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1.
Mult Scler Relat Disord ; 31: 87-92, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953953

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) affecting more than 2.5 million people worldwide. However, the exact etiology of MS remains unknown, recent research indicated that High-mobility group box 1(HMGB1) might contribute to MS pathogenesis. By evaluating HMGB1 levels of peripheral blood mononuclear cells (PBMC), serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients and the controls, to reveal the relationship of HMGB1 levels and MS patients. METHODS: The PubMed, EMBASE, the Cochrane library, China National Knowledge Infrastructure (CNKI) and WanFangData were searched for relevant studies. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated as effect size, random-effects model was used when I2 > 50%. Subgroup analysis was conducted by subtype of MS, categories of controls, country and mean age. RESULTS: A total of 7 studies with 364 patients of MS and 222 controls were included. The results of this study showed that HMGB1 protein levels of PBMC and CSF in patients with MS were significantly higher than those of controls (SMD = 4.36, 95% CI = 3.69-5.02, and SMD = 0.85, 95% CI = 0.42-1.28, respectively), but we found no significant difference in HMGB1 mRNA level of PBMC and serum HMGB1 protein level between MS patients and controls. In the subgroup analysis, RRMS patients had a higher HMGB1 level in serum (p < 0.05) and CSF (p < 0.01) compared to healthy controls and non-inflammatory neurological disorder controls. In Asians, MS patients had a considerably higher HMGB1 level in serum (p < 0.05), PBMC (protein) (p < 0.01) and CSF (p < 0.01) compared to healthy controls and non-inflammatory neurological disorder controls. CONCLUSION: MS patients had higher HMGB1 protein levels in PBMC and CSF compared to controls. HMGB1 might be a new treatment target for MS.


Assuntos
Proteína HMGB1/sangue , Proteína HMGB1/líquido cefalorraquidiano , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Humanos , Leucócitos Mononucleares/metabolismo , Esclerose Múltipla/epidemiologia , RNA Mensageiro/metabolismo
2.
JAMA Intern Med ; 178(11): 1451-1457, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30264133

RESUMO

Importance: A critical question in health care is the extent of scientific evidence that should be required to establish that a new therapeutic agent has benefits that outweigh its risks. Estimating the costs of this evidence of efficacy provides an important perspective. Objective: To estimate costs and assess scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) from 2015 to 2016. Design and Setting: This study identified 59 novel therapeutic drugs using the annual summary reports from the FDA Center for Drug Evaluation and Research. ClinicalTrials.gov, FDA reviews, and peer-reviewed publications that were publicly available in 2017 were used to identify 52 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors. Main Outcomes and Measures: Estimated mean cost and 95% CIs based on industry benchmark data from 60 countries. Measures of trials' scientific characteristics included trial design (no control group, placebo, and active drug), end point (surrogate outcome, clinical scale, and clinical outcome), patient enrollment, and treatment duration. Results: A total of 138 pivotal clinical trials provided the basis for approval of 59 new therapeutic agents by the FDA from 2015 to 2016, with a median estimated cost of $19.0 million (interquartile range, $12.2 million-$33.1 million). Estimated costs ranged from less than $5 million for trials without a control group for 3 orphan drugs with fewer than 15 patients each to $346.8 million (95% CI, $252.0 million-$441.5 million) for a noninferiority trial with end points assessing clinical benefit. Twenty-six of 138 trials (18.8%) were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million-$16.9 million). Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million). Costs also varied by trial end point, treatment duration, patient enrollment, and therapeutic area. Conclusions and Relevance: The highest-cost trials were those in which the new agent had to be proved to be noninferior with clinical benefit end points compared with an agent already available or those that required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.


Assuntos
Ensaios Clínicos como Assunto/economia , Aprovação de Drogas/economia , Indústria Farmacêutica/economia , Projetos de Pesquisa , Humanos , Estados Unidos , United States Food and Drug Administration
3.
Biomed Chromatogr ; 31(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28544073

RESUMO

The acute cardiotoxicity induced by Veratrum nigrum (VN) is explored by analyzing heart tissue metabolic profiles in mouse models and applying reversed-phase liquid chromatography mass spectrometry and hydrophilic interaction liquid chromatography mass spectrometry that are based on ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. An animal model of acute heart injury was established in mice via intra-gastric administration of VN. Then, electrocardiogram and echocardiograph monitoring of cardiac function and pathological examination were performed on mice in both the control and VN groups, and it was verified that acute heart injury was caused. Meanwhile, comparing the results of the control and VN groups, we detected 36 differential endogenous metabolites of heart tissue, including taurine, riboflavin, purine and lipids, which are related to many possible pathways such as purine metabolism, taurine and hypotaurine metabolism and energy metabolism. Our study provides a scientific approach for evaluating and revealing the mechanisms of VN-induced cardiotoxicity via the metabolomic strategy.


