETTING: An experimental study was designed using 120 male Wistar rats which were randomly divided into three groups including SCI, SCI + phosphate buffer saline (vehicle) and SCI + trehalose. All rats were subjected to SCI. Immediately after SCI, vehicle and trehalose groups received intrathecal injection of buffer and trehalose, respectively. OUTCOME MEASURES: The level of tissue TNFα, IL-1ß, nitric oxide, malondialdehyde, myeloperoxidase, glial fibrillary acidic protein (GFAP) as well as hindlimb function were assessed at 4 hours, 1, 3 and 7 days post-SCI. RESULTS: Data indicated an early significant decrease in inflammatory and oxidative responses following SCI in trehalose treated group. Moreover, trehalose reduced GFAP expression as soon as 1-day post-trauma. Furthermore, trehalose treatment increased the score of hindlimb function. CONCLUSION: Our results indicated that treatment with trehalose reduces the development of secondary injury associated with SCI. This effect likely underlies improved neurological function.


Assuntos
Proteína Glial Fibrilar Ácida/biossíntese , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Trealose/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Inflamação/etiologia , Masculino , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo
10.
J Neurochem ; 149(5): 679-698, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30311190

RESUMO

The anti-diabetic drug and peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, rosiglitazone, alters astrocyte activation; however, its mechanism remains less-known. We hypothesized participation of epidermal growth factor receptor (EGFR), known to control astrocyte reactivity. We first detected that rosiglitazone promoted glial fibrillary acidic protein (GFAP) expression in primary astrocytes as well as the mouse cerebral cortex, associated with increased EGFR activation. Screening for EGFR ligands revealed a rosiglitazone-mediated increase of heparin-binding epidermal growth factor (HB-EGF) in astrocytes, resulting in HB-EGF release into culture medium and mouse cerebrospinal fluid too. Treatment with HB-EGF-siRNA and EGFR inhibitors showed that the rosiglitazone-induced HB-EGF and p-EFGR were interdependent, which participated in GFAP increase. Interestingly, we observed that rosiglitazone could induce cellular and secreted-HB-EGF in neurons also, contributing toward the activated EGFR-induced GFAP in astrocytes. Probing whether these effects of rosiglitazone were PPARγ-linked, revealed potential PPARγ-responsive elements within HB-EGF gene. Moreover, gel-shift, site-directed mutagenesis, chromatin-immunoprecipitation and luciferase-reporter assays demonstrated a PPARγ-dependent HB-EGF transactivation. Subsequently, we examined effects of rosiglitazone in a high-fat diet-fed diabetes mouse model, and supporting observations in the normal cortical cells, identified a rosiglitazone-induced GFAP, astrocyte and neuronal HB-EGF and secreted-HB-EGF in the cerebral cortex of diabetic mice. Moreover, assessing relevance of increased HB-EGF and GFAP revealed an anti-apoptotic role of rosiglitazone in the cerebral cortex, supported by a GFAP-siRNA as well as HB-EGF-siRNA-mediated increase in cleaved-caspase 3 and 9 levels in the rosiglitazone-treated astrocyte-neuron coculture. Overall, our study indicates that rosiglitazone may protect the brain, via a PPARγ-dependent HB-EGF/EGFR signaling and increased GFAP.


Assuntos
Astrócitos/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Neurônios/efeitos dos fármacos , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Proteína Glial Fibrilar Ácida/biossíntese , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/biossíntese , Hipoglicemiantes/efeitos adversos , Camundongos , Neurônios/metabolismo , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Regulação para Cima
11.
Anat Histol Embryol ; 48(1): 74-86, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30450567

RESUMO

The optic nerve (ON) is an important organ in the visual system of animals, which transfers electrical impulses towards the brain from the retina. High enrichment of glial cells in ON is known to support neuron and regulate retinal homoeostasis. However, research on immunohistochemical of glial cells proteins in the camel is scanty in available literature. Hence, the current work is an attempt to investigate the histomorphology of camel ON with regard to the expression patterns of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and Iba1 for the three glial subtypes, namely astrocytes, oligodendrocytes and microglia, respectively. Optic nerves from fourteen dromedary camels were dissected and preserved in 10% formalin. Then, the paraffin-embedding sections were subjected for histochemical and immunohistochemical analysis. Our results demonstrated that ON axons aggregate into fascicles that surrounded by light and densely stained glial cells. Then, we examined the myelin sheath using Heidenhain's and Mallory's phosphotungstic acid staining. Immunoassay results revealed that GFAP is enriched in the ON and distributed evenly, whereas MBP and Iba1 were present at scanty levels. Further analysis of mRNA level of GFAP, MBP and Iba1 in the ON confirmed an elevation of GFAP expression compared to MBP and Iba1. We further found partial co-localization of different types of glial cells that reflect their coordinated function in the ON. Although our data provide the first evidence for differential expression pattern of glial proteins, further molecular studies still required to reveal the specific function of these molecules in the camel ON.


