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.Hydrocephalus is a common brain disorder that affects children and individuals of all ages. It is the most common congenital abnormality in children (one out of 500 births) (1). If left untreated, hydrocephalus can lead to permanent brain damage and result in cognitive and physical handicap.Contemporary surgical management of hydrocephalus is based on the popular conceptualization of circulation theory. The circulation theory of hydrocephalus states that cerebrospinal fluid (CSF) produced by the choroid plexus flows along specific pathways to be absorbed by the venous sinuses. An obstruction in any part of these pathways leads to hydrocephalus. Surgical management of hydrocephalus is therefore directed at detecting and removing the source of obstruction (such as removal of tumor or blockage of pathways) or diverting the fluid bypassing the obstruction. As such, the most common treatment for hydrocephalus is the surgical implantation of a shunt system to divert the flow of CSF from the ventricles. However, although most cases of hydrocephalus are managed with a shunt system, it is rare for the device to last a lifetime without complications. Treatment of hydrocephalus leads to approximately 38 000 admissions per year in the US. Costs for treatment range from US $1.4-2 billion per year and approximately US $1 billion is spent on the revision of malfunctioning shunts (2).This may be a result of poor shunt design or a flawed approach to treatment.Circulation theory rests on the assumption that the brain parenchyma is impermeable to water, and is therefore incapable of independently absorbing the CSF that accumulates in the ventricles. However, we have previously seen that the brain is, in fact, permeable to water due to the presence of aquaporin channels and other ion channels (3,4). This permeability of brain parenchyma to water and several other observations question the validity and applicability of circulation theory to design treatment strategies for hydrocephalus.In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water permeable tissue. Alteration in osmolarity resulting from increase in the concentration of macromolecules and ions has been shown to increase the fluid content and hence the size of the ventricles (5-7). Any osmotic gradient between the ventricular or interstitial CSF and the blood is equilibrated with transport of water between the two compartments. Therefore, water movement into the ventricle is secondary to the presence of osmotic gradients due to excess macromolecules. Thus, water movement into and out of the ventricles is not independent but is dependent upon the presence and resolution of osmotic gradients due to increase or decrease in the macromolecular content (8).Within this article, we review the role played by osmotic gradients and macromolecular ventricular clearance in hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. At least two primary pathways of macromolecular ventricular clearance have been studied: paravascular pathways (also known as glymphatic pathways) and olfactory lymphatic pathways.In particular, we focus on the role played by efflux transporters, specifically p-gp (ABC-B1) in the pathogenesis of hydrocephalus. Efflux transporters are responsible for the transport and clearance of both endogenous (endobiotics) and exogenous (xenobiotics) substances. An understanding of these transporters is critical to designing effective pharmacological treatment for this problematic disorder.