BLOOD BRAIN BARRIER

1. BLOOD BRAIN BARRIER
Dr Himanshu Soni
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2. Introduction
1882, Paul Ehrlich – first demonstration using
intravascular dye injection.
Brain and spinal cord were not stained !!
However, some areas did get stained : pineal
gland, posterior pituitary, tuber cinerum, optic
recess, area postrema.
First time concept – Blood Brain Barrier
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3. 1898 – Lewandowsky coined the term “blood
brain barrier”; demonstrated neurotoxic agents
affected when directly injected, but not when IV
70 years later, Reese and Colleagues – localised
barrier to capillary endothelial cells
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4. Formation
 Complex system consists
of
1. Specialised basal
membrane
2. Pericytes
3. Astrocytic feet
4. Endothelial cells
 Brain endothelial
cells
1. Continuous tight
junctions
2. No detectable
transendothelial pathways
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5. Formation
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6. “tight” junctions
Composed of dimer subunits – transmembrane
proteins :
1. Occludin (first discovered but not essential)
2. Claudin (essential protein)
3. Junctional adhesion molecule (JAM) or ESAM
Anchored to endothelial cells by proten
complexes
1. Zone occluding – 1 (ZO – 1), ZO – 2, ZO – 3
Adherens junctiions containing specific integral
membrane proteins
1. VE cadherins
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7. “tight” junctions
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8. “basal membrane”
Continuous basal
membrane outside the
endothelial lining
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9. “glia limitans” Astrocytic feet
Astrocytic foot processes release specific factors
& are necessary for development of BBB.
Contain water channels (aquaporin – 4) that
allow water uptake and contribute to brain
swelling
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10. “transport carriers”
Carriers for glucose and essential amino acids
facilitate their movement since brain cannot
synthesize them.
Secondary transport systems – for efflux of small
molecules and nonessential amino acids from the
brain to the blood.
Sodium ion transporters on luminal membrane
and Na-K-ATPase on anti-luminal membrane
account for Na movement. Large number of
endothelial mitochondria provide energy.
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11. “transport carriers”
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12. Development
Early 1920s, immature BBB in newborn –
false!!
Recent studies
no difference in permeability detected between
newborn and adult BBB capillaries.
No difference in updake of glucose, AA, purines,
choline, nucleosides observed
Conclusion – newborn BBB has restrictive
properties similar to that of the adult.
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13. Permeability
Molecular weights >60k Da – donot pass
 L-DOPA – readilly cross
 Plasma protein bound compounds – do not pass
Size and lipid solubility !
Highly lipid soluble
Alcohol, nicotine
Antibiotics – many does, others dont!
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14. _

15. Water
Moves freely in and out of the brain as osmolarity
changes
Clinically useful – poorly permeable compounds like
mannitol can osmotically dehydrate the brain and
reduce ICP.
Gases
CO2, O2, volatile anesthetics diffuse rapidly
The rate at which their concentration equilibrate with
plasmy is limited primarily by the cerebral blood
flow rate
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16. Glucose
Brain endothelium – rich in GLUT – 1 transporter
They carry glucose across BBB.
Glut – 1 deficiency
Severe learning difficulties
Low CSF glucose and not plasma, identifies !
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17. Amino acids
Essential AA need to be supplied to the brain hence they
rapidly enter, with precursor of dopamine, L-DOPA
They enter via Leucine-preferring or L-type transport
proteins.
They compete for entry, hence, elevation of levels of one
AA will inhibit uptake of others. Important in conditions
like Phenylketonuria (PKU).
Small neutral amino acids – alanine, glycine, proline and
GABA are markedly restricted in entry
These are non-essential and are transported by alanine-
prefering or A-type transporter.
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18. Functions
 The blood-brain barrier (BBB) protects the neural tissue from
variations in blood composition and toxins.
 Extracellular concentrations of hormones, amino acids and
potassium undergo frequent fluctuations, especially after
meals, exercise or stressful times.
 Since many of these molecules regulate neuronal excitability,
a similar change in the composition of interstitial fluid in the
CNS can lead to uncontrolled brain activity.
 Blood borne infections of the brain are rare.
 BBB becomes permeable during inflammation, allowing
macrophages to move across.
 Antibodies are too large to cross BBB.
 Certain Biochemical poisons are too large to pass BBB, for
e.g. Botulinum toxin can affect peripheral nerves but not
CNS.
