Blood-brain barrier

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

Types of blood-brain barrier

1) Blood-ECF barrier

• in the CNS capillary bed

2) Blood-CSF barrier

• 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

• 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

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

• 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

Transport systems

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)

• 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