The Blood-Brain Barrier

Specialized cells surrounding the brain microvessels are:

endothelial cells, pedicures, and astrocytes

Endothelial cells of the BBB

lack fentrations, have tight junctions, lack pinocytic vesicles, and have increased mitochondria

Pericytes of the BBB

stabilize BBB, influence endothelial cells proliferation, regulate permeability to water and some other molecules, and attract and organize Astrocyte processes

Astrocytes of the BBB

processes cover of 95% of the brain microvessel surface, facilitate cell-cell communication in and out of BBB, and modulate permeability of certain substances

Aqueous diffusion

Extremely limited at BBB, only very small nonpolar gases (O2, CO2); functionally negligible for drugs

Transcellular lipophilic diffusion

small, lipophilic molecules; dominant route for the overwhelming majority of CNS active drugs

Transporter-mediated transport

Does not use ATP directly, but does require a specific protein; glucose, amino acids, nucleosides, some antivirals or cancer drugs

Receptor-mediated transcytosis

active mechanism that requires ATP; insulin transferrin, Trajan horse drug strategies

Adsorptive transcytosis

requires ATP, charge based, nonspecific, albumin and some peptides

Active efflux by ATP “pumps”

P-glycoprotein (unidirectional); often dominates over inward transport and limits BBB penetrance of many drugs

Factors that determine a molecule’s ability to cross BBB

Size, lipophilicity, ionization, avoid active efflux pathways, have specific active transport mechanisms in place

Circumventricular Organs

Sense blood levels and release substances into the blood

Area postrema

vomiting center