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1.
Sci Rep ; 7: 40013, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-28045138

RESUMO

Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer's disease and Parkinson's disease in vivo. Here, we showed that intraperitoneal injection of TFP5 significantly decreased the size of ischemia in early-stage of adult ischemic stroke rats. Relative to controls, rats treated with TFP5 displayed reduced excitotoxicity, neuroinflammation, apoptosis, astrocytes damage, and blood-brain barrier disruption. Our findings suggested that TFP5 might serve as a potential therapeutic candidate for acute adult ischemic stroke.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/sangue , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle
2.
Neuroscience ; 343: 337-345, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-27998781

RESUMO

AIM: We compared the efficacy of a modified truncated 24-aa peptide (TFP5), derived from the cyclin-dependent kinase 5 (CDK5)-activating cofactor p35, with mild hypothermia (MH), and determined whether the efficacy of TFP5 is affected by MH. METHODS: Ischemic stroke was induced in adult male Sprague-Dawley rats for 2h. Immediately after initiating reperfusion, TFP5, MH, or the combination of the two were administrated. 48h after reperfusion, neurological outcomes were evaluated. RESULTS: Rats that received either MH, TFP5, or the combined treatment showed smaller brain infarct size than normothermia control (NT), and there was no apparent difference among these three treatment groups. The neurological deficit was significantly improved only by the combined treatment. MH or TFP5 ameliorated the blood-brain barrier (BBB) disruption in ischemic regions with similar efficacy, whereas the combination of them had a trend toward better effect. Besides, the cleavage of p35 into p25 and apoptosis in ischemic regions was inhibited by TFP5 or the combination, but not by MH alone. CONCLUSIONS: TFP5 is comparable to MH in improving neurological outcomes in early-stage adult ischemic stroke. When TFP5 is given along with MH, less neurological deficit tends to be achieved.


Assuntos
Isquemia Encefálica/terapia , Hipotermia Induzida , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Acidente Vascular Cerebral/terapia , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Terapia Combinada , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Imunoglobulina G/metabolismo , Masculino , Metaloproteinase 9 da Matriz/sangue , Distribuição Aleatória , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
3.
Brain Res ; 1643: 113-22, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27134036

RESUMO

In order to evaluate whether glibenclamide can extend the therapeutic window during which induced hypothermia can protect against stroke, we subjected adult male Sprague-Dawley rats to middle cerebral artery occlusion (MCAO). We first verified the protective effects of hypothermia induced at 0, 2, 4 or 6h after MCAO onset, and then we assessed the effects of the combination of glibenclamide and hypothermia at 6, 8 or 10h after MCAO onset. At 24h after MCAO, we assessed brain edema, infarct volume, modified neurological severity score, Evans Blue leakage and expression of Sulfonylurea receptor 1 (SUR1) protein and pro-inflammatory factors. No protective effects were observed when hypothermia was induced too long after MCAO. At 6h after MCAO onset, hypothermia alone failed to decrease cerebral edema and infarct volume, but the combination of glibenclamide and hypothermia decreased both. The combination also improved neurological outcome, ameliorated blood-brain barrier damage and decreased levels of COX-2, TNF-α and IL-1ß. These results suggest that glibenclamide enhances and extends the therapeutic effects of delayed hypothermia against ischemia stroke, potentially by ameliorating blood-brain barrier damage and declining levels of pro-inflammatory factors.


Assuntos
Edema Encefálico/prevenção & controle , Encefalite/prevenção & controle , Glibureto/administração & dosagem , Hipertermia Induzida/métodos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Edema Encefálico/etiologia , Ciclo-Oxigenase 2/metabolismo , Encefalite/etiologia , Encefalite/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Sulfonilureias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Biochem Biophys Res Commun ; 474(1): 175-181, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27107700

RESUMO

Hypothermia followed by slow rewarming is neuroprotective for ischemic stroke. However, slow rewarming causes patients' longer stay in intensive care unit and increases the risk of hypothermic complications. Hypothermia followed by rapid rewarming (HTRR) is more convenient; but it exacerbates intracranial hypertension for patients with massive hemispheric infarcts. The present study aims to investigate in detail how HTRR exacerbates ischemic brain injury and what are underlying mechanisms. Rats subjected to transient focal ischemia by middle cerebral artery occlusion were treated with normothermia or hypothermia followed by rapid rewarming. Neurological outcome, neuronal injury, blood-brain barrier integrity and expressions of inflammatory cytokines were observed. Results showed that HTRR at a rate of 3 °C/20 min increased both neurological deficit score and Longa score, enhanced the loss of neurons and the plasma level of neuron-specific enolase. Rapid rewarmed rats also displayed increased Evans blue dye extravasation, matrix metalloproteinase 9 level and tight junction impairment. Meanwhile, interleukin-1ß, -6, tumor necrosis factor α and cyclooxygenase-2 were markedly elevated in rapid rewarmed rats. Anti-inflammatory agent minocycline suppressed HTRR-induced elevation of inflammatory cytokines and improved neurological outcome. These results indicated that HTRR significantly impaired neurovascular unit and augmented proinflammatory response in stroke.


Assuntos
Hipotermia Induzida/efeitos adversos , Reaquecimento/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Resultado do Tratamento
5.
Sci Rep ; 6: 24073, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-27044405

RESUMO

Extracellular high mobility group box 1 (HMGB1) has been demonstrated to function as a proinflammatory cytokine and induces neuronal injury in response to various pathological stimuli in central nervous system (CNS). However, the regulatory factor involved in HMGB1-mediated inflammatory signaling is largely unclear. Regulatory RNase 1 (Regnase-1) is a potent anti-inflammation enzyme that can degrade a set of mRNAs encoding proinflammatory cytokines. The present study aims to determine the role of Regnase-1 in the regulation of HMGB1-mediated inflammatory injury in CNS. Cultured microglia and rat brain were treated with recombinant HMGB1 to examine the induction of Regnase-1 expression. Moreover, the role of Regnase-1 in modulating the expression of inflammatory cytokines and neuronal injury was then investigated in microglia by specific siRNA knockdown upon HMGB1 treatment. Results showed that HMGB1 could significantly induce the de novo synthesis of Regnase-1 in cultured microglia. Consistently, Regnase-1 was elevated and found to be co-localized with microglia marker in the brain of rat treated with HMGB1. Silencing Regnase-1 in microglia enhanced HMGB1-induced expression of proinflammatory cytokines and exacerbated neuronal toxicity. Collectively, these results suggest that Regnase-1 can be induced by HMGB1 in microglia and negatively regulates HMGB1-mediated neuroinflammation and neuronal toxicity.


Assuntos
Regulação da Expressão Gênica , Proteína HMGB1/metabolismo , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Inflamação , Masculino , Camundongos , Microglia/metabolismo , Neurônios/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/metabolismo , Transdução de Sinais
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