The brain can be considered among the most important organs of an organism, where crucial information for vital functions is generated, processed and stored. Homeostatic balance in the brain is essential to ensure an organism’s normal function. Several mechanisms have evolved to protect the brain from disbalances and maintain a functional environment for its neurons. The function of the BBB is to prevent cells, microorganisms and other molecules to pass from the periphery to the brain under physiological conditions.
A compromised BBB would mean that the endothelial tight junctions have become loose in certain places allowing for cells, including those of the immune system (such as macrophages or T cells), microorganisms (such as bacteria and viruses) but also large molecules (such as antibodies and drugs) to be able to cross this barrier. The BBB is formed by the capillary endothelium of the vessels perfusing the brain. Owing to the presence of epithelial-like, high resistance tight junctions that cement together all the endothelia in brain capillaries, there is no ‘para-cellular’ pathway for solute or drug transport from blood to brain. In addition, the pinocytosis or ‘trans-cellular’ pathway of solute transport across the endothelium is reduced 100-fold in brain endothelium compared to endothelial cells in peripheral tissues. In addition, the highly active efflux pump, such as the P-glycoprotein, offers another layer of protection to the CNS by expelling molecules back in the blood.
Increased BBB permeability has been described as a mechanism of neuroinvasion for several viruses such as the flavivirus West Nile virus. In general, the BBB remains intact during RABV infection although several lines of evidence suggest that opening the BBB ameliorates the course of RABV infection in animal models. Preliminary unpublished data of experiments performed in mice support the hypothesis that opening of the BBB would have a beneficial effect on recovery. The mechanism of this action is believed to be the ability of cells of the immune system to enter the brain and fight infection. Furthermore it would offer the opportunity of administration of compounds that under normal circumstances could not pass the BBB and enter the CNS.
Our initial experiments to influence the BBB will be carried out using an in vitro BBB model, which perfectly mimics the situation in humans and mice. Within ASKLEPIOS we will provide both in vitro and in vivo (mouse model) proof-of-principle, of whether opening the BBB will improve therapeutic efficacy of the envisaged combination therapy.