RESUMEN
OBJECTIVES: Ischemia/reperfusion can induce neuronal apoptosis in the brain and lead to function deficits. The activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is neuroprotective against transient cerebral ischemia. The neuroprotective mechanisms of PKA mainly involve the regulation of gene transcription via the PKA/CREB pathway. The present study aims to investigate the neuroprotective effect of meglumine cyclic adenylate, an activator of PKA, under a rat model of global cerebral ischemia/reperfusion and to reveal the underlying mechanism involving signal transducer and activator of transcription 3 (STAT3)-Ser727 phosphorylation and mitochondrion modulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to 15 min global cerebral ischemia, and meglumine cyclic adenylate was treated through tail intravenous injection 30 min before ischemia. Cresyl violet staining was used to evaluate neuron injury at 5 d of reperfusion. Western blotting was used to detect p-Ser727-STAT3, total STAT3, cytochrome c (Cyt c) and active caspase-3 in the tissues of hippocampal CA1 region at 6 h of reperfusion. STAT3-S727A was overexpressed in HT22 cells to reveal the significance of STAT3-Ser727 phosphorylation in the neuroprotective effect of meglumine cyclic adenylate. RESULTS: Pretreatment with meglumine cyclic adenylate not only significantly ameliorated neuron loss in CA1 region after global cerebral ischemia but also enhanced STAT3-Ser727 phosphorylation, increased mitochondrial STAT3, and decreased cytosolic Cyt c and active caspase-3. Overexpression of STAT3-S727A in HT22 cells eliminated meglumine cyclic adenylate-induced increase of p-Ser727-STAT3, mitochondrial STAT3, cytosolic Cyt c and active caspase-3. CONCLUSION: Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury via promoting p-Ser727-STAT3-associated mitochondrion modulation and inhibiting apoptosis pathway.
Asunto(s)
Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Masculino , Animales , Fármacos Neuroprotectores/farmacología , Ratas Sprague-Dawley , Fosforilación , Caspasa 3/metabolismo , Factor de Transcripción STAT3/metabolismo , Apoptosis , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismoRESUMEN
OBJECTIVE: To study the characteristics of pharyngeal respiratory pressure before and after onset of airflow obstruction events in obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: The respiratory pressure in nasopharynx, oropharynx, and hypopharynx in 8 patients with OSAHS and 9 normal persons were evaluated through catheter manometer. Base on mean respiratory pressure and the ratio of negative respiratory pressure persistent time, the characteristics of pharyngeal respiratory pressure before and after the event onset were analyzed. RESULTS: During sleep, the pharyngeal respiratory pressure in normal persons had similar and periodical wave shape. The ratio of negative respiratory pressure persistent time was less than 0.5. In patients with OSAHS, when the obstruction of airflow happened, the pharyngeal respiratory pressure fluctuated violently, the wave shape became irregular, and the negative expiratory pressure was evident. The mean respiratory pressure was 1 to 2 order of magnitude larger than in normal persons, even reaching -990 Pa. The ratio of persistent negative pressure time was larger than normal. During the intermittent period, the wave shape of pharyngeal respiratory pressure was regular and periodical, the pressure wave shape was different from onset of obstruction. However, in the intermittent period, the mean respiratory pressure, the ratio of negative respiratory pressure persistent time, and other characteristics were still statistically different from normal persons (P < 0.05). CONCLUSIONS: During the intermittent period, the pharyngeal respiratory pressure in patients with OSAHS during sleep is basically different from the pharyngeal respiratory pressure in normal person. The characteristics of pharyngeal respiratory pressure in intermittent period indicates that both structural and functional abnormalities in pharyngeal cavity in patients with OSAHS, which affect the respiratory airflow during sleep are inherent. The effects are more prominent during onset period, suggesting that the characteristics of the pharyngeal pressure of breathing during the onset period will be more important to the mechanism of airflow obstruction.