A proposed role for efflux transporters in the pathogenesis of hydrocephalus

Hydrocephalus is a common brain disorder that is treated only with surgery. The basis for surgical treatment rests on the circulation theory. However, clinical and experimental data to substantiate circulation theory have remained inconclusive. In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water-permeable tissue. As the osmolarity of ventricular CSF increases within the cerebral ventricles, water movement into the ventricles increases and causes hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. Efflux transporters, (p-glycoprotein), are located along the blood brain barrier and play an important role in the clearance of macromolecules (endobiotics and xenobiotics) from the brain to the blood. There is clinical and experimental data to show that macromolecules are cleared out of the brain in normal and hydrocephalic brains. This article summarizes the existing evidence to support the role of efflux transporters in the pathogenesis of hydrocephalus. The location of p-gp along the pathways of macromolecular clearance and the broad substrate specificity of this abundant transporter to a variety of different macromolecules are reviewed. Involvement of p-gp in the transport of amyloid beta in Alzheimer disease and its relation to normal pressure hydrocephalus is reviewed. Finally, individual variability of p-gp expression might explain the variability in the development of hydrocephalus following intraventricular hemorrhage.