Drug development by signal transduction therapy in the ischemic brain injury.

凋亡信号被认为是神经退行性疾病中神经元延迟死亡的原因。本文提出了缺血性损伤亚急性治疗的新策略。上调细胞凋亡过程中存活信号的分子靶向治疗药物已成为研究热点。钒及其衍生物是一般的蛋白酪氨酸磷酸酶抑制剂，具有抗糖尿病作用。与胰岛素生长因子-1（IGF-1）一样，原钒酸盐激活了大脑中pi3激酶/Akt和MAP激酶信号通路。我们已经确定了原钒酸盐对沙鼠短暂性前脑缺血、大鼠中动脉闭塞（MCAO）模型和心肌缺血的有效神经保护作用。与我们的假设一致，Akt磷酸化叉头转录因子、Bad和糖原合成酶激酶3β参与了原钒酸盐的细胞保护作用。此外，缺血、创伤和许多神经退行性疾病后的神经元死亡可归因于细胞内Ca^<2+>浓度的过度升高，从而导致毒性一氧化氮（NO）的产生和钙活化蛋白酶（calpain）的激活。我们最近记录了一种新型钙调素拮抗剂DY-9760e对脑和心脏缺血的强大细胞保护作用。预期，DY-9760e通过抑制NO的产生和calpain/caspase的激活来拯救缺血性损伤的神经元和心肌细胞。我们还发现DY-9760e抑制血脑屏障破坏和脑水肿的形成，这与较差的临床结果有关。我们的新策略专注于脑水肿的抑制，将为神经退行性疾病的亚急性或慢性治疗提供新的治疗策略。

The apoptotic signal is believed to account for delayed neuronal death in the neurodegenerative disorders. We here proposed novel therapeutic strategies for sub-acute therapy in the ischemic injury. The novel drugs have been developing for molecular-target therapy up-regulating the survival signals during apoptosis. Vanadium and its derivatives are general protein tyrosine phosphatase inhibitors, having anti-diabetic action. Like insulin growth factor-1(IGF-1), administration of orthovanadate activated PI3-kinase/Akt and MAP kinase signaling in the brain. We have defined the potent neuroprotective effect of orthovanadate in gerbil transient forebrain ischemia, in the rat middle artery occlusion (MCAO) model and in myocardial ischemia. Consistent with our hypothesis, phosphorylation of forkhead transcription factors, Bad and glycogen synthase kinase 3β by Akt contributed to the cytoprotective action of orthovanadate.In addition, neuronal death after ischemia, trauma and numerous neurodegenerative disorders has been attributed to excessive elevation of intracellular Ca^<2+> concentration, thereby leading toxic nitric oxide (NO) production and activation of calcium-activated protease, calpains. We recently documented powerful cytoprotective actions of a novel calmodulin antagonist, DY-9760e, on brain and heart ischemia. Expectedly, DY-9760e rescued neurons and cardiomyocytes from ischemic injury through inhibition NO production and calpain/caspase activation. We also found that DY-9760e inhibited blood-brain barrier disruption and brain edema formation associated with a worse clinical outcome. Our novel strategy focused on inhibition of brain edema will provide novel therapeutic strategy for sub-acute or chronic treatments in the neurodegenerative disorders.