Liu Christina H, You Zerong, Ren JiaQian, Kim Young R, Eikermann-Haerter Katharina, Liu Philip K
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
FASEB J. 2008 Apr;22(4):1193-203. doi: 10.1096/fj.07-9557com. Epub 2007 Nov 20.
We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of beta-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2* = 1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched beta-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders.
我们旨在测试在血脑屏障（BBB）被破坏时检测活体脑内胶质增生的可行性。我们设计了一种新型磁共振（MR）探针，其包含与在神经胶质细胞和星形胶质细胞中发现的胶质纤维酸性蛋白（GFAP）的脑信使核糖核酸（mRNA）互补的短DNA序列相连的超顺磁性氧化铁纳米颗粒（SPION，一种T2敏感性造影剂）。作为对照，我们还使用了与β-肌动蛋白mRNA互补的序列。我们的目标是证明这种新探针SPION-gfap，通过滴眼液滴入结膜囊给药时能够递送至脑内。我们通过穿刺伤、全脑缺血和皮质扩散性抑制在C57BL6小鼠中诱导血脑屏障渗漏；在探针给药1天后，我们使用转录MRI技术在活体小鼠中获取T2* MR图像和R2*（R2* = 1/T2*）图谱。我们发现SPION-gfap探针在相减R2图谱中报告了信号升高的病灶，并且这些病灶与死后免疫组织化学中确定为具有广泛胶质网络（胶质增生）的区域相匹配。同样，给予对照探针的动物也表现出R2升高的病灶，这些病灶与血管壁中表达β-肌动蛋白的内皮细胞相匹配。我们得出结论，我们的模块化MR探针通过滴眼液给药，能够有效地报告活体动物中与急性神经疾病相关的胶质增生。由于在急性神经疾病中经常观察到血脑屏障渗漏，本研究还验证了急性神经疾病后将MR探针无创递送至活体动物脑内的方法。
