Astrocyte

Neuron

Blood vessel

Oligodendrocyte
 BARRIER
BRAIN
BLOOD

(BBB)
 Blood Brain Barrier (BBB)
Lecture Objectives:

Present the concept of BBB and discuss:

- Nature and Characteristics of BBB
- Maintenance of BBB
- Changes in BBB in Health and Disease
- Ways to overcome BBB
- BBB in experimental neuroscience (mainly as a hindrance in
drug testing and development)
- Perspectives of BBB in medicine and medical research
 Blood Brain Barrier (BBB)

Lecture Outline:

- Introduction and history

- Site and Role of BBB
- Nature of BBB: constituting cells
- Selective permeability of BBB
- BBB in health and disease (infections, viruses, hormones ..)
- How to get across BBB?
- Significance in Medicine
In the 19th century..

- Chemists developed industrial dyes for

use in textile industry

- histologists used them to stain tissues

- some dyes turned out to be useful as

therapeutic agents but

- when injected into animals they did not

enter brain.

Why?
Paul R. Ehrlich (1854-1915)
- introduced salvarsan (syphilis)
- noticed blood brain barrier

There had to be something in the brain tissue that kept the

dyes out.

Barrier?

Between blood and brain?

Blood Brain Barrier!

 Lina S. Shtern (1878-1968):

“Hematoencephalic Barrier”

Л.С.Штерн

Paul Ehrlich was a bacteriologist who was more interested in staining tissues. It was one of
his students (Edwin Goldman in 1913) who showed that brain can be stained if the dyes
are injected directly into the cerebrospinal fluid.

It is sometimes claimed that the concept of BBB was formulated by Lina S. Shtern in 1921.
Shtern was more neurologically oriented and, perhaps, the credit should go to her.
What is the role of BBB?
Brain has many different cells, they have receptors on
the outside that can change their activity (neurones).

Neuroactive compounds have to be kept out

Neurotoxic compounds have to be kept out

Desirable substances must be allowed to enter

How tight is BBB?

 Can anything get across BBB? If so, how?

Oil/water partition coefficient: “lipophilic” or

“hydrophilic” nature of chemical compounds.

More lipophilic compounds pass more easily across

the Blood Brain Barrier (BBB)
 Actively
transported
across BBB
Compounds can pass across BBB if

they can dissolve in the lipid component of BBB (caffeine,

nicotine, ethanol..)

they are actively transported (D-glucose, essential amino acids..)

What is the nature of BBB?

Non-fenestrated capillaries in brain
 Pericyte

Tight
Junction

Non-fenestrated capillaries with tight junctions

Non-fenestrated capillaries with tight junctions

Their structural and functional character is maintained by adjacent astrocytes

 Astrocyte
(endfeet surround the capillaries)

Pericyte (secrets the basement membrane)

Basement membrane

Endothelial cell (capillary)

Neurons, astrocytes and brain capillaries may form a “Neurovascular Unit” (NVU)

NVU is a more advanced concept closely related to structure/function of BBB but

not covered in this lecture (Neuwelt EA et al. Nat Rev Neurosci 12 169-182 2011).
Some lipid soluble undesirables (illegal or toxic drugs!)
can get through

Large molecules (proteins) do not normally get through

but sometimes do (including viruses; HIV)

Can BBB be damaged?

 Can BBB be damaged or altered?
- by high blood pressure

- by infections (inflammatory response?)

- by specific compounds (NAAG*, Quinolinic acid, hormones, VEGF**)

- in brain tumours

- in multiple sclerosis?

- by brain oedema (stroke, head injury)

* N-Acetyl-aspartyl-glutamate
** Vascular endothelial growth factor
 Can BBB be absent or leaky?

- if damaged by high blood pressure

- if altered by infections (inflammatory response?)

- if opened by specific compounds (NAAG, Quinolinic acid, hormones, VEGF)

- in brain tumours

- in multiple sclerosis?

- in conditions accompanied by brain oedema (stroke, head injury)

- even in healthy organism, some parts of brain have a naturally low BBB
(circumventricular organs: organum vasculosum of lamina terminalis,
area postrema..)!

How do “desirable” substances (D-glucose, vitamins..) get into the

brain tissue from blood?
 How do “desirable” substances (D-glucose, vitamins..)
get into the brain tissue from blood?

Active transport (fast)

- D-glucose (but not L-glucose)

- essential amino acids

Via cerebrospinal fluid (CSF)

- vitamins
- hormones

Route via CSF is slower than the active transport

q De Vivo disease: Glucose transport (via GLUT1) is compromised, patients tend

to have serious problems, incl. mental retardation
What about if neuroscientists or physicians want to get a
drug into the brain?

Will BBB block their efforts?

How can chemists help to get the drugs across BBB?

- make them more lipophilic, e.g. by adding an aromatic

component to the molecule

GABA (γ-aminobutyric acid) Baclofen (specific for GABAB receptors)

- synthesizing “prodrugs”, compounds with little or no pharmacological

activity but readily crossing BBB, then converting to active compounds
Heroin is a
“prodrug”
 How do chemists get the drugs across BBB?

- make them more lipophilic, e.g. by adding an aromatic

component to the molecule

Such treatment may change

chemical or pharmacological
characteristics of the
compounds

There are other ways how to overcome BBB: “High Intensity Focused Ultrasound”
 Blood Brain Barrier should not be forgotten

- in brain pathology

(oedema, stroke, head injury, brain tumours, infections, multiple sclerosis

and other conditions, even cancer!*)

- in pharmacotherapy
- by pharmaceutical chemists
- when testing drugs in animal experiments

* e.g. CAR, cancer associated retinopathy

 Blood Brain Barrier should not be forgotten

- in brain pathology

(oedema, stroke, head injury, brain tumours, infections, multiple sclerosis

and other conditions, even cancer!)
- in pharmacotherapy
- by pharmaceutical chemists
- when testing drugs in animal experiments

BBB is certainly not forgotten:

Saunders NR, Ek CJ, Hapgood MD and Dziegelewska KM (2008) Barriers in the
brain: a renaissance? Trends in Neurosciences 31 (6) 279-286
 Blood Brain Barrier is not forgotten:

BBB contains
• glucose (GLUT1) transporters and amino acid transporters
• essential fatty acid transporters
• ABC transporters (able to “expel” neurotoxic compounds)
Blood Brain Barrier is not forgotten:

BBB contains
• glucose (GLUT1) transporters and amino acid transporters
• essential fatty acid transporters
• ABC transporters (able to “expel” neurotoxic compounds)
 Blood Brain Barrier is not forgotten:

BBB contains
• glucose (GLUT1) transporters and amino acid transporters
• essential fatty acid transporters
• ABC transporters (able to “expel” neurotoxic compounds)

Deficient expression and/or genetic variations of the BBB-located

transporters or damage they may sustain during the lifetime (environment
or life-style) could very well contribute to the neurodegeneration seen in

§ Alzheimer’s disease
§ Amyotrophic lateral sclerosis
§ Brain ischaemia (stroke or head injury)
§ other neurodegenerative conditions?

This is a largely unexplored area of neuroscience.. ..!

 Learning outcomes (Blood Brain Barrier):

n Nature: non-fenestrated endothelial cells with tight junctions

n Maintenance: by adjacent astrocytes
n Role: to protect brain from neuroactive/neurotoxic substances
n Can it get damaged? Yes, in pathological conditions
n How to get across? By active transport or by becoming more lipophilic
n Damage/alteration of BBB components (specific transporters) can itself
be a part of aetiologies of neurodegenerative diseases..

The End