DKI评价AQP4介导瘦素干预早期缺氧缺血性脑水肿的研究

Brain edema is main pathological changes in early stage of neonatal hypoxic-ischemic encephalopathy (HIE). In our previous study, we established a newborn piglet model of hypoxic-ischemic brain damage (HIBD) and found that aquaporin-4 (AQP4) joined in early brain edema formation with negative correlation with the ADC values, and inhibiting its expression could effectively relieve brain edema. DWI could evaluate the process dynamically, however, it could not provide more details of diffusion limited. The role of leptin in neural protection has been acknowledged, but mechanism of alleviating early brain edema has not yet been elucidated. Recent studies indicate that CGRP inhibits AQP4 expression, and leptin could promote the expression of CGRP. In order to verify the validation of leptin intervention in early brain edema via reducing AQP4 expression, we would use newborn piglet HIBD model, leptin is injected into abdominal cavity, and apply diffusion kurtosis imaging (DKI) to dynamically observe changes of kurtosis parameters within 24h after hypoxic-ischemia, and make correlation analysis with CGRP, AQP4 expression in the corresponding parts, combined with the behavioral scoring, pathology and cerebral markers NSE/S100β. According to these changes, we aim to evaluate effect of leptin intervention of hypoxic-ischemic brain edema and explore the intervention mechanism, which could provide experimental and theoretical basis for the evaluation of HIE and intervention ways of AQP4 target using DKI.

脑水肿是新生儿缺氧缺血性脑病（HIE）早期主要病理改变。我们前期研究建立新生猪缺氧缺血性脑损伤（HIBD）模型，发现水通道蛋白4（AQP4）参与早期脑水肿形成，表达与ADC值呈负相关，抑制其表达可有效减轻脑水肿，DWI可动态评价此过程，但不能提供更多扩散受限的细节。瘦素在神经保护方面的作用得到公认，但减轻早期脑水肿的机制尚未阐明。最近研究表明：降钙素基因相关肽(CGRP)可抑制AQP4表达，而瘦素能促进CGRP表达。为验证瘦素通过抗AQP4表达干预早期脑水肿，本课题拟采用新生猪HIBD模型，腹腔注射瘦素，应用扩散峰度成像（DKI）动态观察脑缺氧缺血后24h内各参数变化，并与相应部位CGRP、AQP4表达做相关性分析，结合行为学、病理学及脑标志物血清学改变，评价瘦素干预早期缺氧缺血性脑水肿的效果并探讨其干预机制，为应用DKI活体动态评价HIE及AQP4为靶点的干预方法提供实验和理论依据。

研究背景：脑水肿是新生儿缺氧缺血性脑病（HIE）早期主要病理改变。我们前期研究建立新生猪缺氧缺血性脑损伤（HIBD）模型，发现水通道蛋白4（AQP4）参与早期脑水肿形成，表达与ADC值呈负相关，抑制其表达可有效减轻脑水肿，DWI可动态评价此过程，但不能提供更多扩散受限的细节。瘦素在神经保护方面的作用得到公认，但减轻早期脑水肿的机制尚未阐明。.主要研究内容：本课题拟采用新生猪HIBD模型，腹腔注射瘦素，应用扩散峰度成像（DKI）动态观察脑缺氧缺血后24h内各参数变化，结合行为学、病理学及脑标志物血清学改变，评价瘦素干预早期缺氧缺血性脑水肿的效果并探讨其干预机制，为应用DKI活体动态评价HIE及AQP4为靶点的干预方法提供实验和理论依据。.重要结果：缺氧缺血发生后3-24h，实验组、瘦素干预组病变处DKI相关参数值（平均扩散峰度MK、径向峰度Kr、轴向峰度Ka）较对照组逐渐升高；DTI相关参数值（平均扩散系数MD、垂直扩散张量Dr、轴向扩散张量Da）则逐渐降低；且各时间点瘦素干预组DKI相关参数值较实验组低，DTI相关参数则相反。DKI相关参数值变化率大于DTI相关参数值变化率。瘦素干预组病灶面积始终小于实验组，且MK图病灶面积小于MD图。瘦素干预组血清NSE浓度小于实验组。病理结果显示瘦素干预组神经损伤程度明显小于实验组。 .科学意义：瘦素能够有效减轻新生猪缺氧缺血性脑水肿，且DKI能够更加动态、敏感、真实地评价缺氧缺血性脑水肿脑组织微结构的变化。