Hydrocephalus is a chronic brain disorder characterized by expansion of the ventricles and in some cases, significant neurological damage. Perhaps the greatest paradox in the hydrocephalus field is the failure of researchers to consistently measure transmantle pressure gradients (ventricle to subarachnoid space) in humans and in animal models of the communicating form of the disorder. Without such a gradient it is difficult to conceptualize how ventricular distention occurs. Based on the results of a mathematical model, one group has proposed that ventricular expansion may result from a relative reduction in interstitial pressure in the peri-ventricular area leading to the formation of an intra-mantle rather than a transmantle pressure gradient (Pena et al., Acta Neurochir 81: 59, 2002). Clues from studies in non-CNS tissues such as skin suggest that the dissociation of ß1 integrins with the surrounding matrix fibers results in a significant reduction of interstitial fluid pressure (Wiig et al., Acta Anaesthesiol Scand 47: 111, 2003). We examined these concepts in the rat brain and observed that the intraventricular injection of anti ß1 integrin antibodies resulted in a significant reduction in periventricular pressures to values significantly below those monitored in the ventricular system. In addition, many of these animals developed hydrocephalus (Nagra et al., Am J Physiol 297: R1312, 2009). We conclude that changes in the periventricular matrix generate pressure gradients favourable for ventricular expansion suggesting a novel mechanism for hydrocephalus development.

However, a number of issues need further clarification. If the pressures were to decline in the periventricular tissues, some removal of fluid must occur from the tissues.

We feel that Aquaporin-4 (AQP4) is a likely candidate for this effect as it is the predominant water channel in the brain. Indeed, in preliminary studies, the administration of blocking antibodies resulted in an up-regulation of AQP4 protein levels. In addition, in some experiments we negated capillary function by stopping the heart with KCL (capillary pressures = 0). Under these conditions, periventricular interstitial fluid pressures increased after anti ß1 integrin antibody administration into a lateral ventricle supporting the view that the capillary absorption of parenchymal water may play a pivotal role in the generation of pressure gradients in our hydrocephalus model.

Significance of these studies:

Apart from providing a mechanism to explain ventriculomegaly, it is of special interest to note that there are a number of ways to modulate aquaporin function using newly developed drugs and molecular techniques. This provides the exciting possibility that some forms of hydrocephalus may be treatable with pharmacological agents thus reducing the dependence on problematic shunts.