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19. Absent BBB
BBB lacking areas –
1. The chemoreceptor trigger zone in the area postrema in the floor of
the fourth ventricle,
2. subfornical organ in the anterior wall of the third ventricle,
3. the median eminence of the hypothalamus,
4. choroid plexus,
5. organum vasculosum
6. lamina terminalis, and
7. the pineal
8. and posterior pituitary glands.
These areas are collectively known as the
circum-ventricular organs
Many are involved in hormonal control
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20. Absent BBB
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21. Their capillaries have fenestrations instead of
tight junctions.
Many drugs produce nausea and vomiting as a
prominent side effect because the lack of a BBB
allows unfettered access directly from the blood
stream to the area postrema and chemoreceptor
trigger zone.
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22. Clinical Significance
Mannitol – osmotic dehydrant !
L-DOPA – in Parkinson’s disease
Glut-1 deficiency – severe learning diff.
PKU – reduce brain uptake of other AA
Botulinum – does not affect CNS
Alcohol, Nicotine – readily affect CNS
Gases – conc. Primarily depend on Blood flow.
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23. P-GLYCOPROTEINS
Are ATP driven pumps, on endochelial cells
Pump out hydrophobic compounds, from
endothelium back to the blood, hence limit their
permeability.
E.g. Cyclosporin A, vinblastine
Hence, confer multi-drug resistance to cancer cells
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24. “enzymatic BBB”
Most blood neurotransmitters donot enter the brain
because of low lipid solubility.
L-DOPA, precursor of dopamine, has high affinity
for L-type transporter and enters brain more easily
then predicted based on its lipid-solubility.
But the penetration of L-DOPA is limited by
presence of L-DOPA decarboxylase and
MonoAmine Oxydase in the endothelium.
This “enzymatic BBB” limits passage of L-DOPA
into brain and hence larger doses are required in
Parkinson’s disease.
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25. MonoAmine Oxidase – inactivates
neurotransmitters released by neuronal activity.
The monoamine uptake is present on the anti-
luminal side.
Several other neurotransmitter-metabolizing
enzymes such as cholinesterases, GABA
transaminases, aminopeptidases, endopeptidases
are contained in endothelial cells. In addition,
drug and toxin metabolising enzymes are present
too, thus enzymatic BBB protects from
circulating NT and toxins.
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26. Compromised BBB in Diseases
Tumors, encephalitis, multiple sclerosis, stroke
Decrease production of claudin
Tumors secrete VEGF and others, inducine formation of
new leaky capillaries
Ultimately cause compromised BBB and brain
edema.
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27. DRUG DELIVERY
For drugs which have low lipid solubility or no
transporters /carriers, can be facilitated by
1. Direct delivery into the CSF – meningitis, cancers
2. Vasoactive compounds – bradykinin, histimine
they can alter BBB permeability in pathological
conditions and bot in normal people.
can be used to deliver chemotherapeutics.
3. Synthesize lipid soluble drugs. For e.g. Heroin and
morphine are similar, but heroin has two acetyl
groups, hence more soluble and more rapid onset.
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28. KERNICTERUS
Indirect bilirubin enters the brain across BBB easily
causing higher concentrations in the extracellular
spaces and causing kernicterus.
MENINGITIS
Caused by Pneumococcus, hemophilus
Disrupts BBB, increase penetration to toxins
Antibiotics used to treat may aggravate CNS
inclammation by releasing toxins from the cell walls
like LPS.
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29. MULTIPLE SCLEROSIS
It is suggested that, primarily this is a disease of
weakened BBB, exposing the myelin in the brain or
the spinal cord to the macrophages.
Oxidative stress plays an important role in
breakdown of BBB, anti-oxidants like lipoic acid
may be able to stabilise.
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30. DEVIC’S DISEASE
Neuromyelitis Optica
Has high levels of antibodies against protein –
aquaporin-4.
Thus disrupting BBB and causing effects similar to
multiple sclerosis.
SLEEPING SICKNESS
Late Neurological Trypanosomiasis
The protozoa is found in the brain tissue, thought to
cross through choroid plexus
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31. PML
Progressive multifocal leucoencephalopathy
A demyelinating disease of the CNS caused by the
reactivation of a latent papavovirus ( the JC polyoma
virus)
It crosses the BBB.
Seen in immunocompromised patients, usually
AIDS.
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32. HIV ENCEPHALITIS
HIV laden macrophages in the blood, crosses the
BBB thereby releasing the virus in the parenchyma.
The virus then attacts the attention of microglia and
activates the inflammatory cascade.
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33. Thank you
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