The Effects Of Derivatives Of Breviscapine And Panax Notoginseng On The Expression Of Trx, CDK5 And HSP 70

Stroke is one of the common cerebrovascular diseases, and is a major cause of death and disability. There are two main types of strokes, ischemia and cerebral hemorrhage. Ischemic stroke accounts for nearly 85%. The treatments for ischemia are scavenging free radicals, dilation of vessels, promoting blood circulation and removing blood stasis. Recombinant tissue plasminogen activator (rtPA) is the only drug approved by FDA to treat the stroke. Thrombolysis can reduce morbidity but is only suitable to a small amount of stroke patients. Since the limit treatment for patients following stroke, searching novel therapeutic drugs has become important. Since traditional Chinese medicine has a relatively wider therapeutic window, lesser side effects and is economical, has gained a lot of notice.After cerebral ischemia, cells in ischemic core die, many cells in the ischemic penumbra can survive. Thus, if treated properly, there is opportunity to rescue this region. It is useful to inhibit oxidative stress and inflammation occurred after cerebral ischemia.Breviscapine and panax notoginseng are traditional Chinese medicine. Breviscapine can scavenge reactive oxygen species, inhibit neuronal apoptosis induced by ischemia, inhibit the accumulation of blood clot, increase the blood flow in the brain, and ameliorate microcirculation in the brain. Panax notoginseng is an antioxidant; it can reduce the volume of infraction after cerebral ischemia, reduce the damage to neurons, and improve neuronal function.Thioredoxin is a small 12 kDa multifunctional protein with a redox-active site-Cys-Gly-Pro-Cys-, which was found in E. coli in 1964. Trx operates together with NADPH and Trx reductase as a protein disulfide reducing system. Trx promotes cell growth and angiogenesis and protects cells from apoptosis. Trx also interacts with many signal pathways, and regulates protein folding and transcription factors.HSP70 is a 70 kDa protein of the heat shock protein family, which is the most expressed protein in the heat shock protein family. HSP70 protects cells by assisting protein folding and turnover, reducing the accumulation of misfolded proteins, maintaining the function of mitochondria, inhibiting apoptosis, necrosis and inflammation.Cyclin-dependent kinases are a family of Ser/Thr kinase with the roles in controlling cell cycle progression. Unlike traditional members of the cyclin family, CDK5 is initially characterized to have no role in cell cycle. Evidences showed that CDK5 can maintain neurons survival. Meanwhile CDK5 is involved in dendrite extension and synapse formation.We studied the effects of derivatives of breviscapine and panax notoginseng on the expression of Trx, CDK5 and HSP70 in PC 12 cells and in mice. Our results showed that Trx was induced in PC 12 cells by DY-09001, SQ-09003 and SQ-09004 which are derivative of breviscapine, one component of panax notoginseng saponins and panax notoginseng saponins respectively. SQ-09003 and SQ-09004 induced Trx expression through ERK and PI3K/Akt pathways, DY-09001 through PI3K/Akt pathway but not ERK pathway. The three drugs had no effect on expression of CDK5 and HSP70. After intraperitoneal injection of the three derivatives in C57BL/6 mice, we found that:a, DY-09001 increased the expression of Trx and HSP70 in cortex, but had no effect on CDK5 expression; in hippocampus, DY-09001 had no effect on the expression of Trx, CDK5 and HSP70 at the concentration of 20 mg/kg and 40 mg/kg, and decreased Trx expression at the concentration of 80 mg/kg. b, SQ-09003 increased the expression of Trx and HSP70 in cortex, but had no effect on CDK5 expression; in hippocampus, SQ-09003 had no effect on the expression of Trx, CDK5 and HSP70 at the concentration of 20 mg/kg and 40 mg/kg, and decreased Trx expression at the concentration of 80 mg/kg. c, SQ-09004 did not change the expression of Trx, CDK5 and HSP70 in cortex; in hippocampus, SQ-09004 did not change the expression of Trx, CDK5 and HSP70, except that CDK5 was inhibited at the concentration of 80 mg/kg.Meanwhile, in order to study the effects of these derivatives in cerebral ischemia models, we successfully built middle cerebral artery occlusion model in mice.