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BLOOD BRAIN BARRIER
DR.SAMEEP KOSHTI
INTRODUCTION
• The blood–brain barrier (BBB) is a
• highly selective semipermeable membrane barrier that
separates the circulating blood from the
brain extracellular fluid in the central nervous
system (CNS).
• formed by brain endothelial cells, which are connected
by tight junctions.
• allows the passage of water, some gases, and lipid-
soluble molecules by passive diffusion, as well as the
selective transport of molecules such as glucose and
amino acids that are crucial to neural function.
• Furthermore, it prevents the entry
of lipophilic potential neurotoxins by way of
an active transport mechanism mediated by P-
glycoprotein.
• Astrocytes have been claimed to be necessary to
create the blood–brain barrier.
• A few regions in the brain, including
the circumventricular organs, do not have a
blood–brain barrier.
BLOOD-BRAIN BARRIER MAINTAINS THE CONSTANCY OF
THE BRAIN'S INTERNAL ENVIRONMENT
• (BBB) protects the neural tissue from variations in blood composition
and toxins.
• Elsewhere in the body the 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.
• The endothelial cells forming the blood-brain barrier are highly
specialized to allow precise control over the substances that enter or
leave the brain.
DISCOVERY OF BLOOD-BRAIN BARRIER.
• in the 1880s, Paul Ehrlich observed that intravenous administration of
certain dyes (e.g. trypan blue) stained all organs except the brain and
the spinal cord.
• He concluded that the dyes had a lower affinity for binding to the
nervous system as compared to other tissues.
• In 1913, Edwin Goldman, an associate of Ehrlich, demonstrated the
very same dyes, when directly injected into the cerebrospinal fluid
(CSF), readily stained nervous tissue but not other tissues.
• The term “blood-brain barrier” was coined, however, by
Lewandowsky in 1898, after he and his colleagues had performed
experiments to demonstrate that neurotoxic agents affected brain
function only when directly injected into the brain but not when
injected into the vascular system. .
• It took an additional 70 years until Reese and
colleagues localized the barrier to the capillary
endothelial cells within the brain by electron-
microscopic studies
•Occludin was the first integral membrane protein found to be
exclusively localized within the tight junctions.
•Claudins have been shown to be required for the formation of tight
junctions.
•In adherens junctions, the endothelial specific, integral membrane
proteins VE-cadherins are found.
•Junctional adhesion molecules (JAM), and
•Recently discovered endothelial cell-selective adhesion molecules
(ESAM), are localized in the tight junctions of the BBB.
•Their precise function in BBB integrity remains to be determined.
• All areas of the brain do not have a blood-brain barrier. The structures located at strategic
positions in the midline of the ventricular system and lack the BBB are collectively referred to
as circumventricular organs (CVOs).
• In these non-barrier regions, the tight junctions between endothelial cells are discontinuous
thus allowing entry of molecules. Many of these areas participate in hormonal control.
• Areas of brain without a blood-brain barrier:
1. Pituitary gland
2. Median eminence
3. Area postrema
4. Preoptic recess
5. Paraphysis
6. Pineal gland
7. Endothelium of choroid plexus
HIGHLY LIPID SOLUBLE MOLECULES
• Substances with High Lipid Solubility May Move
Across the BBB by Simple Diffusion.
• Diffusion is the major entry mechanism for most
psychoactive drugs.
• The lipid solubility is estimated by oil/water
partition coefficient.
Water
• As a consequence of its high permeability, water
moves freely into and out of the brain as the
osmolarity of the plasma changes.
• This phenomenon is clinically useful, since the
intravenous administration of poorly permeable
compounds such as mannitol will osmotically
dehydrate the brain and reduce intracranial
pressure.
• Gases
• Gases such as CO2, O2 and volatile anesthetics
diffuse rapidly into the brain.
• As a consequence, the rate at which their
concentration in the brain comes into equilibrium
with plasma is limited primarily by the cerebral
blood flow rate.
• Essential amino acids, and also the precursor
of dopamine, L-DOPA, enter the brain as
rapidly as glucose.
Protection of Brain from Blood-borne Neurotoxins
and Drugs
• P-glycoproteins are ATP-driven pumps which confer
multi-drug resistance to cancer cells by pumping
drugs out of the cells.
