| Background and Purpose: Ischemic stroke has been estimated to account for70-80%of stroke in the general population. It is caused by acute interruption ofarterial supply to a segment of brain and results in the global ischemic putrescence.Ischemic stroke is the second leading cause of death, and is a leading cause of serious,longterm disability in adults in the world. Up to now, intravenous thrombolytictreatment using recombinant tissue plasminogen activator (rt-PA) is the only oneFDA-approved pharmacological treatment for ischemic stroke. However, the seriouscomplication of thrombolysis is hemorrhagic transformation (HT). A hemorrhagicinfarction can be defined as an area of bleeding within ischemic cerebral tissuefollowing an acute ischemic stroke, and is the reperfusion after the ischemic regionrecanalization. The main reason for HT is the disruption of the blood–brain barrierand the loss of microvascular integrity. The blood–brain barrier is mainly composedof endothelial cell tight junctions, pericyte, basal lamina and astrocyte endfoot. As animportant cytokine, transforming growth factor-beta1(TGF-β1) can not onlyup-regulate type-1plasminogen activator inhibitor (PAI-1) expression in astrocytes，which is the physiological inhibitor of t-PA, but also remodel extracellular matrix.Furthermore, TGF-β1suppresses inflammation. In our study, we establish athromboembolic ischemic stroke model in rat, administer intravenously rt-PAcombined TGF-β1. Then we valuate the effect of TGF-β1on the HT induced byrt-PA. Methods: A focal cerebral ischemia of rat was established by embolizing athromboembolic ischemic stroke model. The effects of TGF-β1on the HT induced byrt-PA in cerebral ischemia were then evaluated.1. From two point five to three-monthmale SD rats were employed in the experiment. Fresh arterial blood from femoralartery were mixed with thrombin and immediately injected into a PE-50catheter forthe clots preparation in vitro. The thromboembolic stroke model was established byinjection of clots into the internal carotid artery via PE-50catheter in the rightexternal carotid artery.2. Evaluation of brain injuries.(1) Infarct size andhemorrhage：After ischemia for24h, the brain tissues were isolated from rats,evaluated hemorrhage and then subjected to TTC staining. Infarct sizes were thenobserved and calculated.(2) Neurological scoring: Neurological function wasevaluated by using Bederson’s scoring system after the rats were subjected toischemia3h and24h.(3) Basal lamina integrity: After ischemia for24h, the braintissues were isolated from rats and subjected to paraffin section.Immunohistochemistry staining was performed. Morphology of collagen type IV andlaminin was then observed under microscope and the images were captured.3. Bloodbrain barrier permeability：It was expressed as the amount of Evan’s blue leakingacross blood–brain barrier after ischemia for24h.4. The expression of MMPs. Afterischemia for24h, the brain tissues were isolated from rats and subjected gelatin gelzymography to determine the MMP-9and MMP-2activities.Results:1. Compared to rt-PA group, TGF-β1combination with rt-PA improvedneurological dysfunction that induced by MCAO.2. Compared to rt-PA group, TGF-β1combination with rt-PA decreased thehemorrhage that induced by rt-PA after MCAO.3. Compared to rt-PA group, TGF-β1combination with rt-PA attenuated basal laminainjury that induced by rt-PA after MCAO. 4. Compared to rt-PA group, TGF-β1combination with rt-PA decreased theblood–brain barrier permeability and increased the important component part ofblood–brain barrier synthesis.5. Compared to rt-PA group, TGF-β1combination with rt-PA reduced the expressionof MMP-9.Conclusions: TGF-β1combination with rt-PA significantly protected rats from HTinduced by rt-PA in ischemic stroke... |
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