Assuntos
Cardiotoxinas/toxicidade , Cromatografia Líquida de Alta Pressão/métodos , Metaboloma/efeitos dos fármacos , Extratos Vegetais/toxicidade , Veratrum/química , Animais , Cardiotoxicidade/metabolismo , Cardiotoxinas/química , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Extratos Vegetais/química
4.
Brain Res ; 1650: 196-202, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27608957

RESUMO

OBJECTIVE: To determine serum activities of angiotensin-converting enzyme (ACE) as a marker in diagnosis and determine the severity of Alzheimer's disease (AD), METHODS: We measured serum ACE activities in 59 moderate-severe AD, 19 mild AD, 45 amnestic mild cognitive impairment (aMCI) and 39 controls. RESULTS: We found that patients in moderate-severe AD stages showed significantly higher ACE in comparison to aMCI and controls (ANOVA, LSD post hoc test: p: 0.02 and p: 0.01, respectively). Logistic regression analysis showed that if ACE activities added 200 U/L, the superiority of AD risk was 1.18 times higher than before compared with the control group (OR 1.18, 95% CI 1.01-1.74; P=0.49). By means of multivariate linear regression analysis, we found that age (ß coefficient: 7.77; P: 0.01) was significantly associated with ACE activities. However, ACE activities were found to be significantly negatively associated with measures of orientation and immediate recall among the AD patients (r<0, P<0.05), whereas ACE activities were not associated with any MMSE scores among the non-AD groups (P > 0.05).uuuu CONCLUSIONS: ACE serum activity that correlates with age is likely to constitute a potential risk factor for the development of AD. ACE serum activity might be a useful biomarker for disease status with increasingly high ACE from mild stage to moderate-severe stage. Moreover, patients with aMCI could take ACE inhibitor (ACEI) to decrease the incidence of AD, and patients with AD could take ACEI to retard cognitive decline in early AD.


Assuntos
Peptidil Dipeptidase A/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Inibidores da Enzima Conversora de Angiotensina , Biomarcadores/sangue , Transtornos Cognitivos/etiologia , Disfunção Cognitiva , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/fisiologia , Fatores de Risco
5.
J Neurosci Res ; 88(10): 2197-206, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20175208

RESUMO

Glial cell line-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) are strong neurotrophic factors, which function as antiapoptotic factors. However, the neuroprotective effect of GDNF and HGF in ameliorating ischemic brain injury via an antiautophagic effect has not been examined. Therefore, we investigated GDNF and HGF for changes of infarct size and antiapoptotic and antiautophagic effects after transient middle cerebral artery occlusion (tMCAO) in rats. For the estimation of ischemic brain injury, the infarct size was calculated at 24 hr after tMCAO by HE staining. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) was performed for evaluating the antiapoptotic effect. Western blot analysis of microtubule-associated protein 1 light chain 3 (LC3) and immunofluorescence analysis of LC3 and phosphorylated mTOR/Ser(2448) (p-mTOR) were performed for evaluating the antiautophagic effect. GDNF and HGF significantly reduced infarct size after cerebral ischemia. The amounts of LC3-I plus LC3-II (relative to beta-tubulin) were significantly increased after tMCAO, and GDNF and HGF significantly decreased them. GDNF and HGF significantly increased p-mTOR-positive cells. GDNF and HGF significantly decreased the numbers of TUNEL-, LC3-, and LC3/TUNEL double-positive cells. LC3/TUNEL double-positive cells accounted for about 34.3% of LC3 plus TUNEL-positive cells. This study suggests that the protective effects of GDNF and HGF were greatly associated with not only the antiapoptotic but also the antiautophagic effects; maybe two types of cell death can occur in the same cell at the same time, and GDNF and HGF are capable of ameliorating these two pathways.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Encéfalo/fisiopatologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Animais , Encéfalo/patologia , Infarto da Artéria Cerebral Média/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Espaço Intracelular/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Wistar , Serina-Treonina Quinases TOR , Fatores de Tempo
7.
J Cereb Blood Flow Metab ; 29(4): 715-25, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19142198

