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1.
J Neurosci ; 33(30): 12364-74, 2013 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-23884942

RESUMO

Transient global ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons in humans and animals. It is well established that estrogens ameliorate neuronal death in animal models of focal and global ischemia. However, the role of signal transducer and activator of transcription-3 (STAT3) and its target genes in estradiol neuroprotection in global ischemia remains unclear. Here we show that a single intracerebral injection of 17ß-estradiol to ovariectomized female rats immediately after ischemia rescues CA1 neurons destined to die. Ischemia promotes activation of STAT3 signaling, association of STAT3 with the promoters of target genes, and STAT3-dependent mRNA and protein expression of prosurvival proteins in the selectively vulnerable CA1. In animals subjected to ischemia, acute postischemic estradiol further enhances activation and nuclear translocation of STAT3 and STAT3-dependent transcription of target genes. Importantly, we show that STAT3 is critical to estradiol neuroprotection, as evidenced by the ability of STAT3 inhibitor peptide and STAT3 shRNA delivered directly into the CA1 of living animals to abolish neuroprotection. In addition, we identify survivin, a member of the inhibitor-of-apoptosis family of proteins and known gene target of STAT3, as essential to estradiol neuroprotection, as evidenced by the ability of shRNA to survivin to reverse neuroprotection. These findings indicate that ischemia and estradiol act synergistically to promote activation of STAT3 and STAT3-dependent transcription of survivin in insulted CA1 neurons and identify STAT3 and survivin as potentially important therapeutic targets in an in vivo model of global ischemia.


Assuntos
Isquemia Encefálica/fisiopatologia , Estradiol/fisiologia , Proteínas Associadas aos Microtúbulos/genética , Fator de Transcrição STAT3/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Estradiol/farmacologia , Feminino , Injeções Intraventriculares , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Ovariectomia , Fosforilação/fisiologia , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Survivina
2.
Nat Neurosci ; 12(5): 618-26, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19349976

RESUMO

Dysregulation of Akt signaling is important in a broad range of diseases that includes cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. We found that global ischemia in intact rats triggered expression and activation of the Akt inhibitor CTMP (carboxyl-terminal modulator protein) in vulnerable hippocampal neurons and that CTMP bound and extinguished Akt activity and was essential to ischemia-induced neuronal death. Although ischemia induced a marked phosphorylation and nuclear translocation of Akt, phosphorylated Akt was not active in post-ischemic neurons, as assessed by kinase assays and phosphorylation of the downstream targets GSK-3beta and FOXO3A. RNA interference-mediated depletion of CTMP in a clinically relevant model of stroke restored Akt activity and rescued hippocampal neurons. Our results indicate that CTMP is important in the neurodegeneration that is associated with stroke and identify CTMP as a therapeutic target for the amelioration of hippocampal injury and cognitive deficits.


Assuntos
Infarto Encefálico/metabolismo , Isquemia Encefálica/metabolismo , Proteínas de Transporte/metabolismo , Degeneração Neural/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/fisiopatologia , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Degeneração Neural/fisiopatologia , Neurônios/metabolismo , Palmitoil-CoA Hidrolase , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
3.
Am J Physiol Regul Integr Comp Physiol ; 292(3): R1254-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17082353

RESUMO

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.


Assuntos
Ácido Aspártico/análise , Creatina/análise , Hipocampo/metabolismo , Hipóxia Encefálica/metabolismo , Tálamo/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Hipocampo/química , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Gravidez , Tálamo/química , Fatores de Tempo
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