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 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.
