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

细胞凋亡信号被认为是神经退行性疾病中迟发性神经元死亡的原因。我们在这里提出了新的治疗策略，亚急性治疗缺血性损伤。通过上调细胞凋亡过程中的生存信号，开发了新型的分子靶向治疗药物。凡诺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，给予原钒酸盐激活脑中的PI 3-激酶/Akt和MAP激酶信号传导。我们已经确定了有效的神经保护作用的原钒酸在沙土鼠短暂前脑缺血，在大鼠中动脉闭塞（MCAO）模型和心肌缺血。与我们的假设一致，Akt对叉头转录因子Bad和糖原合成酶激酶3β的磷酸化有助于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）的产生和钙激活蛋白酶的激活，钙蛋白酶我们最近报道了一种新型钙调素拮抗剂DY-9760 e对脑和心脏缺血的强大细胞保护作用。DY-9760 e通过抑制NO的产生和钙蛋白酶/半胱天冬酶的激活，对缺血性神经元和心肌细胞起到保护作用。我们还发现，DY-9760 e可抑制血脑屏障破坏和脑水肿形成，这与更差的临床结局相关。我们的新策略专注于抑制脑水肿，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.