Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins
Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins
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DOI：
10.1016/j.bbrc.2005.11.095
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发表时间：
2006-01-20
影响因子：
3.1
通讯作者：
Nakashima, K
中科院分区：
文献类型：
--
作者：
Nakaso, K;Nakamura, C;Nakashima, K
作为治疗帕金森病（PD）的策略，神经保护受到了相当大的关注。Deprenyl（司来吉兰）是一种很有前途的神经保护候选药物，但其细胞保护机制尚未完全阐明。在这里，我们报告了一种新的细胞保护机制deprenyl涉及PI 3 K和Nrf 2介导的诱导氧化应激相关蛋白。丙炔苯丙胺增加SH-SY 5 Y细胞中HO-1、PrxI、TrxI、TrxRxI、γ GCS和p62/A170的表达。Deprenyl还诱导Nrf 2的核积累，并增加Nrf 2与人基因组HO-1增强子区的结合活性。Nrt 2介导的抗氧化分子的诱导由PI 3 K控制。事实上，此外，神经营养因子受体TrkB被鉴定为丙炔苯丙胺激活PI 3 K-Nrf 2的上游信号。这些结果表明，丙炔苯丙胺的细胞保护作用，部分依赖于Nrf 2介导的诱导抗氧化蛋白，这表明PI 3 K-Nrt 2系统的激活可能是一个有用的治疗策略PD。(c)2005年爱思唯尔公司All rights reserved.
Neuroprotection has received considerable attention as a strategy for the treatment of Parkinson's disease (PD). Deprenyl (Selegiline) is a promising candidate for neuroprotection; however, its cytoprotective mechanism has not been fully clarified. Here, we report a novel cytoprotective mechanism of deprenyl involving PI3K and Nrf2-mediated induction of oxidative stress-related proteins. Deprenyl increased the expression of HO-1, PrxI, TrxI, TrxRxl, gamma GCS, and p62/A170 in SH-SY5Y cells. Deprenyl also induced the nuclear accumulation of Nrf2 and increased the binding activity of Nrf2 to the enhancer region of human genomic HO-1. The Nrt2-mediated induction of antioxidative molecules was controlled by PI3K. Indeed, furthermore, neurotrophin receptor TrkB was identified as an upstream signal for PI3K-Nrf2 activation by deprenyl. These results suggest that the cytoprotective effect of deprenyl is, in part, dependent on Nrf2-mediated induction of antioxidative proteins, suggesting that activation of the PI3K-Nrt2 system may be a useful therapeutic strategy for PD. (c) 2005 Elsevier Inc. All rights reserved.