Brain oedema is thought to form and to clear through the use of water-protein channels, aquaporin-4 (AQP4), which are found in the astrocyte endfeet. The model developed here is used to study the function of AQP4 in the formation and elimination of oedema fluid in ischaemia-reperfusion injury. The cerebral space is assumed to be made of four fluid compartments: astrocyte, neuron, ECS and blood microvessels, and a solid matrix for the tissue, and this is modelled using multiple-network poroelastic theory. AQP4 allows the movement of water between astrocyte and the ECS and the microvessels. It is found that the presence of AQP4 may help in reducing vasogenic oedema shown by a decrease in brain tissue extracellular pressure. However, the astrocyte pressure will increase to compensate for this decrease, which may lead to cytotoxic oedema. In addition, the swelling will also depend on the ionic concentrations in the astrocyte and extracellular space, which may change after ischaemic stroke. Understanding the role of AQP4 in oedema may thus help the development of a treatment plan in reducing brain swelling after ischaemia-reperfusion.
Cerebral hypoperfusion involved a reduction in cerebral blood flow, leading to neuronal dysfunction, microglial activation and white matter degeneration. The effects on the blood-brain barrier (BBB) however, have not been well-documented. Here, two-vessel occlusion model was adopted to mimic the condition of cerebral hypoperfusion in Sprague-Dawley rats. The BBB permeability to high and low molecular weight exogenous tracers i.e. Evans blue dye and sodium fluorescein respectively, showed marked extravasation of the Evans blue dye in the frontal cortex, posterior cortex and thalamus-midbrain at day 1 following induction of cerebral hypoperfusion. Transmission electron microscopy revealed brain endothelial cell and astrocyte damages including increased pinocytotic vesicles and formation of membrane invaginations in the endothelial cells, and swelling of the astrocytes' end-feet. Investigation on brain microvessel protein expressions using two-dimensional (2D) gel electrophoresis coupled with LC-MS/MS showed that proteins involved in mitochondrial energy metabolism, transcription regulation, cytoskeleton maintenance and signaling pathways were differently expressed. The expression of aconitate hydratase, heterogeneous nuclear ribonucleoprotein, enoyl Co-A hydratase and beta-synuclein were downregulated, while the opposite observed for calreticulin and enhancer of rudimentary homolog. These findings provide insights into the BBB molecular responses to cerebral hypoperfusion, which may assist development of future therapeutic strategies.