Assuntos
Astrócitos/metabolismo , Camelus/anatomia & histologia , Proteínas de Ligação a DNA/biossíntese , Proteína Glial Fibrilar Ácida/biossíntese , Microglia/metabolismo , Microscopia/veterinária , Proteína Básica da Mielina/biossíntese , Neuroglia/metabolismo , Oligodendroglia/metabolismo , Nervo Óptico/citologia , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Feminino , Masculino , Bainha de Mielina/ultraestrutura , Nervo Óptico/metabolismo
12.
Neurosci Lett ; 690: 196-201, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30366012

RESUMO

This study investigated the effect of adrenomedullin (AM) on mechanical pain sensitivity and its possible mechanisms. Intrathecal injection of AM receptor agonist AM1-50 (20 µg) once per day briefly reduced mechanical pain threshold on days 1 and 2 but induced prolonged mechanical allodynia on day 3. However, AM1-50 did not change mechanical pain sensation when the AM receptor antagonist AM22-52 (20 µg) was intrathecally co-administered. Daily administration of AM1-50 (20 µg) for 3 days increased expression of phosphorylated extracellular signal-regulated protein kinase (pERK) and neuronal nitric oxide synthase (nNOS) in the spinal dorsal horn. The AM-induced increase in pERK and nNOS was inhibited by the co-administration of AM22-52. The chronic administration of AM1-50 also increased expression of microglial maker Iba1 and astrocytic marker GFAP (glial fibrillary acidic protein) in the spinal dorsal horn in an AM22-52-sensitive manner. Furthermore, the application of AM1-50 (10 nM, 3 h) to dorsal root ganglion (DRG) explant cultures induced an increase in the expression of transient receptor potential vanilloid 1 (TRPV1). The treatment with AM1-50 did not change TRPV1 expression in DRG in the presence of AM22-52 (2 µM). These results suggest that the increased AM bioactivity induced mechanical allodynia and may contribute to the mechanical pain hypersensitivity under pathological conditions. The mechanisms may involve the activation of ERK signaling pathway and spinal glia as well as the recruitment of nNOS and TRPV1 in the spinal dorsal horn or DRG. The present study indicates that inhibition of the activation AM receptor might provide a fruitful strategy to relieving chronic pain.


Assuntos
Adrenomedulina/fisiologia , Gânglios Espinais/metabolismo , Hiperalgesia/fisiopatologia , Medula Espinal/metabolismo , Adrenomedulina/administração & dosagem , Adrenomedulina/agonistas , Adrenomedulina/antagonistas & inibidores , Adrenomedulina/farmacologia , Animais , Proteínas de Ligação ao Cálcio/biossíntese , Células Cultivadas , Interações Medicamentosas , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , Proteína Glial Fibrilar Ácida/biossíntese , Hiperalgesia/metabolismo , Injeções Espinhais , Masculino , Proteínas dos Microfilamentos/biossíntese , Óxido Nítrico Sintase Tipo I/biossíntese , Medição da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Corno Dorsal da Medula Espinal/metabolismo , Canais de Cátion TRPV/biossíntese
13.
Med Sci Monit ; 24: 8822-8830, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520434

