Delivering pharmacologic agents directly into the brain has been proposed as a means of bypassing the blood brain barrier.However,despite 16 years of research on a number of central nervous system disorders,an effective treatment using this strategy has only been observed in the brain tumor glioblastoma multiforme.Within this study we propose a novel system for delivering drugs into the brain named the simple diffusion (SDD) system.To validate this technique,rats were subjected to a single intracranial (at the caudate nucleus),or intraperitoneal injection,of the compound citicoline,followed two hours later by a permanent middle cerebral artery occlusion (pMCAO).Results showed that 12 h after pMCAO,with 0.0025 g kg-1 citicoline,an infarct volume 1/6 the size of the intraperitoneal group was achieved with a dose 1/800 of that required for the intraperitoneal group.These results suggest that given the appropriate injection point,through SDD a pharmacologically effective concentration of citicoline can be administered.
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 mm 2 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.
