The blood-brain barrier: bottleneck in brain drug development

Abstract

The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain approximately 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.

Figures

FIG. 1.

Whole body autoradiogram of an adult mouse sacrificed 30 min after intravenous injection of radiolabeled histamine, a small molecule that readily enters all organs of the body, except for the brain and spinal cord.

FIG. 2.

A review of the Comprehensive Medicinal Chemistry database shows that, of more than 7000 small-molecule drugs, only 5% treat the CNS, and these drugs only treat four disorders: depression, schizophrenia, chronic pain, and epilepsy., There are few effective small- or large-molecule drugs for the majority of CNS disorders, with the exception of Parkinson’s disease, e.g., l-DOPA, and multiple sclerosis, e.g., cytokines.

FIG. 3.

Trans-cranial drug delivery to the brain. A: Autoradiogram of rat brain 48 h after an intracerebral implantation of a polymer carrying radiolabeled NGF. The size of the polymer approximates the magnification bar, indicating the NGF has not significantly diffused from the implantation site. B: Autoradiogram of rat brain 24 h after an intracerebroventricular injection of BDNF into an LV. The BDNF distributes to the ependymal surface of the ipsilateral LV and the third ventricle (3V), but not into brain parenchyma. C: Convection enhanced diffusion in the primate brain forces fluid through the brain tissue. The direction of fluid flow, principally via white matter tracts, can be traced with immunocytochemistry using an antibody to GFAP, which shows an astrogliotic reaction in the path of fluid flow. The hole in the brain left by the catheter is noted by the asterisk. The fluid moved from the catheter in the putamen (Pu) via the internal capsule (ic) white matter to the caudate (Cd).

FIG. 4.

India ink study shows vascular density in the cortex of adult rat brain. Reprinted with permission from Bar. The vascular system of the cerebral cortex. Adv Anat Embryol Cell Biol 59:I–VI,1–62. Copyright © 1980, Springer-Verlag. All rights reserved.

FIG. 5.

BBB CMT systems are shown for seven different classes of nutrients, and the genes for five of these systems has been identified. GLUT1 = glucose transporter type 1; MCT1 = monocarboxylic acid transporter type 1; LAT1 = large neutral amino acid transporter type 1; CAT1 = cationic amino acid transporter type 1; CNT2 = concentrative nucleoside transporter type 2.

FIG. 6.

BBB AET systems are comprised of an energy-dependent system at one side of the brain capillary endothelium and an energy-independent system at the opposite endothelial membrane. As a hypothetical example, members of the ABC gene family are shown at the luminal endothelial membrane, and members of the SLC gene family are shown at the abluminal endothelial membrane.

FIG. 7.

BBB RMT systems are shown for three classes of systems. An example of a bidirectional RMT system is the endothelial transferrin receptor (TfR), which mediates the transport of holo-transferrin (Tf) in the blood to brain direction, and the transport of apo-Tf in the brain to blood direction. A reverse RMT system such as the neonatal Fc receptor (FcRn) transports IgG in the brain to blood direction only. An endocytosis system is illustrated by the type I scavenger receptor (SR-BI), which mediates the endocytosis of acetylated low-density lipoprotein into the endothelial compartment without transcytosis across the BBB.

FIG. 8.

Step 1 in CNS drug development is the availability of effective BBB drug or gene targeting technology. In the absence of a BBB technology, then the CNS drug developer is limited to lipid-soluble low molecular weight drugs, and only a few CNS diseases consistently respond to this class of molecule.