Comparative studies of Tao-Ren-Cheng-Qi Tang or San-Huang-Xie-Xin Tang with aspirin on neuroprotection and lowering the neurobehavioral deficits in rat ischemic stroke: evaluation the risks of inducing gastric bleeding, intracerebral hemorrhage, and subarachnoid hemorrhage (2-2)

Stroke is the third leading cause of mortality and morbidity in the world and is frequently associated with long-term disability. In traditional Chinese medicine (TCM), many formulas have been used clinically for centuries to treat stroke-induced disability. In China, a survey of treatments used in regular practice showed that over 70% of doctors believed that Chinese herb products are more effective treatments for acute ischemic stroke, and 66% of doctors used them routinely for most patients. Tao-Ren-Cheng-Qi Tang consisting of peach kernel, cassia twig, glauber salt, rhubarb, and licorice have long been used by traditional Chinese physicians to treat ischemic stroke. San-Huang-Xie-Xin Tang, another well-recognized Chinese formula composed by rhubarb, berberine, and baicalin is also reported to have therapeutic effects on bleeding and cardiovascular diseases. On the other hand, anti-platelet drugs are routinely used to prevent ischemic stroke clinically, of which aspirin is the most commonly used drug. Nevertheless, many studies indicate that taking aspirin will increase the risk of excessive bleeding. Hence, the development of new interventions geared toward a wider therapeutic window is necessary to meet the large need for this important and undertreated disorder. In Taiwan, a large amount of patients often simultaneously use TCM and aspirin to treat or prevent cerebralvascular diseases. Consequently, to investigate the interactions and possible risks of these drugs combination is important and warrant study. A combination of three doses of Tao-Ren-Cheng-Qi Tang or San-Huang-Xie-Xin Tang with two different doses of aspirin were used in this project to investigate their interactions and risks during the autologous blood clot-induced ischemic stroke and neurobehavioral deficits in rats. In addition, this project will also be performed the bleeding risk assessment of gastric bleeding (GB), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) and explores the possible mechanisms. The project is expected to be completed in two years, and the items are summarized below. The first annual plan: the autologous blood clot-induced ischemic stroke in rats will be treated with low, medium, and high doses of Tao-Ren-Cheng-Qi Tang (0.25, 0.5, and 1.25 g/kg/d) or San-Huang-Xie-Xin Tang (0.1, 0.2, 0.5 g/kg/d) with two different doses of aspirin (2 and 5 mg/kg/d) for 1, 2, and 3 months, the improvement of brain ischemic areas and neurological behavioral deficits will be assessed. Meanwhile, the changes of blood flow will be measured. Furthermore, the expressions of apoptosis-related proteins such as MMP-9, caspases, HIF-1TNF-, etc. and free radicals such as hydroxyl radical (OH˙) will be detected to clearly know the underlying mechanisms. The second annual plan: the risks of GB, ICH, and SAH will be further evaluated during the administration of drugs. The hemoglobin levels in gastric fluid and brain tissue will be measured to evaluate the extent of GB and ICH; the quantitative image analysis system will be used to measure the SAH area. Furthermore, in order to clarify the possible mechanisms of these bleeding responses, the assays of density of blood clot, bleeding time of rat tail, platelet aggregation activity, and prothrombin time will also be analyzed. In addition, the distribution and integrity of vessels in cerebral cortex and textured body will be observed by immunofluoresence microscope in this project. From this project, we can suggest that a combined treatment of Tao-Ren-Cheng-Qi Tang or San-Huang-Xie-Xin Tang with aspirin may provide a convenient intervention with a wider therapeutic window for treating ischemic stroke clinically.