The Experimental Study On Thrombolysis Combined With Neuroprotection Following Focal Cerebral Ischemia

The experimental study on thrombolysis combined with neuroprotection following focal cerebral ischemiaDoctoral student: Li ZhixinSupervisor: Professor HeNengshuProfessor Zhang YuntingIschemic cerebral infarction is one of the common diseases with high mortality and disability. Recent years there has been tremendous expansion in both the breadth and depth of the understanding of ischemic pathophysiology on the cellular and molecular levels that accompany or mediate ischemic brain injury. With the concept of cerebral ischemic penumbra, availability of new imaging technology and observed benefit of thrombolysis in acute myocardial infarction, the efforts to develop further cerebral ischemic therapy were encouraged. Clinical interest is now mainly focused on thrombolysis and neuroprotective therapy. Systemic or local thrombolysis is optimal for restoring the blood flow and rescuing the ischemic brain tissue, especially on ischemic penumbra, from complete infarction. However, the time window of thrombolytic effectiveness is very narrow, immediate recanalization of the occluded artery, and rapid increase in blood supply also accompanied with serious complications on ischemic tissue and may lead to further damage as a result of reperfusion. So elucidating the dynamic evolution of ischemic penumbra is very important for guiding the therapy. Neuroprotection, because of different mechanisms, would be expected to show better results when used after onset of focal ischemia and thrombolysis. However, due to the complexity of ischemic brain injury, various types of neuroprotective intervention are effective in animal models, but none has yet been proven effective in patients. Recent studies have showed that apoptosis might play an important role in ischemic reperfusion injury, but the molecular mechanism of apoptosis has not yet been fully understood. Therfore it is necessary to carry out further study to investigate the role of apoptosis in neuronal death and clarify the regulation of gene related to the cell death and survival. The present study firstly-5-investigated the temporal and spatial distribution of neuronal apoptosis following focal cerebral ischemia, and then studied the effective of combination therapy by intra-arterial Urokinase and bFGF using embolic MACO model, the potential neuroprotective mechanism of bFGF was further discussed.Part I Cerebral ischemic penumbra and apoptosisPurpose: By examining the changes of MRI images , histopathology and apoptosis following cerebral ischemia in rats, to study the mechanism of neuronal death on Ischemic Penumbra.Materials and Methods: The focal transient middle cerebral artery occlusion(MACO) model was induced using a nylon thread in rats, the rats were divided randomly into different ischemic interval with 24h reperfusion groups , and ischemia 4h with different reperfusion interval groups. Neuroscore, light microscope, electron microscope and TUNEL method were used to investigate the neurological deficits, histopothological, ultratructrual and neuronal apoptosis changes, MRI DWI and T:WI were also performed at different time points. Results: The neurological deficits and high signal intensity of basal ganglia on DWI was reversible at 0. 5h ischemia and was normal on T^WI after reperfusion; With the prolonging of ischemic and reperfusion interval, the neurological deficits were severer , the high signal volume on DWI and T2WI was gradually spread from basal ganglia to cortex. Light microscope showed that there were a few ishemic neurons (<25%)and light brain edema in Ih ischemic group, which were much more obvious in ischemic 2h group. In ischemia 4h with different reperfussion interval groups, obvious brain edeman and ishemic neurons(>75%) was mainly observed in basal ganglia, within 12-48h, 25-50% of neurons in cortex were ischemic neurons. TUNEL results showed that the apopotic neurons were incresed in Ih ischemic group, which were distributed in basal ganglia and cortex, the apopotic neurons peaked in number at 4h, which were mainly...