RESUMO

BACKGROUND Astrocytomas are the most common primary brain neoplasms. Biological indicators of astrocytomas can reflect its biological characteristics. The aim of this study was to assess the expression of the pathological glial fibrillary acidic protein (GFAP) Topo IIα and O6-methylguanine-DNA methyltransferase (MGMT) in astrocytomas using magnetic resonance (MR) diffusion kurtosis imaging (DKI) to evaluate the biological characteristics of astrocytomas. MATERIAL AND METHODS Sixty-six patients with pathologically proven astrocytomas were enrolled in this study. All patients underwent conventional MRI head scanning, DKI scanning, and enhanced scanning under the same conditions. Spearman's rank correlation analysis and Bonferroni correction were used to compare the values of DKI and the expression levels of GFAP, Topo IIα, and MGMT between the 2 groups. RESULTS Mean kurtosis (MK) values were negatively correlated with the expression of GFAP (r=-0.836; P=0.03). However, these were positively correlated with the expression of Topo IIα (r=0.896; P=0.01). Moreover, fractional anisotropy (FA) values were not correlated with the expression of GFAP (r=0.366; P=0.05), Topo IIα (r=-0.562; P=0.05), or MGMT (r=-0.153; P=0.10). CONCLUSIONS MK was significantly associated with the expression of GFAP and Topo IIα. To a certain extent, applying DKI may show the biological behavior of tumor cell differentiation, proliferation activity, invasion, and metastasis, and guide individual treatment.


Assuntos
Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/biossíntese , Enzimas Reparadoras do DNA/biossíntese , DNA Topoisomerases Tipo II/biossíntese , Proteína Glial Fibrilar Ácida/biossíntese , Proteínas de Ligação a Poli-ADP-Ribose/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adulto , Idoso , Anisotropia , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
14.
Part Fibre Toxicol ; 15(1): 36, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201004

RESUMO

BACKGROUND: Engineered nanoparticles are smaller than 100 nm and designed to improve or creating even new physico-chemical properties. Consequently, toxicological properties of materials may change as size reaches the nm size-range. We examined outcomes related to the central nervous system in the offspring following maternal inhalation exposure to nanosized carbon black particles (Printex 90). METHODS: Time-mated mice (NMRI) were exposed by inhalation, for 45 min/day to 0, 4.6 or 37 mg/m3 aerosolized carbon black on gestation days 4-18, i.e. for a total of 15 days. Outcomes included maternal lung inflammation (differential cell count in bronchoalveolar lavage fluid and Saa3 mRNA expression in lung tissue), offspring neurohistopathology and behaviour in the open field test. RESULTS: Carbon black exposure did not cause lung inflammation in the exposed females, measured 11 or 28-29 days post-exposure. Glial fibrillary acidic protein (GFAP) expression levels were dose-dependently increased in astrocytes around blood vessels in the cerebral cortex and hippocampus in six weeks old offspring, indicative of reactive astrogliosis. Also enlarged lysosomal granules were observed in brain perivascular macrophages (PVMs) in the prenatally exposed offspring. The number of parvalbumin-positive interneurons and the expression levels of parvalbumin were decreased in the motor and prefrontal cortices at weaning and 120 days of age in the prenatally exposed offspring. In the open field test, behaviour was dose-dependently altered following maternal exposure to Printex 90, at 90 days of age. Prenatally exposed female offspring moved a longer total distance, and especially males spent significantly longer time in the central zone of the maze. In the offspring, the described effects were long-lasting as they were present at all time points investigated. CONCLUSION: The present study reports for the first time that maternal inhalation exposure to Printex 90 carbon black induced dose-dependent denaturation of PVM and reactive astrocytes, similarly to the findings observed following maternal exposure to Printex 90 by airway instillation. Of note, some of the observed effects have striking similarities with those observed in mouse models of neurodevelopmental disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Exposição Materna/efeitos adversos , Nanopartículas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fuligem/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Feminino , Proteína Glial Fibrilar Ácida/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Gravidez
15.
Microsc Res Tech ; 81(10): 1143-1153, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30168883

RESUMO

This review aimed to summarize the different histopathological techniques and procedures utilized during investigating the different animal models of depression in order to explore the pathophysiological aspect of depression and testing the efficacy of the antidepressant drugs or new treatments. This will be helpful while designing researches aiming to achieve these objectives. It was found that the major obstacle during investigating the animal models of depression was the restricted availability of validated animal models. The chronic stress models have face, construct, and predictive validity. It was found that the histological techniques used in investigating the animal models of depression that was described in the literatures fall under three categories; the light microscopic, the electron microscopic and the molecular biological studies. The light microscope studies were performed using the routine histological staining and immunohistochemical technique that aimed to describe the hippocampal histopathological changes induced by depression. Establishment of a preclinical behavioral science laboratory is highly recommended. It will encourage and support the conduction of high quality, multidisciplinary researches targeting anxiety and other psychiatric disorders and will indirectly improve the health care provided to the psychiatric patients. RESEARCH HIGHLIGHTS: Chronic stress models are valid ones. Light microscope was utilized to examine the routinely or immunohistochemically stained sections in hippocampus of animal models of depression while electron microscope was utilized to examine its ultrastructure.