• These proteins are expressed in brain endothelial
cells that can limit the BBB permeability of
hydrophobic compounds, such as cyclosporin A and
vinblastine, by pumping them from the endothelial
cells back to the blood.
• Metabolic processes within the brain capillary endothelial cells are
important to blood-brain function.
• In contrast, L-DOPA, the precursor for dopamine, has an affinity for
the L-type transporter. Therefore, it enters the brain more easily from
the blood than would be predicted based on its lipid solubility.
• Patients with Parkinson's disease are treated with L-DOPA rather than
with dopamine because of this fact.
• However, the penetration of L-DOPA into the brain is limited by the
presence of enzymes L-DOPA decarboxylase and monoamine oxidase
within the capillary endothelial cells.
• This "enzymatic blood-brain barrier" limits passage of L-DOPA into the
brain and explains the need for large doses of L-DOPA in the
treatment of Parkinson's disease. Therapy is currently enhanced by
concurrent treatment with an inhibitor of L-DOPA decarboxylase.
• The brain endothelial capillary also contains a variety of
other neurotransmitter-metabolizing enzymes such as :
• Cholinesterases,
• GABA transaminases,
• Aminopeptidase and
• Endopeptidases.
• In addition, several drug and toxin metabolizing enzymes
are also found in the brain capillaries.
• Thus the "enzymatic blood brain barrier" protects the brain
not only from circulating neurotransmitters but also from
many toxins.
DRUGS AND THE BLOOD-BRAIN BARRIER
• The systemic administration of penicillin results in only a small
amount entering the central nervous system.
• In the presence of meningitis, however, the meninges become more
permeable locally, at the site of inflammation, thus permitting
sufficient antibiotic to reach the infection.
• Chloramphenicol and the tetracyclines readily cross the blood-brain
barrier and enter the nervous tissue. The sulfonamide drugs also
easily pass through the blood-brain barrier.
• Lipid-soluble substances such as the anesthetic agent thiopental
rapidly enter the brain after intravenous injection.
BLOOD-BRAIN BARRIER IN THE FETUS AND NEWBORN
• In the fetus, newborn child, or premature infant,
where these barriers are not fully developed,
• toxic substances such as bilirubin can readily enter
the central nervous system and produce yellowing
of the brain and kernicterus.This is not possible in
the adult.
COMPROMISED BBB AND DISEASE.
BBB dysfunction can lead to neuronal damage and disturbed
brain function.
• encephalitis,
• multiple sclerosis (MS),
• stroke or
• tumors
induce deterioration of the BBB with devastating influence on
neuronal function.
These conditions decrease the production of the tight junction
protein claudin.
• Brain tumors cause
• complete breakdown of the BBB that leads to
peritumoral edema.
• Secrete specific factors [e.g. vascular endothelial
growth factor (VEGF) that induces formation of new
blood vessels (or angiogenesis)] which tend to be
leaky.
BYPASSING THE BBB WITH DRUGS.
• 1) One way to bypass the BBB is to deliver the drug directly
into the CSF. This approach can be used to treat patients
with meningitis or cancerous cells in the CSF.
• 2) Certain vasoactive compounds such as bradykinin and
histamine, which do not alter BBB in normal people, can
enhance permeability of BBB in pathological
conditions. These compounds can be used to deliver
chemotherapeutic agents into the brain.
• 3) Drugs can be synthesized with high BBB permeability to
improve entry into the brain.
HEROIN VS MORPHINE
• For example, heroin and morphine are very similar
in structure.
• However, heroin, which has two acetyl groups, is
more lipid soluble.This greater lipid solubility of
heroin explains its more rapid onset of action.
• Once within the brain, the acetyl group of heroin is
removed enzymatically to produce morphine, which
only slowly leaves the brain.
Blood brain barrier - Dr Sameep Koshti (Consultant Neurosurgeon)

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Slit ventricles syndrome - Dr Sameep Koshti (Consultant Neurosurgeon)
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Posterior circulation stroke syndromes - Dr Sameep Koshti (consultant Neurosu...
