Transportation across the BBB

BY;
Aicwamu Emmanuel
BNS
28TH JUNE 2021
objectives
Substances that cross the BBB
Substances that don’t cross the BBB
Routes across the BBB
Clinical applications
Substances that cross the BBB
Oxygen
Carbon dioxide
Water
Glucose
Amino acids
Electrolytes
Some drugs e.g. L-dopa, sulphonamide, tetracycline, anesthetic gases i.e. ether.
Other lipid soluble substances, e.g. vitamins
Substances that cannot cross the BBB
injurious chemicals
Pathogens
Some drugs e.g. penicillin, and the catecholamine, dopamine.
Bile pigments.
in infants, bile pigments enter the brain during jaundice , it can cause damage to basal
ganglia leading to kernicterus.
abstract
small lipid soluble molecules and blood gases like oxygen, carbon dioxide passively diffuse.
Essential nutrients e.g. glucose , amino acids require specific transport proteins in order to
reach the brain.
Routes across the BBB
Paracellular pathway (aqueous diffusion)
Diffusion of substances between the cells is called Paracellular diffusion.
It is non saturable and non-competitive.
In the brain however, it doesn’t occur to any great extent at the BBB, due to tight junctions.
Only small water molecules can diffuse through the BBB by apparently passing through the tight
junctions.
Transport proteins
Also called carrier-mediated transport.
Binding of a solute e.g. glucose or amino acids to a protein transport on one side of the
membrane triggers a conformational changein the protein hence its transportation.
This is from a region of high to low concentration.
If compounds need to be moved against a concentration gradient,ATP may be provided to
facilitate the process.
continuation
The transport of glucose across the BBB into brain is mediated by glucose transporter GLUT-1
other transporters include GLUT-3.
Also provide routes for drug delivery to the brain and CNS to treat some neurological problems.
Lipophilic (transcellular) diffusion
pathway
This is diffusion of substances across the cells.
Non saturable and non-competitive.
The higher the lipophilicity of a substance along with a molecular weight less than 450, the
greater the diffusion into the brain.
If two identical substances vary in molecular weight, smaller substance will penetrate faster.
Small organic molecules e.g. O2,CO2,NO and H2O are highly permeable across the endothelial
cells by dissolving in their lipid plasma membrane.
Hydrogen bonding property is also a major determinant.
Receptor mediated endocytosis
Transport of peptides and proteins across cellular barriers has been associated in a number of
systems e.g. insulin.
Insulin-like growth factors (IGF-1, IGFII), angiotensin II, atrial and brain natriuretic
peptide(ANP,BNP), IL-1and transferrin.
Receptor mediated endocytosis across the BBB has been shown for few peptides and proteins.
E.g. insulin, transferrin, certain cytokines and leptin.
While angiotensin-II and ANP may exert their effects by binding on luminal cytoplasmic
membrane of brain micro vessel endothelia. Maybe involved in regulation of BBB permeability
for other substances.
Adsorptive transcytosis(AMT)
Starts with uptake either through clathrin-coated pits.
This process is an energy requiring process. For endocytosis at the luminal side of EC, transport
across the EC and for exocytosis at the basolateral side.
Density of mitochondria in cerebral EC is roughly five times greater than in the peripheral
endothelia increasing the energy potential.
This process may not involve specific plasma receptors and that endocytosis is initiated through
charge-charge interaction between poly-cationic substances and negative charges on endothelial
surface.
Efflux pumps
Are responsible for extruding drugs from the brain.
This mechanism is a major obstacle for accumulation of a wide range of biological active
molecules in the brain. With ATP binding cassette(ABC) transporter P-gp and multidrug resistant
protein(MRP) being principle efflux mechanism of these agents.
clinical application
Alzheimer’s disease. Due to increased glucose transport, unregulation of glucose transporter
GLUT-1. Altered agrin levels.
Accumulation of amyloid beta, by decreased levels of p-glycoprotein transporter.
Parkinson’s disease; dysfunction of the BBB by reduced efficacy of p-gp
Epilepsy; transient BBB opening in epileptogenic foci and unregulated expression of p-gp. and
other transporters in the astrocytes and endothelium.
HIV-BBB disruption.
Pain; inflammatory pain alters BBB tight junction protein expression and permeability.
continuation
Stroke
Trauma
Brain tumors