RESUMO
Salidroside, an active ingredient in Rhodiola rosea, has potent protective activity against cerebral ischemia. However, the mechanisms underlying its pharmacological actions are poorly understood. In this study, we employed a mouse middle cerebral artery occlusion (MCAO) and cellular oxygen and glucose deprivation (OGD) models to test the hypothesis that salidroside may restore mitochondrial quality control in neurons by modulating the relevant signaling. The results indicated that salidroside mitigated almost 40% the ischemia-induced brain infarct volumes in mice and the OGD-decreased viability of neurons to ameliorate the mitochondrial functions. Furthermore, salidroside treatment alleviated the OGD- or ischemia-induced imbalance of mitochondrial fission and fusion, mitophagy and promoted mitochondrial biogenesis in neurons by attenuating the AMPK activity. Moreover, salidroside alleviated 50% the OGD-promoted mitochondrial calcium fluorescence intensity and 5% mitochondria-associated membrane (MAM) area by down-regulating GRP75 expression independent of the AMPK signaling. Finally, similar findings were achieved in primary mouse neurons. Collectively, these data indicate that salidroside effectively restores the mitochondria dynamics, facilitates mitochondrial biogenesis by attenuating the AMPK signaling, and maintains calcium homeostasis in neurons independent of the AMPK activity.
Assuntos
Proteínas Quinases Ativadas por AMP , Isquemia Encefálica , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Cálcio/metabolismo , Glucose/metabolismo , Glucosídeos , Isquemia/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neurônios , FenóisRESUMO
BACKGROUND: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. OBJECTIVE: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. METHODS: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro. RESULTS: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3ß signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3ß in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. CONCLUSIONS: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3ß signaling pathway.
Assuntos
Axônios/patologia , Berberina/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Transdução de Sinais/fisiologia , Proteínas tau/metabolismo , Animais , Axônios/efeitos dos fármacos , Berberina/farmacologia , Células Cultivadas , Cromonas/farmacologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Modelos Animais de Doenças , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Feminino , Glucose/farmacologia , Masculino , Morfolinas/farmacologia , Gravidez , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , EstreptozocinaRESUMO
Fistular onion stalk is used as a traditional herbal medicine, and its extract exhibits certain beneficial effects on cardiovascular disease. In this study, the effects of fistular onion stalk extract on the pathological features, circulating inflammatory cytokines, local renin-angiotensin-aldosterone system (RAAS) and signaling pathway activities were examined using an in vivo model of atherosclerosis. Atherosclerosis of the aorta was induced by loading Sprague Dawley rats with a high-fat diet and vitamin D2. Fistular onion stalk extract administration began five weeks after the induction of atherosclerosis and continued for 12 weeks. Rats treated with fistular onion stalk extract showed a significant reduction in the pathological region compared with the vehicle-treated controls. Inhibition of atherosclerosis was associated with preservation of the vascular wall and immune cell infiltration. The extract also reduced the levels of the local inflammatory cytokines interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α. Furthermore, the extract downregulated the local activity of the RAAS. In addition, extract treatment inhibited several inflammatory signaling pathways by preventing phosphorylation, including the nuclear factor κB, Janus kinase/signal transducers and activators of transcription and mitogen-activated protein kinase pathways. These data indicate that fistular onion stalk extract may be useful for the attenuation of atherosclerosis, and the mechanism includes the regulation of the local inflammatory response.