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Normal pressure hydrocephalus (NPH) - Dr Sameep Koshti (Consultant Neurosurgeon)
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Intervertebral disc anatomy - Dr Sameep Koshti (Consultant Neurosurgeon)
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Hydrocephalus - Dr Sameep Koshti (Consultant Neurosurgeon)
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Development of brain and spinal cord- Dr Sameep Koshti (Consultant Neurosurgeon)
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Cranio vertebral junction (CV Junction) - Dr Sameep Koshti (Consultant Neuros...
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Csf flow dynamics and ICP management - Dr Sameep Koshti (consultant Neurosurg...
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C2 fracture - Dr Sameep Koshti (Consultant Neurosurgeon)
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Pons cross sectional anatomy - Dr Sameep Koshti (consultant Neurosurgeon)
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Blood supply of brain and Stroke - Dr Sameep Koshti (Consultant Neurosurgeon)
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Blood brain barrier - Dr Sameep Koshti (Consultant Neurosurgeon)

  • 2.
  • 3. INTRODUCTION • The blood–brain barrier (BBB) is a • highly selective semipermeable membrane barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system (CNS). • formed by brain endothelial cells, which are connected by tight junctions. • allows the passage of water, some gases, and lipid- soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.
  • 4. • Furthermore, it prevents the entry of lipophilic potential neurotoxins by way of an active transport mechanism mediated by P- glycoprotein. • Astrocytes have been claimed to be necessary to create the blood–brain barrier. • A few regions in the brain, including the circumventricular organs, do not have a blood–brain barrier.
  • 5. BLOOD-BRAIN BARRIER MAINTAINS THE CONSTANCY OF THE BRAIN'S INTERNAL ENVIRONMENT • (BBB) protects the neural tissue from variations in blood composition and toxins. • Elsewhere in the body the 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. • The endothelial cells forming the blood-brain barrier are highly specialized to allow precise control over the substances that enter or leave the brain.
  • 6. DISCOVERY OF BLOOD-BRAIN BARRIER. • in the 1880s, Paul Ehrlich observed that intravenous administration of certain dyes (e.g. trypan blue) stained all organs except the brain and the spinal cord. • He concluded that the dyes had a lower affinity for binding to the nervous system as compared to other tissues. • In 1913, Edwin Goldman, an associate of Ehrlich, demonstrated the very same dyes, when directly injected into the cerebrospinal fluid (CSF), readily stained nervous tissue but not other tissues. • The term “blood-brain barrier” was coined, however, by Lewandowsky in 1898, after he and his colleagues had performed experiments to demonstrate that neurotoxic agents affected brain function only when directly injected into the brain but not when injected into the vascular system. .
  • 7. • It took an additional 70 years until Reese and colleagues localized the barrier to the capillary endothelial cells within the brain by electron- microscopic studies
  • 8.
  • 9.
  • 10. •Occludin was the first integral membrane protein found to be exclusively localized within the tight junctions. •Claudins have been shown to be required for the formation of tight junctions. •In adherens junctions, the endothelial specific, integral membrane proteins VE-cadherins are found. •Junctional adhesion molecules (JAM), and •Recently discovered endothelial cell-selective adhesion molecules (ESAM), are localized in the tight junctions of the BBB. •Their precise function in BBB integrity remains to be determined.
  • 11.
  • 12.
  • 13. • All areas of the brain do not have a blood-brain barrier. The structures located at strategic positions in the midline of the ventricular system and lack the BBB are collectively referred to as circumventricular organs (CVOs). • In these non-barrier regions, the tight junctions between endothelial cells are discontinuous thus allowing entry of molecules. Many of these areas participate in hormonal control. • Areas of brain without a blood-brain barrier: 1. Pituitary gland 2. Median eminence 3. Area postrema 4. Preoptic recess 5. Paraphysis 6. Pineal gland 7. Endothelium of choroid plexus
  • 14.
  • 15.
  • 16.
  • 17.
  • 18.
  • 19.
  • 20. HIGHLY LIPID SOLUBLE MOLECULES • Substances with High Lipid Solubility May Move Across the BBB by Simple Diffusion. • Diffusion is the major entry mechanism for most psychoactive drugs. • The lipid solubility is estimated by oil/water partition coefficient.
  • 21.
  • 22. Water • As a consequence of its high permeability, water moves freely into and out of the brain as the osmolarity of the plasma changes. • This phenomenon is clinically useful, since the intravenous administration of poorly permeable compounds such as mannitol will osmotically dehydrate the brain and reduce intracranial pressure.