RESUMO

In the ischemic brain, reperfusion with tissue plasminogen activator (tPA) sometimes causes catastrophic hemorrhagic transformation (HT); however, the mechanism remains elusive. Here, we show that the basement membrane, and not the endothelial cells, is vulnerable to ischemic/reperfusion injury with tPA treatment. We treated a spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) with vehicle alone, tPA alone, or a free radical scavenger, edaravone, plus tPA. Light and electron microscopic analyses of each microvascular component revealed that the basement membrane disintegrated and became detached from the astrocyte endfeet in tPA-treated animals that showed HT. On the other hand, edaravone prevented the dissociation of the neurovascular unit, dramatically decreased the HT, and improved the neurologic score and survival rate of the tPA-treated rats. These results suggest that the basement membrane that underlies the endothelial cells is a key structure for maintaining the integrity of the neurovascular unit, and a free-radical scavenger can be a viable agent for inhibiting tPA-induced HT.


Assuntos
Membrana Basal/patologia , Isquemia Encefálica/complicações , Hemorragia Cerebral/induzido quimicamente , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Animais , Antipirina/análogos & derivados , Antipirina/farmacologia , Antipirina/uso terapêutico , Isquemia Encefálica/terapia , Edaravone , Depuradores de Radicais Livres/uso terapêutico , Infarto da Artéria Cerebral Média , Ratos , Ratos Endogâmicos SHR , Reperfusão , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico
8.
Neurochem Res ; 34(4): 707-10, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18770029

RESUMO

Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.


Assuntos
Isquemia Encefálica/terapia , Acidente Vascular Cerebral/terapia , Animais , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/uso terapêutico , Biliverdina/uso terapêutico , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Di-Hidropiridinas/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Ratos , Células-Tronco/patologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Tecidos Suporte
9.
Neurol Res ; 30(7): 731-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18593521

RESUMO

The therapeutic effect of a novel RNA viral vector, Sendai virus (SeV)-mediated glial cell line-derived neurotrophic factor (GDNF) gene (SeV/GDNF), on the infarct volume, was investigated after 90 minutes of transient middle cerebral artery occlusion (tMCAO) in rats with relation to nuclear translocation of apoptosis inducing factor (AIF). The topical administration of SeV/GDNF induced high level expression of GDNF protein, which effectively reduced the infarct volume when administrated 0 and 1 hours as well after the reperfusion. Twenty-four hours after ischemia, the obvious nuclear translocation of AIF was found in neurons of peri-infarct area, which significantly reduced with administration of SeV/GDNF 0 or 1 hour after reperfusion, as well as the number of TUNEL positive cells. These results demonstrate that SeV vector-mediated gene transfer of GDNF effectively reduced ischemic infarct volume after tMCAO and extended the therapeutic time window compared with previous viral vectors, and that promoting neuronal survival of GDNF might be related to the reduction of AIF nuclear translocation, indicating the high therapeutic potency of SeV/GDNF for cerebral ischemia.


Assuntos
Fator de Indução de Apoptose/metabolismo , Técnicas de Transferência de Genes , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Hipóxia-Isquemia Encefálica/terapia , Vírus Sendai/genética , Transporte Ativo do Núcleo Celular/genética , Animais , Apoptose/genética , Fator de Indução de Apoptose/genética , Infarto Encefálico/genética , Infarto Encefálico/metabolismo , Infarto Encefálico/terapia , Modelos Animais de Doenças , Vetores Genéticos/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/metabolismo , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/terapia , Masculino , Degeneração Neural/genética , Degeneração Neural/prevenção & controle , Degeneração Neural/terapia , Ratos , Ratos Wistar , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima/genética
10.
Curr Neurovasc Res ; 5(2): 112-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18473827

