多模态MRI评价远端缺血预处理通过调节AQP4抗缺血性脑水肿的机理

Limb remote ischemic preconditioning (LRP) which is hopeful for the prevention and cure of stroke,ameliorates ischemic brain edema effectively. Our previous research found that there were correlations between the changes part of the indicators in multimodal MRI including DWI,DKI induced by LRP and the expression of aquaporin4(AQP4) in cerebral ischemia rat model ,thus we speculate that LRP should protect against stroke through regulating the expression of AQP4 ，but the involved mechanism is unclear. Researches show that nitric oxide play a crucial role in cerebral protecting induced by other ways of preconditioning,NO also involve in the control of arginine vasopressin which is proved to be the main regulative factor of AQP4.What’s more ,NO plays a complex role in regulating hypoxia-inducible factor-1（HIF-1）which is a upstream transcription factor of AQP4.So we assume that the regulation of LRP on AQP4 is NO dependent.The project here intends to verify the effects of AQP4 in the protection effect of LRP against cerebral ischemic encephaledema, using the AQP4-/- rats and combining detection means with use of multimodal MRI, behavioral, morphological as well as molecular related indexes. Next it intends to show the regulation on AQP4 expression propelled by LRP is NO dependent by the use of NOS-/- rats.All work of the project is expected to clarify the mechanism of LRP protecting against ischemia and facilitate LRP-based anti-stroke therapies.

肢体远端缺血预处理（LRP）能有效抑制缺血性脑水肿，有望用于防治脑卒中。我们前期研究发现LRP所引起的脑缺血模型大鼠在DWI、DKI上部分度量指标的改变与水通道蛋白4（AQP4）的表达呈不同程度相关，推断LRP通过调节AQP4拮抗脑卒中，但其具体机制不明。研究表明一氧化氮（NO）在其他预处理方式介导的脑保护中起到重要作用，NO亦被证实可参与调控精氨酸加压素（AVP），后者是AQP4的主要调节因素，同时NO对AQP4的上游转录因子低氧诱导因子-1（HIF-1）具有复杂的调控作用，因此我们假设LRP对AQP4的调节具有NO依赖性。本项目拟用AQP4敲基因大鼠，联合多模态MRI及行为学、形态学、分子学指标进一步探讨AQP4在LRP抗脑水肿中的作用；其次利用NOS敲基因大鼠验证LRP对AQP4的调节具有NO依赖性。本项目旨在阐明LRP抗缺血性脑卒中的机制，为基于LRP的抗脑卒中提供实验和理论依据。

肢体远端缺血预处理（LRP）能有效抑制缺血性脑水肿，有望用于防治脑卒中。我们应用多模态MRI（DKI、DTI、AQP-MRI）对LRP抑制脑缺血进行评价，证实LRP能够改善DKI、DTI及AQP-MRI相关度量指标的改变，并且部分度量指标的改变与水通道蛋白4（AQP4）的表达不同程度相关。LRP能够调节脑缺血后AQP4的表达及转录，单纯应用AQP抑制剂能够拮抗缺血性脑卒中，但当添加AZA后进行LRP诱导，我们发现LRP的神经保护作用减弱，同时伴随着一系列血管生成指标、氧化应激指标的改变，该结果提示AQP4在脑缺血中的复杂性作用，而LRP的神经保护性作用很可能依赖于AQP4的表达。针对LRP调节AQP4的机制，我们发现单纯LRP诱导时，血清内NO水平及脑匀浆的AVP表达水平发生改变，该结果符合我们之前的推断：LRP对AQP4的调节作用具有NO依赖性。但目前的科学推断有待基因敲除大鼠结果出来后进一步明确。