Guo Jian-Yi, Ding Jun, Yuan Fang, Chen Hao, Chen Shi-Wen, Tian Heng-Li
Department of Neurosurgery, Shanghai 6th People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
Int J Mol Sci. 2013 Jun 5;14(6):12013-22. doi: 10.3390/ijms140612013.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a dual-specificity lipid and protein phosphatase. The loss of PTEN was originally discovered in numerous human cancers. PTEN inhibition by bisperoxovanadium (bpV) reduces neurological damage after ischemic brain injury. The purpose of this study was to identify the optimal neuroprotective dose of bpV when administrated after focal ischemia/reperfusion (I/R) injury in rats. Focal I/R injury was induced using the middle cerebral artery occlusion method. bpV at doses of 0.25, 0.50 and 1.0 mg/kg were injected intraperitoneally just after reperfusion, with saline serving as a vehicle control. A maximal reduction in brain injury was observed with 1.0 mg/kg bpV. This dose of bpV also significantly blocked apoptosis in the penumbral cortex of rats. This beneficial effect was associated with the increasing levels of Akt phosphorylation in the penumbral cortex. These results demonstrate that the pharmacological inhibition of PTEN protects against I/R injury in a dose-dependent manner and the protective effect might be induced through upregulation of the phosphoinositide-3 kinase/Akt pro-survival pathway, suggesting a new therapeutic strategy to combat ischemic brain injury.
PTEN（第10号染色体缺失的磷酸酶及张力蛋白同源物）是一种双特异性脂质和蛋白质磷酸酶。PTEN缺失最初在多种人类癌症中被发现。双过氧钒（bpV）抑制PTEN可减轻缺血性脑损伤后的神经损伤。本研究的目的是确定大鼠局灶性缺血/再灌注（I/R）损伤后给予bpV的最佳神经保护剂量。采用大脑中动脉闭塞法诱导局灶性I/R损伤。再灌注后立即腹腔注射0.25、0.50和1.0mg/kg剂量的bpV，以生理盐水作为溶剂对照。1.0mg/kg bpV观察到脑损伤最大程度减轻。该剂量的bpV还显著阻断了大鼠半暗带皮质的细胞凋亡。这种有益作用与半暗带皮质中Akt磷酸化水平的升高有关。这些结果表明，PTEN的药理学抑制以剂量依赖方式保护免受I/R损伤，且保护作用可能通过上调磷酸肌醇-3激酶/Akt促生存途径诱导，提示了一种对抗缺血性脑损伤的新治疗策略。
