a) Definition and function of the BBB.
The demonstration by Paul Ehrlich that intravenously injected vital dyes did not stain the brain and the spinal cord but stained other
organs, has given rise to the concept of a barrier between the blood and the brain [Ehrlich P.,1885]. The BBB is present in virtually all vertebrates but absent in the brains of invertebrates. Thus in
evolutionary terms, the BBB parallels the myelin as myelin is lacking in the invertebrate nervous system [Pardridge W.M. et al, 1986, b]. The main morphological feature of the BBB is the presence of high-resistance tight junctions (or occluding junctions) which seal the brain endothelial cells together into a continuous tube separating the blood from the brain tissue. The molecular description of these tight junctions of the BBB is virtually still lacking but it appears that the properties of the BBB are induced and maintained by the local environment and especially by the astrocytes [Stewart P.A. et al, 1981] [Janzer R.C. etal, 1987] [Golstein G.W., 1988] [Pardridge W.M. et al, 1986].
In the human healthy brain, the BBB is omnipresent except for about half a dozen of small areas in the circumventricular organs such as the median eminence of the floor of the third ventricle, the area postrema surrounding the caudal tip of the fourth ventricle, and the choroid plexus : these regions are probably sites of local
exchange between the blood and brain for peptides or other substances which may then have access to the cerebrospinal fluid (CSF) through the low-resistance tight junctions of the ependymal cells lining the surface of the ventricles. The BBB therefore is to be differentiated from the blood-CSF barrier in terms of structure and in terms of function. Moreover, the composition of the brain
interstitial fluid and of the CSF are different.
The transport through the BBB is selective and regulates the entry of fluid, electrolytes, small molecules and proteins. It
maintains the composition of the brain extracellular fluid which is very different from that of the blood plasma especially by keeping a low concentration of proteins in the brain interstitial fluid. The
transport through the BBB is governed mainly by the specific chemical characteristics of the penetrating substance rather than by its molecular size. On the BBB, specific membrane proteins (carrier proteins) involved in the transport of specific molecules have been described e.g for insulin [Pardridge W.M. et al, 1985, b] or for phenylalanine [Choi T.B. et al, 1986]. Conversely, the BBB is known to be highly impermeable to the centrally active
neurotransmitters and thus prevents their loss to the blood plasma after their synthesis in the brain. However, the BBB is not totally impermeable to the plasma proteins as a minimal degree of leakage can be observed: this phenomenon may be due to a residual
pinocytosis seen in the brain vessels although pinocytic vesicles are characteristically minimal in the brain endothelial cells [Pardridge W.M. et al, 1986, b] [Reese T.S et al, 1967].
b) Anatomical structure of the BBB.
For a complete understanding of the BBB, one first has to understand the organisation of the vascular tree. The blood is confined to a close circuit of vessels lined by a simple squamous epithelium, the endothelium. For the entire vasculature, an
approximate number of 6.1013 endothelial cells is estimated and their solid mass should approximate 1 kg. It is now known that endothelial cells differ in their nature and their composition between different organs and also between different types of vessels within the same organ [Zetter B.R.,1981 and 1988] [Rupnick M.A. et al, 1987].
The vascular tree is made up of different types of vessels organised in series from the arterial to the venous system as follows: elastic arteries, muscular arteries, arterioles, capillaries, pericytic venules, muscular venules and small, medium and large-sized veins. Vessels larger than 100 pm in diameter are considered part of the macrovasculature whereas smaller vessel are part of the
microvasculature. The microvasculature corresponds to the arterioles, capillaries and emerging venules as well as the
arteriovenous anastomoses. Anatomically speaking, the BBB involves only the microvasculature and more specifically the capillaries and their emerging venules as it is only in these types of vessels that exchanges between blood and tissue occur. The vessels in the rest of the vasculature tree possess a continuous vessel wall which prevents significant exchanges [Simionescu N. et al, 1990].
Continuous capillaries are not only a feature of the CNS as they are also found in muscular tissue (skeletal, cardiac and smooth muscle) but also in the exocrine pancreas and the gonads [Palade G.E., 1961] [Simionescu N. et al, 1990]. The structure of the vessels is organised into three layers or ’tunics' : the intima , the media and the adventitia. In the brain capillaries, the intima consists of a single layer of thin endothelial cells and a basal lamina (basement
membrane) in close contact with the pericytes. The endothelial cells are joined together by tight junctions. These occluding junctions display a different organisation from that seen in other epithelia [Simionescu N. et al, 1990]. The media is normally composed of muscular cells but it is virtually lacking in the brain capillaries. The adventitia consists of the brain connective and neural tissue which, in the brain, is tightly packed around the vessels. The passage of
substances from the blood to the brain is further restrained by the foot processes of the astrocytes which are closely applied to the vessel wall and cover 70 % of its surface [Golstein G.W., 1988].
The postcapillary (pericytic) venules range from 10 to 50 pm in diameter and appear to have a comparable vessel wall as the transition between the capillaries and the venules occurs gradually. Immunologicaly, the post capillary venule is an important site for inflammation and allergic reactions and exhibits a high concentration of adhesion molecules [Raine C.S. et al, 1990]. Prineas has also
described structures resembling lymphatics around the brain vessel especially in the Virchow-Robin space [Prineas J.W., 1979]. The Virchow-Robin space (VRS) has recently been reviewed by Esiri and Gay [Esiri M.M. et al, 1990]. The VRS is the space between the brain vessels and the cerebral matter. The VRS is now known to be an extension of the subpial space rather than of the subarachnoid space in man. The pia is made of a single layer of cells linked together by desmosome and gap junction. From the pia, the space extends as far as the capillaries. At this level the VRS is occluded by the glia limitans formed by the foot processes of the astrocytes.