RESUMO

In the brain after infarction or trauma, the tissue becomes pannecrotic and forms a cavity. In such situation, a scaffold is necessary to produce new tissue. In this study, we implanted a new porous gelatin-siloxane hybrid derived from gelatin and 3-(glycidoxypropyl) trimethoxysilane (gelatin-GPTMS) scaffolds into a brain defect, and investigated whether it makes a new brain tissue. In addition, vascular endothelial growth factor (VEGF) was added on gelatin-GPTMS scaffolds and its effect on tissue regeneration was examined. At 30 days after the implantation, the marginal territory of the scaffolds became occupied by newly formed tissue. Immunohistochemical analysis revealed that the new tissue was constituted by endothelial, astroglial and microglial cells, some of which were labeled for bromodeoxyuridine (BrdU). Addition of VEGF promoted numbers of these cells. Thus, combination of gelatin-GPTMS scaffolds and VEGF is preferable for brain regeneration.


Assuntos
Lesões Encefálicas/cirurgia , Gelatina , Regeneração Nervosa/efeitos dos fármacos , Siloxanas , Tecidos Suporte , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Implantes Absorvíveis , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Bromodesoxiuridina/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Gelatina/uso terapêutico , Masculino , Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Wistar , Siloxanas/uso terapêutico
11.
Brain Res ; 1188: 1-8, 2008 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-18035335

RESUMO

Biliverdin (BV), one of the byproducts of heme catalysis through heme oxygenase (HO) system, is a scavenger of reactive oxygen species (ROS). We hypothesized that BV treatment could protect rat brain cells from oxidative injuries via its anti-oxidant efficacies. Cerebral infarction was induced by transient middle cerebral artery occlusion (tMCAO) for 90 min, followed by reperfusion. BV or vehicle was administered intraperitoneally immediately after reperfusion. The size of the cerebral infarction 2 days after tMCAO was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) stain. Superoxide generation 4 h after tMCAO was determined by detection of oxidized hydroethidine. In addition, the oxidative impairment of neurons were immunohistochemically assessed by stain for lipid peroxidation with 4-hydroxy-2-nonenal (4-HNE) and damaged DNA with 8-hydroxy-2'-deoxyguanosine (8-OHdG). BV treatment significantly reduced infarct volume of the cerebral cortices associated with less superoxide production and decreased oxidative injuries of brain cells. The present study demonstrated that treatment with BV ameliorated the oxidative injuries on neurons and decreased brain infarct size in rat tMCAO model.


Assuntos
Antioxidantes/farmacologia , Biliverdina/farmacologia , Infarto Cerebral/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Aldeídos/metabolismo , Animais , Antioxidantes/metabolismo , Biliverdina/metabolismo , Infarto Cerebral/metabolismo , Infarto Cerebral/fisiopatologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções Intraperitoneais , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Fenantridinas , Ratos , Ratos Wistar , Superóxidos/metabolismo , Sais de Tetrazólio , Resultado do Tratamento
12.
Curr Neurovasc Res ; 4(4): 268-73, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18045152

RESUMO

Statin reduces cerebrovascular events independent of its cholesterol lowering effect. We hypothesized that statin inhibits early atherosclerotic change in common carotid artery (CCA), and investigated its effect on lectin-like oxidized-LDL receptor-1 (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) expression, both of which are early atherosclerotic markers. Stroke-prone spontaneous hypertensive rats (SHR-SP) of 8 weeks old were orally treated with vehicle or simvastatin (20mg/kg) daily. After 4 weeks of simvastatin or vehicle treatment, or 2 weeks of vehicle and 2 weeks of simvastatin treatment, CCA was removed. LOX-1 and MCP-1 expression as well as macrophage infiltration were histologically investigated. Lipid deposition was also investigated by Sudan III staining. Simvastatin groups showed significantly smaller amount of lipid deposition and LOX-1 and MCP-1 expression, independent of serum lipid levels. Macrophage infiltration was also decreased. Reduction of cerebrovascular events by statins may be brought by the direct inhibition of atherosclerotic change.