Assuntos
Ansiedade/patologia , Ansiedade/psicologia , Depressão/patologia , Depressão/psicologia , Hipocampo/metabolismo , Testes Psicológicos , Animais , Antidepressivos/uso terapêutico , Astrócitos/fisiologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Giro Denteado/fisiologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/biossíntese , Humanos , Microscopia Eletrônica , Receptores de Glucocorticoides/fisiologia
16.
J Neural Eng ; 15(5): 056021, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29848804

RESUMO

OBJECTIVE: Picosecond pulse electric fields (psPEF) have the potential to elicit functional changes in mammalian cells in a non-contact manner. Such electro-manipulation of pluripotent and multipotent cells could be a tool in both neural interface and tissue engineering. Here, we describe the potential of psPEF in directing neural stem cells (NSCs) gene expression, metabolism, and proliferation. As a comparison mesenchymal stem cells (MSCs) were also tested. APPROACH: A psPEF electrode was anchored on a customized commercially available 3D printer, which allowed us to deliver pulses with high spatial precision and systematically control the electrode position in three-axes. When the electrodes are continuously energized and their position is shifted by the 3D printer, large numbers of cells on a surface can be exposed to a uniform psPEF. With two electric field strengths (20 and 40 kV cm-1), cell responses, including cell viability, proliferation, and gene expression assays, were quantified and analyzed. MAIN RESULTS: Analysis revealed both NSCs and MSCs showed no significant cell death after treatments. Both cell types exhibited an increased metabolic reduction; however, the response rate for MSCs was sensitive to the change of electric field strength, but for NSCs, it appeared independent of electric field strength. The change in proliferation rate was cell-type specific. MSCs underwent no significant change in proliferation whereas NSCs exhibited an electric field dependent response with the higher electric field producing less proliferation. Further, NSCs showed an upregulation of glial fibrillary acidic protein (GFAP) after 24 h to 40 kV cm-1, which is characteristic of astrocyte specific differentiation. SIGNIFICANCE: Changes in cell metabolism, proliferation, and gene expression after picosecond pulsed electric field exposure are cell type specific.


Assuntos
Linhagem da Célula/genética , Proliferação de Células , Campos Eletromagnéticos , Expressão Gênica/genética , Células-Tronco Neurais/fisiologia , Impressão Tridimensional , Astrócitos/metabolismo , Morte Celular , Eletrodos , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Células-Tronco Mesenquimais , Neurogênese
17.
Life Sci ; 205: 113-124, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29763613

RESUMO

AIMS: Painful diabetic neuropathy (PDN) is one of the most frequent complications of diabetes and the current therapies have limited efficacy. This study aimed to study the neuroprotective effect of duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), in a mouse model of diabetic neuropathy. MAIN METHODS: Nine weeks after developing of PDN, mice were treated with either saline or duloxetine (15 or 30 mg/kg) for four weeks. The effect of duloxetine was assessed in terms of pain responses, histopathology of sciatic nerve and spinal cord, sciatic nerve growth factor (NGF) gene expression and on the spinal expression of astrocytes (glial fibrillary acidic protein, GFAP) and microglia (CD11b). KEY FINDINGS: The present results highlighted that duloxetine (30 mg/kg) increased the withdrawal threshold in von-Frey test. In addition, both doses of duloxetine prolonged the licking time and latency to jump in the hot-plate test. Moreover, duloxetine administration downregulated the spinal expression of both CD11b and GFAP associated with enhancement in sciatic mRNA expression of NGF. SIGNIFICANCE: The current results highlighted that duloxetine provided peripheral and central neuroprotective effects in neuropathic pain is, at least in part, related to its downregulation in spinal astrocytes and microglia. Further, this neuroprotective effect was accompanied by upregulation of sciatic expression of NGF.