  • 23. • Gases • Gases such as CO2, O2 and volatile anesthetics diffuse rapidly into the brain. • As a consequence, the rate at which their concentration in the brain comes into equilibrium with plasma is limited primarily by the cerebral blood flow rate.
  • 24. • Essential amino acids, and also the precursor of dopamine, L-DOPA, enter the brain as rapidly as glucose.
  • 25. Protection of Brain from Blood-borne Neurotoxins and Drugs • P-glycoproteins are ATP-driven pumps which confer multi-drug resistance to cancer cells by pumping drugs out of the cells. • These proteins are expressed in brain endothelial cells that can limit the BBB permeability of hydrophobic compounds, such as cyclosporin A and vinblastine, by pumping them from the endothelial cells back to the blood.
  • 26. • Metabolic processes within the brain capillary endothelial cells are important to blood-brain function. • In contrast, L-DOPA, the precursor for dopamine, has an affinity for the L-type transporter. Therefore, it enters the brain more easily from the blood than would be predicted based on its lipid solubility. • Patients with Parkinson's disease are treated with L-DOPA rather than with dopamine because of this fact. • However, the penetration of L-DOPA into the brain is limited by the presence of enzymes L-DOPA decarboxylase and monoamine oxidase within the capillary endothelial cells. • This "enzymatic blood-brain barrier" limits passage of L-DOPA into the brain and explains the need for large doses of L-DOPA in the treatment of Parkinson's disease. Therapy is currently enhanced by concurrent treatment with an inhibitor of L-DOPA decarboxylase.
  • 27.
  • 28. • The brain endothelial capillary also contains a variety of other neurotransmitter-metabolizing enzymes such as : • Cholinesterases, • GABA transaminases, • Aminopeptidase and • Endopeptidases. • In addition, several drug and toxin metabolizing enzymes are also found in the brain capillaries. • Thus the "enzymatic blood brain barrier" protects the brain not only from circulating neurotransmitters but also from many toxins.
  • 29. DRUGS AND THE BLOOD-BRAIN BARRIER • The systemic administration of penicillin results in only a small amount entering the central nervous system. • In the presence of meningitis, however, the meninges become more permeable locally, at the site of inflammation, thus permitting sufficient antibiotic to reach the infection. • Chloramphenicol and the tetracyclines readily cross the blood-brain barrier and enter the nervous tissue. The sulfonamide drugs also easily pass through the blood-brain barrier. • Lipid-soluble substances such as the anesthetic agent thiopental rapidly enter the brain after intravenous injection.
  • 30. BLOOD-BRAIN BARRIER IN THE FETUS AND NEWBORN • In the fetus, newborn child, or premature infant, where these barriers are not fully developed, • toxic substances such as bilirubin can readily enter the central nervous system and produce yellowing of the brain and kernicterus.This is not possible in the adult.
  • 31. COMPROMISED BBB AND DISEASE. BBB dysfunction can lead to neuronal damage and disturbed brain function. • encephalitis, • multiple sclerosis (MS), • stroke or • tumors induce deterioration of the BBB with devastating influence on neuronal function. These conditions decrease the production of the tight junction protein claudin.
  • 32. • Brain tumors cause • complete breakdown of the BBB that leads to peritumoral edema. • Secrete specific factors [e.g. vascular endothelial growth factor (VEGF) that induces formation of new blood vessels (or angiogenesis)] which tend to be leaky.
  • 33. BYPASSING THE BBB WITH DRUGS. • 1) One way to bypass the BBB is to deliver the drug directly into the CSF. This approach can be used to treat patients with meningitis or cancerous cells in the CSF. • 2) Certain vasoactive compounds such as bradykinin and histamine, which do not alter BBB in normal people, can enhance permeability of BBB in pathological conditions. These compounds can be used to deliver chemotherapeutic agents into the brain. • 3) Drugs can be synthesized with high BBB permeability to improve entry into the brain.
  • 34. HEROIN VS MORPHINE • For example, heroin and morphine are very similar in structure. • However, heroin, which has two acetyl groups, is more lipid soluble.This greater lipid solubility of heroin explains its more rapid onset of action. • Once within the brain, the acetyl group of heroin is removed enzymatically to produce morphine, which only slowly leaves the brain.