Assuntos
Quimiocina CCL2/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Artéria Carótida Primitiva/metabolismo , Colesterol/sangue , Colesterol na Dieta/farmacologia , Depressão Química , Dieta , Gorduras na Dieta/farmacologia , Imuno-Histoquímica , Contagem de Leucócitos , Lipídeos , Masculino , Ratos , Ratos Endogâmicos SHR , Sinvastatina/farmacologia , Triglicerídeos/sangue
13.
Brain Res ; 1176: 143-50, 2007 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-17904110

RESUMO

BACKGROUND: Cerebral ischemia is a major leading cause of death and at the first place cause of disability all over the world. There are a lot of drugs that are in experimental stage for treatment of stroke. Among them are calcium channel blockers (CCBs) that have, in animal models, different effectiveness in healing of ischemic damage in brain. Mechanism of CCBs' action in cerebral ischemia is still unclear, but antioxidative property is supposed to be implicated. In the present study, we investigated antioxidative and neuroprotective properties of two CCBs, azelnidipine and amlodipine. METHODS: Male Wistar Kyoto rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) by a nylon thread. Animals were divided into 3 groups, vehicle, azelnidipine and amlodipine group. In the azelnidipine and amlodipine groups, rats were treated with azelnidipine (1 mg/kg) and amlodipine (1 mg/kg) by gastric gavage for 2 weeks before MCAO. Vehicle group was treated by solution of methyl cellulose for 2 weeks. Rats were killed 24 h after MCAO. Physiological parameters (mean arterial pressure, heart rate, body weight), infarct volume, brain edema index, cerebral blood flow (CBF), oxidative stress markers which are HEL, 4-HNE, AGE and 8-OHdG, and evidence of apoptosis by TUNEL, were investigated. RESULTS: There were no significant differences among groups in mean arterial pressure, heart rate and body weight. Treatment with azelnidipine and amlodipine reduced infarct volume and brain edema. Azelnidipine treated group showed more marked reduction of infarct volume and cerebral edema than amlodipine group. There was no attenuation of CBF in CCBs groups. The number of HEL, 4-HNE, AGE and 8-OHdG positive cells were significantly decreased in the CCBs treated groups. These molecules were again fewer in the azelnidipine group than in the amlodipine group. In TUNEL staining, the numbers of positive cells was smaller in the CCBs treated groups, especially in the azelnidipine group. CONCLUSIONS: Pretreatment of azelnidipine and amlodipine had a neuroprotective effect in ischemic brain. Antioxidative property is one of the important profiles of CCBs that is implicated in brain protection.


Assuntos
Infarto Encefálico/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Anlodipino/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Infarto Encefálico/metabolismo , Infarto Encefálico/fisiopatologia , Di-Hidropiridinas/farmacologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos WKY , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Resultado do Tratamento
14.
Brain Res ; 1159: 1-7, 2007 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-17574219

RESUMO

It is very important to investigate the mechanism of axonal growth in the ischemic brain in order to consider a novel mean of therapy for stroke. Netrins are chemotropic factors for axon with chemoattractant or chemorepellant guidance activities, and deleted in colorectal cancer (DCC) and neogenin are receptors for netrins. In this study, we examined expressions of netrin-1, DCC, and neogenin in the brain after 90 min of transient middle cerebral artery occlusion (tMCAO). Netrin-1 was expressed in neurons at the peri-ischemic area with a peak at 14 days. DCC was expressed both in neurons and astrocytic feet with a peak at 14 days, though neogenin was expressed in endothelial cells at MCA territory with a peak at the same time point. These results suggest that netrin-1 is involved in the promotion of axonal growth. The expression of netrin-1 and DCC was overlapped both in the spatial and temporal patterns, indicating that DCC plays a role in netrin-1's axonal growth promoting effects. The location of neogenin positive cells differed from that of netrin-1 positive cells, thus its angiogenic activity may not have relevance with netrin-1.


Assuntos
Isquemia Encefálica/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Membrana/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Isquemia Encefálica/patologia , Receptor DCC , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Netrina-1 , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo
15.
J Neurosci Res ; 85(10): 2167-74, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17497673

RESUMO

Recent studies have shown that administration of granulocyte colony-stimulating factor (G-CSF) is neuroprotective. However, the precise mechanisms of the neuroprotective effect of G-CSF are not entirely known. We carried out 90-min transient middle cerebral occlusion (tMCAO) of rats. The rats were injected with vehicle or G-CSF (50 mug/kg) immediately after reperfusion and sacrificed 8, 24, or 72 hr later. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was carried out using brain sections of 72 hr, and immunohistochemistry was carried out with those of 8, 24, and 72 hr. TTC-staining showed a significant reduction of infarct volume in the G-CSF-treated group (**P < 0.01). Immunohistochemistry showed a significant decrease of the number of cells expressing tumor necrosis factor-alpha (TNF-alpha) at 8-72 hr, transforming growth factor-beta (TGF-beta) and inducible nitric oxide synthase (iNOS) at 24 and 72 hr after tMCAO in the peri-ischemic area (*P < 0.05 each). Our data suggest that the suppression of inflammatory cytokines and iNOS expression may be one mechanism of neuroprotection by G-CSF.


