Protection by D609 Through Cell-Cycle Regulation After Stroke
Protection by D609 Through Cell-Cycle Regulation After Stroke
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DOI：
10.1007/s12035-010-8100-1
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发表时间：
2010-06-01
影响因子：
5.1
通讯作者：
Hatcher, James F.
中科院分区：
文献类型：
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作者：
Adibhatla, Rao Muralikrishna;Hatcher, James F.
中风后细胞周期调节蛋白的表达发生改变。细胞周期抑制已显示中风后梗死的显著减少。神经酰胺可通过激活蛋白磷酸酶2A（PP 2A）上调细胞周期蛋白依赖性激酶（Cdk）抑制剂p21和p27而诱导细胞周期阻滞。三环癸-9-基-黄原酸酯（D 609）-增加自发性高血压大鼠（SHR）短暂大脑中动脉闭塞（tMCAO）后的神经酰胺水平，可能是通过抑制鞘磷脂合成酶（SMS）。D 609可显著减少大鼠tMCAO后的脑梗死，上调Cdk抑制剂p21的表达，下调磷酸化视网膜母细胞瘤（pRb）的表达。其他人认为bFGF诱导的星形胶质细胞增殖被D 609减弱，这是由于SMS抑制导致神经酰胺增加。D 609还减少氧化磷脂酰胆碱（OxPC）蛋白加合物的形成。D 609可能通过抑制tMCAO后小胶质细胞/巨噬细胞增殖来减少活性氧的产生和OxPC的形成（另请参阅在证明中添加的注释：D 609可能在再灌注早期阻止成熟神经元进入细胞周期，然而，可能不会干扰小胶质细胞/巨噬细胞的后期增殖，所述小胶质细胞/巨噬细胞是脑源性神经营养因子（BDNF）和胰岛素样生长因子（IGF-1）的来源。（1）提供保护）。已经提出D 609通过减弱缺氧诱导因子-1 α和Bcl 2/腺病毒E1 B 19 kDa相互作用蛋白3的表达在tMCAO后提供益处。我们的数据表明，D 609通过抑制SMS，增加神经酰胺水平，并通过上调p21和引起Rb磷酸化不足（通过增加蛋白磷酸酶活性和/或Cdk抑制）诱导细胞周期阻滞，在斯托克卒中后提供益处。
Expressions of cell-cycle regulating proteins are altered after stroke. Cell-cycle inhibition has shown dramatic reduction in infarction after stroke. Ceramide can induce cell-cycle arrest by up-regulation of cyclin-dependent kinase (Cdk) inhibitors p21 and p27 through activation of protein phosphatase 2A (PP2A). Tricyclodecan-9-yl-xanthogenate (D609)-increased ceramide levels after transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR) probably by inhibiting sphingomyelin synthase (SMS). D609 significantly reduced cerebral infarction and up-regulated Cdk inhibitor p21 and down-regulated phospho-retinoblastoma (pRb) expression after tMCAO in rat. Others have suggested bFGF-induced astrocyte proliferation is attenuated by D609 due to an increase in ceramide by SMS inhibition. D609 also reduced the formation of oxidized phosphatidylcholine (OxPC) protein adducts. D609 may attenuate generation of reactive oxygen species and formation of OxPC by inhibiting microglia/macrophage proliferation after tMCAO (please also see note added in proof: D609 may prevent mature neurons from entering the cell cycle at the early reperfusion, however may not interfere with later proliferation of microglia/ macrophages that are the source of brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) in offering protection). It has been proposed that D609 provides benefit after tMCAO by attenuating hypoxia-inducible factor-1 alpha and Bcl2/adenovirus E1B 19 kDa interacting protein 3 expressions. Our data suggest that D609 provides benefit after stoke through inhibition of SMS, increased ceramide levels, and induction of cell-cycle arrest by up-regulating p21 and causing hypophosphorylation of Rb (through increased protein phosphatase activity and/or Cdk inhibition).