The nature of brain interstitial fluid （ISF） has long been a subject of controversy. Most of the previous studies on brain ISF were carded 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.
The extracellular space(ECS) of brain is defined as an irregular channel which is located in the interstitial tissue outside the plasma membranes of neurons,and occupied by interstititial fluid(ISF).Diffusion in ECS is described by a modified diffusion equation from which several parameters can be calculated,such as the diffusion coefficient(D),the tortuosity(λ),the volume fraction(α) and the clearance of molecules.Radiolabeled tracers were used for early diffusion measurements.Presently,the real-time iontophoresis(RTI) method is employed for small ions,whereas the integrative optical imaging(IOI) and the magnetic resonance diffusion weighted imaging(DWI) are developed for macromolecules tracers.Extensive experimental studies with such methods show that in normal brain tissue,the volume fraction of ECS typically is about 20% and the tortuosity is 1.6,although there are regional variations.These parameters change with the brain development and in various pathophysiological states.Knowledge of ECS diffusion properties help us to understand extrasynaptic volume transmission to the development of paradigms for drug delivery in brain.