Assuntos
Anti-Inflamatórios/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Infarto da Artéria Cerebral Média/complicações , Inflamação/patologia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Imuno-Histoquímica , Inflamação/etiologia , Masculino , Sistema Nervoso/fisiopatologia , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Neurosci Lett ; 418(3): 248-52, 2007 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-17449175

RESUMO

Granulocyte colony-stimulating factor (G-CSF) enhances the survival and stimulates the proliferation of neutrophil progenitors. Recently, the neurogenerative effect of G-CSF has been intensely investigated. In this study, we explored the possibility that G-CSF enhanced the cell proliferation in the rat dentate gyrus (DG) after focal cerebral ischemia, using a rat transient middle cerebral artery occlusion (tMCAO) model. At 7 days after tMCAO, the number of 5-bromodeoxyuridine (BrdU)-positive cells in the G-CSF-treated group was significantly increased compared with that in the vehicle-treated group in the ipsilateral SGZ (16.6+/-5.5/mm(2) in the vehicle-treated group versus 33.0+/-7.2/mm(2) in the G-CSF-treated group, **p<0.01) and in the ipsilateral GCL (14.2+/-2.8/mm(2) in the vehicle-treated group versus 21.0+/-3.8/mm(2) in the G-CSF-treated group, *p<0.05). This result showed the possibility of a neurogenerative role of G-CSF after tMCAO in rats.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hipocampo/patologia , Infarto da Artéria Cerebral Média/patologia , Neurônios/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Lateralidade Funcional , Masculino , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Ácidos Siálicos/metabolismo
17.
Brain Res ; 1151: 142-9, 2007 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-17459352

RESUMO

Recently, granulocyte colony-stimulating factor (G-CSF) is expected to demonstrate beneficial effects on cerebral ischemia. Here, we showed the potential benefit of G-CSF administration after transient middle cerebral artery occlusion (tMCAO). Adult male Wistar rats received vehicle or G-CSF (50 microg/kg) subcutaneously after reperfusion, and were treated with 5-bromodeoxyuridine (BrdU, 50 mg/kg) once daily by the intraperitoneal route for 3 days after tMCAO. Nissl-stained sections at 7 days after tMCAO showed significant reduction of the infarction area (31%, P<0.01). At 7 days after tMCAO, BrdU plus NeuN double-positive cells increased by 43.3% in the G-CSF-treated group (P<0.05), and BrdU-positive endothelial cells were increased 2.29 times in the G-CSF-treated group, to a level as high as that in the vehicle-treated group (P<0.01), in the periischemic area. Our results indicate that G-CSF caused potentiation of neuroprotection and neurogenesis and is expected to have practical therapeutic potential in treating individuals after ischemic brain injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/irrigação sanguínea , Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Encéfalo/patologia , Bromodesoxiuridina/metabolismo , Contagem de Células , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo
18.
Brain Res ; 1132(1): 29-35, 2007 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-17189618

RESUMO

In the brain after infarction or trauma, the tissue eventually becomes pannecrotic and forms a cavity. In such situations, a scaffold is necessary for the implanted or migrated cells to produce new tissue. In this present study, therefore, we attempted to restore brain tissue using a novel biomaterial, polydimethylsiloxane-tetraethoxysilane (PDMS-TEOS) hybrid with or without vascular endothelial growth factor (VEGF), which is crucial for new vessel formation. When PDMS-TEOS scaffold was implanted into the artificial brain defect, it remained at the implanted site and kept the integrity of the brain shape. At 30 days after the implantation, the marginal territory of PDMS-TEOS scaffold became occupied by newly formed tissue. Immunohistochemical analysis revealed that the new tissue was constituted by astrocytes and endothelial cells. Addition of VEGF increased the newly produced tissue volume, and the immunohistochemical analysis showed that the numbers of astrocytes and endothelial cells were increased. Double staining with proliferation maker Ki67 demonstrated that VEGF significantly increased newly formed astrocytes and endothelial cells, indicating that addition of VEGF accelerated tissue restoration and angiogenesis. These findings show that implantation of PDMS-TEOS scaffold with VEGF might be effective for treating old brain infarction or trauma.


