Aquaporins: gatekeepers of oedema in traumatic brain injury.

Abstract

[Conclusion] In the present thesis, I have shown that single administration of an AQP4 & 1 antagonist at 5 h, an AQP4 agonist at 48 h and the sequential treatment with both of the compounds at their optimal time points is beneficial to physiological and functional outcome following diffuse TBI. At a physiological level there was an attenuation of post traumatic cerebral oedema and of brain albumin content, with these beneficial effects occurring in the absence of any changes in water channel expression. Functionally, each compound improved functional motor outcome after TBI when they were administered at their optimal time point. Sequential treatment with both compounds proved even more efficacious than single interventions. The sequential treatment with the antagonist and then the agonist augmented what seemed to be a protective response of the brain against posttraumatic oedema, namely an initial downregulation of AQP channels followed by a later upregulation. This alteration in expression was mimicked by initial inhibition with the antagonist followed by facilitation of water transport during the resolution phase of oedema. Taken together these results provide evidence in favour of a pharmaceutical treatment for the attenuation of injury-induced brain swelling, which when administered at the optimal time points may deliver a much needed novel, therapeutic intervention for this life threatening condition.