Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-3232, USA.
Mol Neurobiol. 2010 Jun;41(2-3):206-17. doi: 10.1007/s12035-010-8100-1. Epub 2010 Feb 12.
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-1alpha 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).
细胞周期调节蛋白的表达在中风后发生改变。细胞周期抑制已显示出在中风后梗死面积显著减少。神经酰胺可通过激活蛋白磷酸酶 2A（PP2A）而上调细胞周期蛋白依赖性激酶（Cdk）抑制剂 p21 和 p27，从而诱导细胞周期停滞。三癸基-9-基黄原酸盐（D609）在自发性高血压大鼠（SHR）短暂性大脑中动脉闭塞（tMCAO）后增加神经酰胺水平，可能是通过抑制鞘磷脂合酶（SMS）。D609 在 tMCAO 后显著减少脑梗死，并上调 Cdk 抑制剂 p21 并下调磷酸化视网膜母细胞瘤（pRb）表达。其他人认为，由于 SMS 抑制导致神经酰胺增加，bFGF 诱导的星形胶质细胞增殖被 D609 减弱。D609 还减少了氧化磷脂酰胆碱（OxPC）蛋白加合物的形成。D609 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生成和 OxPC 的形成（另请参见补充说明：D609 可能防止成熟神经元在早期再灌注时进入细胞周期，但可能不会干扰小胶质细胞/巨噬细胞的后期增殖，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，提供保护）。有人提出，D609 通过减弱缺氧诱导因子-1alpha 和 Bcl2/腺病毒 E1B 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，D609 通过抑制 SMS、增加神经酰胺水平、通过上调 p21 诱导细胞周期停滞并导致 Rb 低磷酸化（通过增加蛋白磷酸酶活性和/或 Cdk 抑制），在中风后提供益处。