Assuntos
Materiais Biocompatíveis/farmacologia , Lesão Encefálica Crônica/terapia , Dimetilpolisiloxanos/uso terapêutico , Implantes Experimentais , Silanos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/cirurgia , Proliferação de Células/efeitos dos fármacos , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiologia , Descorticação Cerebral , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Imuno-Histoquímica , Antígeno Ki-67/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Nylons , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/uso terapêutico
19.
Brain Res ; 1093(1): 190-7, 2006 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-16701577

RESUMO

Nitric oxide (NO) can be neuroprotective or neurotoxic during cerebral ischemia, depending on the NO synthase (NOS) isoform involved. In addition to neurotoxic effect in ischemic brain, inducible NOS (iNOS) also adversely affect ischemic outcome by blocking neurogenesis. In the present study, therefore, we studied the chronological and spatial change of the distribution of iNOS and cell proliferation in subventricular zone (SVZ) after transient focal cerebral ischemia. After 90 min of transient middle cerebral artery occlusion (tMCAO), iNOS-positive cells decreased in the ischemic core at 1 to 21 days, and increased in the ipsilateral periischemic area at 1 and 3 days. 5-Bromodeoxyuridine (BrdU)-positive cells appeared in the ischemic core at 3 to 21 days, appeared in the periischemic area at 3 and 7 days, and increased in the ipsilateral SVZ at 7 days. ED-1-positive cells appeared in the ischemic core at 3 to 21 days, and some of them were double positive with BrdU or iNOS, but the majority were BrdU-negative. The present study suggests that astrocytes are born within the periischemic area at early stage after tMCAO and migrate from SVZ into periischemic area at later stage, and that time-dependent and spatial changes of iNOS expression may be involved in the proliferation and differentiation of adult neurogenesis after focal cerebral ischemia.


Assuntos
Encéfalo/enzimologia , Proliferação de Células , Infarto da Artéria Cerebral Média/enzimologia , Regeneração Nervosa/fisiologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Encéfalo/patologia , Imuno-Histoquímica , Masculino , Neurônios/enzimologia , Ratos , Ratos Wistar , Fatores de Tempo
20.
Curr Neurovasc Res ; 3(2): 119-29, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16719795

RESUMO

Angiogenesis occurs in a wide range of conditions. As ischemic tissue usually depends on collateral blood flow from newly produced vessels, acceleration of angiogenesis should be of therapeutic value to ischemic disorders. Indeed, therapeutic angiogenesis reduced tissue injury in myocardial or limb ischemia. In ischemic stroke, on the other hand, angiogenic factors often increase vascular permeability and thus may deteriorate tissue damage. In order to apply safely the therapeutic angiogenesis for ischemic stroke treatment, elucidating precise mechanism of brain angiogenesis is mandatory. In the present article, we review previous reports which investigated molecular mechanisms of angiogenesis. Endothelial cell mitogens, enzymes that degrade surrounding extracellular matrix, and molecules implicated in endothelial cells migration are induced rapidly in the ischemic brain. Their possible neuroprotective or injury exacerbating effects are discussed. Because therapeutic potential of angiogenic factors application had gained much attention, we here extensively reviewed relevant previous reports. In the future however, there is a need to consider angiogenesis in relation with regenerative medicine, as angiogenic factors sometimes possess neuron producing property.


Assuntos
Isquemia Encefálica/terapia , Células Endoteliais/metabolismo , Neovascularização Fisiológica/fisiologia , Regeneração/fisiologia , Acidente Vascular Cerebral/terapia , Proteínas Angiogênicas/metabolismo , Proteínas Angiogênicas/farmacologia , Proteínas Angiogênicas/uso terapêutico , Animais , Isquemia Encefálica/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Endoteliais/efeitos dos fármacos , Proteínas da Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Humanos , Mitógenos/metabolismo , Mitógenos/farmacologia , Mitógenos/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Acidente Vascular Cerebral/fisiopatologia
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