Blood Brain Barrier (BBB)
Substances accessing the brain are carried by the brains
arteries, arterioles, and finally capillaries.
Blood vessels in human brain. A plastic emulsion was injected into postmortem brain vessels. After, brain parenchymal tissue was dissolved to
reveal the cast of the vessels.
Zlokovic & Apuzzo: Neurosurgery 43(4):877-878, 1998. (provided by permission from Lippincott Williams
& Wilkins)
• Unlike the rest of the body, the vessels of the
brain are tightly sealed to restrict substances
within the blood from diffusing into the brain.
Why does it matter?
• 1) The BBB protects the brain from shifts in
ion concentrations in the blood
• 2) The BBB protects the brain from changes in
transmitter concentrations (e.g., adrenaline)
Structural make-up of peripheral vessels
•
•
Peripheral vessels allow more
substances to pass into tissue
Endothelial
cells form the
capillary wall
Intercellular cleft
passage
Pinocytosis
Structural Features
– Prominent pinocytotic vesicles carry
molecules across the endothelial cell
into tissue.
– Open clefts allow molecules to pass
into tissue
– Fenestrae (analogous to the thin
windows of a house relative to the
thick walls) make it easier to pass
across membrane into tissue.
Blood
Fenestrae
Based on Figure B-1 in Kandel, 4th Ed.
Structure of brain vessels
Tight Junction
between apposition
of endothelial cells.
• The BBB helps regulate brain
exposure to substances
• Structural Features:
– Fewer pinocytotic vesicles
– No open clefts
– No Fenestrae
– Tight junctions instead of clefts
• Additional Differences
– Basement membrane formed
– pericytes
– Astrocytic end feet surround
the basement membrane.
Endothelial
cells form the
capillary wall
Less
Pinocytosis
Basement
membrane
and
pericytes
Blood
Astrocyte
Foot process
NO Fenestrae
Based on Figure B-1 and B-2 in Kandel, 4th Ed.
Electron micrograph of CNS vessel
Capillary
Lumen without
blood
E
A
D
Tip of arrowhead touches basal lamina
E,endothelial cell cell body; A, Astrocyte, D, dendrite
http://www.rit.edu/~umagwww/winter2002/
images/gallery_barrier.jpg
What passes through the BBB
and how?
What passes through the BBB
and how?
See Figure B-4 in Kandel (4th Ed)
• Lipid soluble substances can pass through the BBB. These
include
– Barbituates, ethanol, nicotine, iodoantipyrine, and diazepam
• Their uptake is limited only by blood flow, because all of the substance in the
blood will be extracted by the brain with a single pass through the brain.
• Gases
– CO2, O2, N20 and Xe, volatile anesthetics
• Some substances bind to plasma proteins so that their uptake
is less than predicted by the coefficient the predicts extraction
(oil/water partition coefficient)
– Phenobarbital, phenytoin
Transporters are used for active
movement across this barrier
• Categories
and
membrane
location.
Transporters
• Water soluble substances do NOT pass through the
BBB without specialized transporters
–Water passes in through aquaporins, a category of
transporters
•Specialized transporters exist for
•
•
•
•
•
•
Glucose (D-glucose, not L-glucose)
Neutral amino acids (e.g., phenylalanine, L-dopa)
Basic amino acids (e.g., arginine, lysine)
Acidic amino acids (e.g., glutamate)
Electrolytes (sodium, potassium, chloride)
Hormones (thyroid hormone, insulin)
•Substances that have low lipid solubility, and
lack transporters
• Dopamine, penicillin.
• We used to think this was also true for antibodies, but we now
know that is not the case. Instead antibodies cross the BBB.
• The downside is that BBB limits the ability to
deliver treatments to the brain
– Strategies for bypassing the BBB
• Use drugs with transporters (e.g., L-DOPA instead of DA)
• Use drugs that are more lipid soluble
• Use extremely small particles that bypass the tight
junctions*
What you should know
• Know why we have a blood brain barrier (BBB).
• Know the structural differences in central nervous system
vessels that contribute to the BBB.
• What are features of substances that can cross the BBB with
no assistance?
• What mechanisms allows for active transport of substances
that cannot cross by diffusion?
• What are some of the strategies for moving drugs from the
blood into the brain?
References
• The majority of slides come from our textbook.
• All electron micrographs from Brenda J. Anderson
• Laterra, Keep, Betz and Goldstein (1999). BloodBrain-Cerebrospinal Fluid Barriers. In G. Siegel et
al. (Eds) Basic Neurochemistry: Molecular, cellular
and medical aspects, Lippincott-Raven,
Philadelphia
• Also see references on specific slides
Cholinergic control of medium spiny
neurons in the striatum
• Cholinergic receptors
regulate the activity of
medium spiny neurons
both at the postsynaptic
level, and
presynaptically, by
modulating glutamate,
dopamine, and
acetylcholine
neurotransmission.
http://www.frontiersin.org/neuroan
atomy/10.3389/fnana.2011.00006/f
ull