CAJ | 학술논문

目的：应用磁共振分子探针示踪技术，研究大鼠深部脑组织间隙（ interstitial space，ISS）内物质转运与脑组织液引流的规律。结合多孔介质经典扩散方程，建立大鼠脑局部给药的药物分布与清除动力学模型。方法24只SD大鼠随机分为尾状核、丘脑、中脑黑质3组（n＝8）。将细胞外示踪剂惰性分子探针钆喷酸葡胺（gadolinium-diethylenetriaminepentaacetic acid，Gd-DTPA）2μl分别导入三个脑区细胞外间隙，利用磁共振成像（ MRI）动态采集探针在大鼠脑ISS内的分布与清除过程。通过图像后处理获取ISS内示踪分子在大鼠全脑分布的最大分布容积比（ Vdmax％）及半衰期（ t1／2）。应用经典扩散方程，测量ISS有效扩散系数（ D*）、清除率（ k’）与局部迂曲度（λ）。结合上述结果及经典扩散方程，建立大鼠脑组织间隙内药代动力模型。结果示踪分子在大鼠不同脑区ISS内的转运分布区域、清除速率各不相同。尾状核Vdmax％和t1／2大于丘脑和黑质（P＝0．000）。黑质区D*小于尾状核、丘脑（P＝0．021），黑质ISS内迂曲度最大（P＝0．280）。丘脑局部k’大于尾状核和黑质区域（P＝0.000）。结论钆喷酸葡胺（Gd-DTPA）在大鼠深部脑组织内分布呈分区特征，各分区内药物的分布与清除速率各不相同。脑局部给药需考虑脑内ISS的解剖分区以及各个脑分区的物质转运与脑组织液流动参数特征。
목적：응용자공진분자탐침시종기술，연구대서심부뇌조직간극（ interstitial space，ISS）내물질전운여뇌조직액인류적규률。결합다공개질경전확산방정，건립대서뇌국부급약적약물분포여청제동역학모형。방법24지SD대서수궤분위미상핵、구뇌、중뇌흑질3조（n＝8）。장세포외시종제타성분자탐침구분산포알（gadolinium-diethylenetriaminepentaacetic acid，Gd-DTPA）2μl분별도입삼개뇌구세포외간극，이용자공진성상（ MRI）동태채집탐침재대서뇌ISS내적분포여청제과정。통과도상후처리획취ISS내시종분자재대서전뇌분포적최대분포용적비（ Vdmax％）급반쇠기（ t1／2）。응용경전확산방정，측량ISS유효확산계수（ D*）、청제솔（ k’）여국부우곡도（λ）。결합상술결과급경전확산방정，건립대서뇌조직간극내약대동력모형。결과시종분자재대서불동뇌구ISS내적전운분포구역、청제속솔각불상동。미상핵Vdmax％화t1／2대우구뇌화흑질（P＝0．000）。흑질구D*소우미상핵、구뇌（P＝0．021），흑질ISS내우곡도최대（P＝0．280）。구뇌국부k’대우미상핵화흑질구역（P＝0.000）。결론구분산포알（Gd-DTPA）재대서심부뇌조직내분포정분구특정，각분구내약물적분포여청제속솔각불상동。뇌국부급약수고필뇌내ISS적해부분구이급각개뇌분구적물질전운여뇌조직액류동삼수특정。
Objective To explore the drainage process of brain interstitial fluid ( ISF) and transport property in interstitial space ( ISS) in rat deep brain tissue by tracer-based magnetic resonance imaging ( MRI) .On the basis of classical diffusion equation in porous media , to establish distribution and clearance model for local drug administration of brain . Methods A total of 24 Sprague Dawley rats were randomly divided into three groups according to the injection points : caudate putamen (CPu), thalamus (T), and substantia nigra ( SN ) , with 8 rats in each group . The brain ISF was traced with a MRI contrast agent , 2 μl gadolinium diethylenetriaminepentaacetic acid ( Gd-DTPA) , which was injected into the brain ISS .Three-dimensional dynamic distribution of the probes was displayed and quantitative calculations were completed by self -developed image processing software .The distribution ratio referring tracers’ maximum volume of the whole brain (Vdmax%) and the half-life time (t1/2) were obtained.ISS microscopic diffusion parameter (D*), clearance rate (k’), and local tortuosity (λ) were measured based on classical diffusion equation .Hence, we established pharmacokinetics model of the brain ISS . Results The transport distribution area and clearance rates of tracer molecule varied in ISS of different brain regions .The Vdmax% and t1/2 of the caudate putamen were greater than those of the thalamus and substantia nigra (P=0.000).The D*in substantia nigra was less than that in caudate putamen and thalamus (P=0.021), deriving the greatest λin substantia nigra (P=0.280).The k’ in thalamus was greater than that in caudate putamen and substantia nigra (P=0.000). Conclusions Drug distribution in the brain ISS is partitioned , with drug distribution and clearance rates varyingwithin each sub-region.Topical brain anatomy in each brain partition and fluid flow parameter characteristics of partitioned ISS should be considered in local brain delivery .