Assuntos
Antidepressivos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Cloridrato de Duloxetina/uso terapêutico , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Astrócitos/metabolismo , Antígeno CD11b/biossíntese , Antígeno CD11b/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/biossíntese , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Nervo Isquiático/patologia , Síndrome da Serotonina/metabolismo , Medula Espinal/metabolismo , Coluna Vertebral/citologia
18.
Neurochem Res ; 43(5): 1058-1066, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29671236

RESUMO

Reactive astrocyte-mediated neuroinflammatory responses in the spinal dorsal horn have been reported to play a pivotal role in pathological pain. Chronic constriction injury (CCI) enhances the activation of nuclear factor kappa B (NF-κB), which is involved in neuropathic pain (NP). Picroside II (PII), a major active component of Picrorhiza scrophulariiflora, has been investigated for its anti-oxidative, anti-inflammatory, and anti-apoptotic activities. Here, we explored the analgesic effects of PII on a model of CCI-induced NP and investigated the levels of the GFAP protein and the mRNA and protein levels of pro-inflammatory cytokines in the spinal cord, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). CCI significantly induced mechanical allodynia and thermal hyperalgesia. Intraperitoneal administration of PII remarkably reversed the CCI-induced mechanical allodynia and thermal hyperalgesia and reduced the mRNA and protein levels of IL-1ß, IL-6, and TNF-α in the spinal cord. Additionally, according to the in vitro data, the PII treatment inhibited LPS-induced increases in the mRNA and protein levels of IL-1ß, IL-6, and TNF-α and suppressed the NF-κB pathway by inhibiting the phosphorylation of NF-κB/p65 and the degradation of inhibitor of NF-κB (IκB) in astrocytes without toxicity to astrocytes. Overall, the analgesic effect of PII correlated with the inhibition of spinal reactive astrocyte-mediated neuroinflammation through the NF-κB pathway in rats with NP.


Assuntos
Analgésicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Cinamatos/uso terapêutico , Glucosídeos Iridoides/uso terapêutico , NF-kappa B/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Astrócitos/patologia , Células Cultivadas , Constrição Patológica/complicações , Citocinas/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Hiperalgesia/tratamento farmacológico , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Neuralgia/etiologia , Neuralgia/patologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia
19.
Exp Neurol ; 305: 129-138, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29655639

RESUMO

Gliosis is a hallmark of neural pathology that occurs after most forms of central nervous system (CNS) injuries including traumatic brain injury (TBI). Identification of genes that control gliosis may provide novel treatment targets for patients with diverse CNS injuries. Glia maturation factor beta (GMFB) is crucial in brain development and stress response. In the present study, GMFB was found to be widely expressed in adult zebrafish telencephalon. A gmfb mutant zebrafish was created using CRISPR/cas9. In the uninjured zebrafish telencephalon, glial fibrillary acidic protein (GFAP) fibers in gmfb mutants were disorganized and shorter than wild type zebrafish. After TBI, transformation of quiescent type I radial glial cells (RGC) to proliferative type II RGCs was significantly suppressed in the gmfb mutant. RGC proliferation and hypertrophy post-TBI was reduced in gmfb mutants, indicating that reactive gliosis was attenuated. TBI-induced acute inflammation was also found to be alleviated in the gmfb mutant. Morphological changes also suggest attenuation of microglial reactive gliosis. In a mouse model of TBI, GMFB expression was increased around the injury site. These GMFB+ cells were identified as astrocytes and microglia. Taken together, the data suggests that GMFB is not only required for normal development of GFAP fibers in the zebrafish telencephalon, but also promotes reactive gliosis after TBI. Our findings provide novel information to help better understand the reactive gliosis process following TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Fator de Maturação da Glia/biossíntese , Gliose/metabolismo , Animais , Animais Geneticamente Modificados , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Técnicas de Silenciamento de Genes/métodos , Fator de Maturação da Glia/genética , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Gliose/genética , Gliose/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Telencéfalo/crescimento & desenvolvimento , Telencéfalo/metabolismo , Telencéfalo/patologia , Peixe-Zebra
20.
Ann Neurol ; 83(1): 27-39, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29226998

RESUMO

OBJECTIVE: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease. METHODS: In this study, we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell-autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP. RESULTS: Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress-related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis. INTERPRETATION: These results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease. Ann Neurol 2018;83:27-39.


Assuntos
Doença de Alexander/tratamento farmacológico , Proteína Glial Fibrilar Ácida/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Doença de Alexander/genética , Doença de Alexander/patologia , Animais , Biomarcadores/líquido cefalorraquidiano , Química Encefálica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Humanos , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Neurogênese/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
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