Blood brain barrier:

Tight junctions in the endothelium of brain vessels & thick basal lamina surrounding the external face of the capillary & feet of astrocytes.

  • separation of circulating blood and cerebrospinal fluid(CSF) in the central nervous system (CNS)
  • Function:
    • physical barrier
    • system of cellular transport mechanisms
    • maintains homeostasis
      • restrict entrances of harmful chemicals from the blood, and allowing entrance of essential nutrients
  • Why is it important?
    • The brain (neurones) is very vulnerable to changes in it’s environment
    • therefore only substances necessary for normal function are allowed to pass through
  • It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation
  • Not well developed in infants
    • bilirubin can cross the barrier to reach the basal ganglia in the haemolytic disease of the newborn – causing fits
      • kernicterus

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Types of blood-brain barrier

1) Blood-ECF barrier

    • in the CNS capillary bed

2) Blood-CSF barrier

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  • in the choroid plexus
    • lateral 3rd & 4th ventricles
  • Made up of capillaries covered by
    • Pia mater
    • Ependyma (tela choroidea)
      • Ependymal cells are modified:
        • cilia are replaced by microvilli
        • they have numerous enzymes specifically involved in the active transport of ions & metabolites
        • there is a basement membrane beneath the epithelium
      • Tight junctions are present between the ependymal cells
        • at the apices

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  • Freely permeable to water
  • Permeable to
    • non-ionised lipid soluble substances
      • ethanol
      • caffeine
  • Not permeable to
    • protein
    • protein-bound substances (Drugs,hormones)
    • strongly hydrophilic (water soluble) substances (Na,K)
      • use of specialised carrier-mediated transport mechanisms

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Apart from the choroid plexuses, CSF can come into contact with ECF of brain tissue at:

  • Ependymal cell-ECF interface
  • Subarachnoid space-ECF interface

Endothelial cells

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  • The brain endothelial cells are joined by tight junctions of high electrical resistance
    • providing an effective barrier against molecules
      • in peripheral endothelial, there is good transcellular movement of molecules. However, there is no such movement in brain endothelial cells
  • The brain capillaries are in contact with foot processes of astrocytes
    • which essentially separate the capillaries from the neurons

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Transport systems

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Blocks

  • metabolic wastes
    • urea
    • creatinine
  • proteins
  • toxins
  • most drugs

Highly permeable to

  • water
  • glucose
  • essential amino acids
    • strictly no entry for non-essential amino acids
  • some electrolytes
    • strictly no entry for K+
  • lipid-soluble substances
    • fats
    • fatty acids
    • oxygen
    • CO2
    • alcohol
    • nicotine
    • anaesthetics

Areas outside the blood-brain barrier (areas exposed to blood)

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  • those involved in regulation of blood chemistry  & osmolality
  • Circumventricular areas
    • 3rd & 4th ventricles
      • vomiting centre of the brain stem
      • hypothalamus
        • exposed to plama osmolality (thirst centre)
        • -ve feedback by hormones
  • Circumventricular organs(takes up injected dye)
    • posterior pituitary (AVP, OT)
      • neurohemal organs
    • area postrema (ANG II)
      • increase BP, vomiting centre
    • organum vasculosum of the lamina terminalis (OVLT) (ANG II)
      • thirst & ADH secretion
      • in infection, IL-1 acts on OVLT to produce fever
    • Subfornical organ

Drugs & blood-brain barrier

Antibiotics

  • Penicillin
    • only small amounts of systematically administered penicillin can cross
      • drugs that cannot cross BBB needs to be administered intrathecally (through CSF)
    • but the meninges become more permeable locally in meningitis
  • Readily cross BBB
    • Chloramphenicol
    • Tetracyclines
    • Sulphonamides
    • Erythromycin
    • Sulphadiazine

Barbiturates (eg. thiopentone)

  • they are lipid-soluble
    • can cross BBB

Neurotransmitters (eg noradrenaline)

  • water soluble (hydrophilic)
    • can’t cross BBB

Antihistamines

  • Older antihistamines
    • can cross BBB
    • side effect: sedation
  • Newer antihistamines
    • far less likely to cause sedation
    • sometimes occur

Morphines

  • 2 hydroxyl group
    • cant cross BBB (water soluble)

Heroin

  • 2 acetyl groups (COCH3)
  • more lipid soluble
    • crosses BBB readily
    • enzymes in brain convert heroin to morphine which gets trapped in the brain and may have prolonged effects

Other drugs that are highly lipid soluble

  • nicotine
  • caffeine
  • alcohol

Clinical relations to BBB

  • In Cerebrovascular accidents (stroke)
    • trauma can lead to accumulation of interstitial fluid in the brain (oedema)
      • not permeable to BBB
    • excess fluid in brain tissue can be removed by imposing an osmotic gradient across the BBB
    • Mannitol is used for this purpose
      • it does not cross BBB and acts as an effective osmole
        • intravenous infusion of mannitol results in the movement of fluid from brain tissues by osmosis
  • Against microbial invasions
    • most bacteria cannot cross BBB (rare)
      • but can enter the brain from other routes
        • sinus
        • dental procedures
      • since antibodies are big molecules & can’t easily cross the BBB
        • bacterial infections are often serious & difficult to treat
    • some viruses and fungi can
      • treponema pallidum burrows through the vessels
  • Breakdown of BBB
    • injury
      • leakage of fluid
    • brain tumour
      • capillaries are fenestrated
    • infection
      • WBC can cross
    • hypertension
      • raised pressure widens the tight junctions

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