Abstract
The nature of brain interstitial fluid (ISF) has long been a subject of controversy. Most of the previous studies on brain ISF were carried out in vitro. In the present study, a novel method was developed to characterize ISF in the living rat brain by magnetic resonance (MR) imaging using gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) as a tracer. Sprague Dawley rats (n=8) were subjected to MR scanning before and after the introduction of Gd-DTPA into the caudate nucleus. A one-way drainage of brain ISF was demonstrated on the dynamic MR images. According to the traditional diffusion model, the diffusion and clearance rate constants of the tracer within brain extracellular space (ECS) were derived as (3.38+−1.07)×10−4 mm2 s−1 and (7.60±4.18)×10−5 s−1. Both diffusion and bulk flow contributed to the drainage of ISF from the caudate nucleus, which demonstrated an ISF-cerebrospinal fluid confluence in the subarachnoid space at the lateral and ventral surface of the brain cortex at 3 h after the injection. By using this newly developed method, the brain ECS and ISF can be quantitatively measured simultaneously in the living brain, which will enhance the understanding of ISF and improve the efficiency of drug therapy via the brain interstitium.
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References
Abbott N J. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int, 2004, 45: 545–552
Sykova E, Nicholson C. Diffusion in brain extracellular space. Physiol Rev, 2008, 88: 1277–1340
Nicholson C, Phillips J M. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol, 1981, 321: 225–257
Nicholson C, Sykova E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci, 1998, 21: 207–215
Nicholson C. Factors governing diffusing molecular signals in brain extracellular space. J Neural Transm, 2005, 112: 29–44
Kunwar S, Chang S, Westphal M, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol, 2010, 12: 871–881
Han H, Xia Z, Chen H, et al. Simple diffusion delivery via brain interstitial route for the treatment of cerebral ischemia. Sci China Life Sci, 2011, 54: 235–239
Bidros D S, Liu J K, Vogelbaum M A. Future of convection-enhanced delivery in the treatment of brain tumors. Future Oncol, 2010, 6: 117–125
Lopez K A, Waziri A E, Canoll P D, et al. Convection-enhanced delivery in the treatment of malignant glioma. Neurol Res. 2006, 28: 542–548
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. London: Academic Press, 2007. 80–84
Koshlyakov N S, Smirnov M M, Gliner E B. Differential equations of mathematical physics. Amsterdam: North-Holland Publishing Co., 1964. 509
Pluim J P W, Maintz J B A, Viergever M A. Mutual-information-based registration of medical images: a survey. IEEE Trans Med Imag, 2003, 22: 986–1004
Loeckx D, Slagmolen P, Maes F, et al. Nonrigid image registration using conditional mutual information. IEEE Trans Med Imag, 2010, 29: 19–29
Patlak C S, Hospod F E, Trowbridge S D, et al. Diffusion of radiotracers in normal and ischemic brain slices. J Cereb Blood Flow Metab, 1998, 18: 776–802
Ransom B R, Yamate C L, Connors B W. Activity-dependent shrinkage of extracellular space in rat optic nerve: a developmental study. J Neurosci, 1985, 5: 532–535
Nicholson C. Quantitative analysis of extracellular space using the method of TMA+ iontophoresis and the issue of TMA+ uptake. Can J Physiol Pharmacol, 1992, 70: S314–S322
Nicholson C, Tao L. Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J, 1993, 65: 2277–2290
Cabella C, Crich S G, Corpillo D, et al. Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as ’sponges’ of Gd3+ ions. Contrast Media Mol Imaging, 2006, 1: 23–29
Caravan P, Ellison J J, Mcmurry T J, et al. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev, 1999, 99: 2293–2352
Xu F, Han H, Zhang H, et al. Quantification of Gd-DTPA concentration in neuroimaging using T1 3D MP-RAGE sequence at 3.0 T. Magn Reson Imaging, 2011, 29: 827–834
Weller R O, Galea I, Carare R O, et al. Pathophysiology of the lymphatic drainage of the central nervous system: implications for pathogenesis and therapy of multiple sclerosis. Pathophysiology, 2010, 17: 295–306
Yamada S, Depasquale M, Patlak C S, et al. Albumin outflow into deep cervical lymph from different regions of rabbit brain. Am J Physiol, 1991, 261: H1197–H1204
Schley D, Carare-Nnadi R, Please C P, et al. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol, 2006, 238: 962–974
Yamori Y, Horie R, Handa H, et al. Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans. Stroke, 1976, 7: 46–53
Tamura A, Graham D I, Mcculloch J, et al. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab, 1981, 1: 53–60
Berendse H W, Galis-De G Y, Groenewegen H J. Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol, 1992, 316: 314–347
Berendse H W, Groenewegen H J, Lohman A H. Compartmental distribution of ventral striatal neurons projecting to the mesencephalon in the rat. J Neurosci, 1992, 12: 2079–2103
Muldoon L L, Varallyay P, Kraemer D F, et al. Trafficking of superparamagnetic iron oxide particles (Combidex) from brain to lymph nodes in the rat. Neuropathol Appl Neurobiol, 2004, 30: 70–79
Bobo R H, Laske D W, Akbasak A, et al. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA, 1994, 91: 2076–2080
Xu F, Han H, Yan J, et al. Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury. Drug Deliv, 2011, 18: 461–467
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Han, H., Li, K., Yan, J. et al. An in vivo study with an MRI tracer method reveals the biophysical properties of interstitial fluid in the rat brain. Sci. China Life Sci. 55, 782–787 (2012). https://doi.org/10.1007/s11427-012-4361-4
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DOI: https://doi.org/10.1007/s11427-012-4361-4