BLOOD-BRAIN BARRIER PATHOLOGY AND PHARMACOLOGY

The capillaries of the central nervous system forming the blood-brain barrier (BBB) have specific properties and functions. They regulate the brain microenvironment by restricting ionic, fluid and cell movements between the blood and the brain, by supplying brain cells with essential nutrients, and by protecting them from toxic molecules in the blood.

Prof. Ferenc Joó, the first head of the Laboratory of Molecular Neurobiology and his co-workers created the first in vitro model of the BBB by the successful isolation of viable brain microvessels more than 35 years ago. Experiments on isolated brain microvessels provided important data on cerebral endothelial receptors, transporters and signalling mechanisms. Continuing their work we have developed new BBB models by the co-culture of brain endothelial cells, glial cells and pericytes to study cell–cell interaction in the neurovascular unit, modulation of BBB permeability in physiological, pathological, and pharmacological conditions and to screen drug candidate molecules to predict brain penetration (Fig. 1).

Figure 1: Co-culture model of the BBB (Nakagawa, Deli et al., 2007; Nakagawa, Deli et al., 2009)

BBB functions under physiological and pathological conditions

The protective functions of the blood-brain barrier can be injured in several diseases, like bacterial and viral infections of the nervous system and neurodegenerative diseases. In these pathologies the amount of nutrients actively transported by brain endothelial cells is reduced. In parallel, the permeability of the blood-brain barrier is increased for potentially harmful substances from blood, like albumin, which contribute to neuronal death and the progression of the disease. Even relatively small changes in the functions of the blood-brain barrier may lead to serious and chronic neuronal dysfunctions.

We study the effects of key pathogenic factors in nervous system diseases on the morphology and functions of the blood-brain barrier, and how the blood-brain barrier can be protected from the damaging effects. We demonstrated that amyloid peptides, participating in the pathogenesis of Alzheimer's and prion diseases, can directly exert a toxic effect on brain endothelial cells and inhibit their functions. Pentosan treatment protected the cells against the toxic effect. Pentosan, an active ingredient from a plant with structural similarities to heparin, was also effective against bacterial lipopolysaccharide-mediated endothelial cell damage.

Drug targeting to brain

In collaboration with the Department of Pharmaceutical Technology of the University of Szeged, we search for new methods to target drugs to the central nervous system. We focus on (i) the nasal pathway as an alternative gate to the brain (Fig. 2) as well as to the systemic circulation and (ii) nanoparticles, namely niosomes, bilayer vesicles made up of non-ionic surface active agents (Fig. 3) to cross the blood-brain barrier by targeting transport systems.

Figure 2: Pathways of nasal drug delivery

Figure 3A: Vesicular structure of a niosome;
Figure 3B: Niosomes seen by atomic force microscopy
AFM: Dept. of Optics and Quantum Electonics, University of Szeged

Development and exploitation of the results

The protection of brain endothelial cells and the improvement of BBB functions in pathological conditions, the exploration of new approaches for drug transport/targeting to brain may have a therapeutic potential in the treatment of central nervous system diseases.