A proposed role for efflux transporters in the pathogenesis of hydrocephalus

Abstract

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.

New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus

“…Thus, there is neither a dominant site of water entry into the CSF in any of the animal species (wild-type, knockout mice for aquaporins AQP1 and AQP4 [34,35,41] ), nor in patients before or after plexectomy procedures [33] , nor in healthy volunteers or in those with idiopathic normal pressure hydrocephalus [48] . Faster (more dominant) arrival of water into the CSF was observed only in the case of a local osmolarity increase in one of the CSF compartments, which results in an increase in the CSF volume and pressure, leading to the dilation of ventricles [35,44,45] . Accordingly, the CSF volume is regulated by the correlation between hydrostatic and osmotic forces inside the blood and in the ISF/CSF compartment.…”

“…Until now, this hypothesis was named Bulat-Klarica-Orešković hypothesis by several research groups [34,[38][39][40] , and it is supported by independent experimental laboratories [34,39,44,45] as well as by computer-based models [46,47] and critically analyzed clinical data [39,40] .…”

“…Cats infused with hyperosmolar solution had significantly larger ventricles then cats infused with isoosmolar solution [35] . Krishnamurthy et al [44,45,56] have shown in rats that the increase in CSF osmolarity by a chronic intraventricular infusion of hyperosmolar substances leads to the development of hydrocephalus. Hence, in those cases, hydrocephalus is a result of osmotic gradients that favor water transport into the CSF system.…”

“…Hence, in those cases, hydrocephalus is a result of osmotic gradients that favor water transport into the CSF system. Krishnamurty et al [45] have proposed that the main role in the formation of the osmotic gradient in CNS belongs to P-glycoprotein, whose inhibition or activation regulates the concentrations of substances within the brain. It is believed that, at the blood-brain barrier surface, P-glycoprotein prevents the accumulation of harmful osmotic active substances in the brain by their active elimination into peripheral blood vessels [62] .…”

“…During the period of CSF drainage, an intensive nonsurgical therapy for hydrocephalus is recommended [45,67] . That way, enough time could be gained to cure inflammation, remediate the consequences of bleeding into the CSF, improve brain parenchyma blood perfusion, restore CSF isoosmolarity, and resolve other possible pathophysiological causes of hydrocephalus before the decision of permanent shunting.…”