1. 900 mg/kg 시호 추출물이 강제수영검사에서 부동시간을 의미있게 감소시켰음. 2. SH-SY5Y 세포에서 기전연구 ● 시호는 혈청의 유, 무에 관계없이 pAkt, pGSK-3β, pCREB과 BDNF 발현을 농도 의존적으로 증가시켰음. ● β-arrestin 2 siRNA는 시호로 인한 pAkt 증가를 완전히 차단시켰음. 또한 PI3K 억제제인 wortmannin이 시호로 인한 pAkt 증가를 감소시켰음. ● 시호는 혈청의 유, 무에 관계없이 BrdU 표지 된 세포 수를 농도 의존적으로 증가 시켰음.
1. 900 mg/kg 시호 추출물이 강제수영검사에서 부동시간을 의미있게 감소시켰음. 2. SH-SY5Y 세포에서 기전연구 ● 시호는 혈청의 유, 무에 관계없이 pAkt, pGSK-3β, pCREB과 BDNF 발현을 농도 의존적으로 증가시켰음. ● β-arrestin 2 siRNA는 시호로 인한 pAkt 증가를 완전히 차단시켰음. 또한 PI3K 억제제인 wortmannin이 시호로 인한 pAkt 증가를 감소시켰음. ● 시호는 혈청의 유, 무에 관계없이 BrdU 표지 된 세포 수를 농도 의존적으로 증가 시켰음. 시호는 혈청 박탈로 인한 cyclin D1과 pRb (양성 조절자) 발현 감소를 효과적으로 차단하였으며, 또한 혈청박탈로 인한 p27 (음성 조절자) 발현 증가가 시호에 의해 약화되었음. ● 시호는 혈청박탈로 인한 활성 산소 증가를 차단시켰으며, 혈청박탈로 인한 SOD 활성 감소도 농도 의존적으로 막았음. 혈청박탈은 Bax의 발현 증가 및 Bcl-2의 발현 감소를 유도하였고, 시호에 의해 이 단백질들의 발현이 역전되었음.
Abstract▼
Ⅰ.Purpose Kami-shoyo-san (KSS) has been used traditionally to treat depressed patients. We showed previously that KSS has antidepressant-like effects at both behavioral and molecular levels. We investigated the antidepressant-like effects of Bupleurum falcatum (BF), a major component of KSS,
Ⅰ.Purpose Kami-shoyo-san (KSS) has been used traditionally to treat depressed patients. We showed previously that KSS has antidepressant-like effects at both behavioral and molecular levels. We investigated the antidepressant-like effects of Bupleurum falcatum (BF), a major component of KSS, in rats using the forced swimming test (FST) and potential mechanisms of BF action in SH-SY5Y cells. Ⅱ.Contentsand Methods ① Immobility time of BF extract (600 mg/kg, 900 mg/kg) was measured by FST. ② SH-SY5Y cells in medium with or without serum were treated with an aqueous BF extract (10, 100, 1000 ug/ml). ● Western blots were performed to examine the expression of a number of proteins involved in the cAMP response element binding protein(CREB)/brain-derived neurotrophic factor (BDNF)-mediated signaling pathway, thought to be a major target of antidepressant drug action. These included Akt, glycogen synthase kinase-3β (GSK-3β), CREB and BDNF.
● As D2 dopamine receptors have been shown to regulate the Akt/GSK-3β pathway through the β-arrestin 2 scaffolding protein, we used small interfering RNA-mediated knockdown of β-arrestin 2 expression to test whether BF acts on this pathway. ● We investigated the effects of BF on cell proliferation using the bromodeoxyuridine (BrdU) assay, and used Western blot analysis to measure changes in expression of the cell cycle phase regulators cyclin D1, phosphorylated retinoblastoma (pRb) and p27 expression. ● We examined the antioxidant effects of BF on a number of measures, including cell viability, formation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and levels of both B cell lymphoma protein-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Ⅲ.Results ① Rats administered 900 mg/kg had a significant lower immobility time in FST. ② the potential mechanisms of antidepressant action of BF in SH-SY5Y cells ● Treatment with BF extract significantly increased phosphorylation of Akt (Ser473), GSK-3β (Ser9), and CREB (Ser133), and elevated BDNF levels in a dose-dependent manner in SHSH-SY5Y, incubated both with and without serum. ● siRNA-mediated knockdown of β-arrestin 2 completely prevented the BF-induced increase in Akt phosphorylation. Furthermore, the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin also blocked the BF-induced increase in phosphorylated Akt expression. ● BF produced a dose-dependent increase in BrdU incorporation into SH-SY5Y cells, incubated with or without serum. ● BF effectively prevented the serum withdrawal-induced reduction in cyclinD1 and pRb levels (positive regulators) and attenuated the serum withdrawal-induced increase in p27 (negative regulator) expression. ● BF significantly reduced cell death and ROS generation following serum deprivation. BF prevented the serum withdrawal-induced decrease in SOD activity in a dose-dependent manner. Furthermore, serum deprivation significantly upregulated Bax and downregulated Bcl-2; BF reversed these effects. Ⅳ.Expectedcontribution ● We can search quickly herbal medicines that have an antidepressant action. ● It is possible to develop the new medicine from a natural substance. ● It is possible to develop the materials that have not only the antidepressant effects but also the memory acceleration action. ● Our studies will contribute to the scientific research of Oriental medicine, and accelerate the link between the Oriental medicine and the West medicine, and supply the energy to the domestic BT industry and a manufacture medicine industry. ● We can get the possibility of antidepressant development from natural substance, and obtain a base of study, the technical expertise and the specificity. ● Our studies, as the study about the mechanisms of action of antidepressant, will offer the development of neuroscience and the data for a basis of medical science concerning possible mechanism of antidepressant.
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