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Question No. 2
Q: What is the blood-brain barrier?
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Answer No. 2
The unique anatomical and physiological properties of the central nervous system microvasculature that allows it to tightly regulate the movement of molecules, ions, and cells between the blood and the CNS
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Question No. 3
Q: Which structures make up the blood-brain barrier?
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Answer No. 3
- Comprises of 3 cellular layers and a basement membrane
- Together these form a barrier virtually impenetrable barrier to lipophobic molecules
Capillary Endothelium
- Interconnected by tight junctions (50-100x 'tighter' than peripheral capillaries) restricting the passage of substances from the capillaries to the brain ECF
- Differ from extracerebral capillaries in having a high density of mitochondria
- Have a relative paucity of pinocytic vesicles for vesicular transport
Basement Memebrane
- Surrounds the endothelium
- 40-50nm thick
- Rich in proteoglycans, heparin sulphate, collagen type IV and laminin
Pericytes
- Reside next to capillaries
- Possesses smooth muscle like action
Astrocytes
- A type of supportive glial cell
- Projections called foot processes ensheath >95% of vessel surface
- Secrete chemicals that reduce the permeability of the capillary endothelial cells
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Question No. 4
Q: How does the endothelium of the blood-brain barrier differ from the rest of the body?
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Answer No. 4
Continuous Non-Fenestrated (General)
Continuous Non-Fenestrated (Blood-Brain Barrier)
Continuous Fenestrated
Non-continuous (Sinusoidal)
Muscle, thymus, bone, lung
Brain
Kidney
Liver
- Continuous endothelial cytoplasm without fenestrae and continuous basement membrane which restricts passage of substances across the endothelium
- Tight junctions between cells limiting paracellular movement of, ions, solutes, and water - regulation of transport varies across endothelium and influenced by both physiological and pathophysiological stimuli
- Vesicles transport substances through cytoplasm in a bidirectional pathway (transcytosis)
- Similar baseline characteristics to general non-fenestrated endothelium
- Possess very 'restrictive' tight junctions between cells to prevent paracellular transport
- Close contact with pericytes and astroctyes which aid barrier function
- Circular pores of fenestrae that penetrate the endothelium
- Thick continuous basement membrane
- Allows the passage of small macromolecules through the endothelium
- Does not form a continuous lining between the lumen and surrounding tissues
- Gaps between adjacent cells and absent basement membrane
- Poses no barrier to blood and constituents
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Question No. 5
Q: Which structures in the brain lie outside the blood-brain barrier?
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Answer No. 5
- Certain areas of the brain have a reduced blood-brain barrier and retain a direct connection with the systemic circulation in order to
- Detect alterations in composition of the blood
- Allow secretion of hormones
- Areas that are outside the BBB are known as 'circumventricular organs':
Hypothalamus
- Hypothalamic osmoreceptors monitor the osmolarity of systemic blood
Area postrema
- Contains a chemoreceptor trigger zone
- In the presence of noxious substances, sends afferent signals to the vomiting centre triggering vomiting
Anterior & posterior pituitary gland
- Secretes eight pituitary hormones directly into the systemic circulation
Choroid plexus
- Uses plasma from systemic blood to produce CSF
Pineal gland
- Secretes melatonin directly into the systemic circulation.
Subfornical organ
- Contains a chemoreceptor area
- Monitors blood angiotension II leveI as part of the regulation of body fluids
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Question No. 6
Q: Do neonates have fully functioning blood-brain barrier?
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Answer No. 6
- Widely believed that the blood-brain barrier of neonates is immature at birth resulting in increased permeability
- Renders the brain more vulnerable to drugs or toxins entering the foetal circulation
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Question No. 7
Q: Which substances does the blood-brain barrier prevent from entering the brain?
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Answer No. 7
Catecholamines
- A number of catecholamines (such as noradrenaline and dopamine) act as neurotransmitters in the central nervous system
- Unregulated entry across the blood brain barrier can result in permanent neuroexcitatory damage
Amino acids
- Similarly to catecholamines a number of amino-acids (such as glycine and glutamic acid) act as neurotransmitters in the central nervous system
- Unregulated entry across the blood brain barrier can result in permanent neuroexcitatory damage
Ammonia (NH3)
- Ammonia is potentially neurotoxic in significant concentrations
- It is a small lipophilic molecule which may be expected to cross the BBB
- It is rapidly metabolised by the enzymatic barrier to glutamine, preventing passage across the BBB in relevant quantities
Macromolecules
- Plasma proteins such as albumin and plasminogen are damaging to nervous tissue and can lead to apoptosis
- The BBB prevents passage of such molecules leading to low CSF levels
- Results in a lower ability to buffer changes in pH
Charged Ions
- The BBB is impermeable to H+ and HCO3- ions due to their charge
- However it is permeable to CO2 which can pass freely through into the CSF
- In this way CO2 from arterial blood can become converted in to H+ and HCO3- ions which become trapped lowering the pH of CSF
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Question No. 8
Q: How do substances cross the blood-brain barrier and which substances pass by each route?
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Answer No. 8
Route
Examples
Free Membrane Diffusion
Small Lipophilic molecules and gases:
- O2, CO2
- Anaesthetics
- Ethanol, nicotine
Membrane Channels
Small ions and water:
- H2O
- Na, K+, Cl-
Carrier-Mediated Transport
- Energy transport systems:
- Glucose (GLUT-1)
- Lactate, pyruvate (MCT1)
- Creatine (CrT)
- Amino acid transport systems
- Large neural amino acids (LAT1)
- Neurotransmitter precursors
Receptor-Mediated Transport (via transcytosis)
- Insulin
- Leptin
- IgG
- TNFa
Adsorption mediated transport (via transcytosis)
- Histone
- Albumin
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Question No. 9
Q: Which important drugs pass freely through the blood-brain barrier?
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Answer No. 9
Opioid Analgesics
- Morphine
- Codeine
- Fentanyl
Anaesthetic Agents
- Propofol
- Fentanyl
- Ketamine
- Volatile anaesthetics
Anetiepileptics
- Benzoziazepines
- Barbiturates
- Phenytoin
Antidepressants
- Triciylic antidepressants
- SSRIs
- MOAs
CNS Stimulants
- Cocaine
- Amphetamines
- MDMA
Antibiotics
- Carbapenems
- 3rd & 4th generation cephalosporins
- Fluoroquinolones
- Aciclovir
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Question No. 10
Q: How can the passage of drugs to the CNS across the blood-brain barrier be enhanced?
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Answer No. 10
Route
Explanation
Example
Bypass the BBB
- Direct administration into the CSF bypasses the BBB to reach structures within the CNS
- Intrathecal antibiotics to treat meningitis or ventriculitis
- Intrathecal chemotherapy agents to treat CNS malignancy
Increase the lipophilicity of drug
- Increased lipophilicity of aids passive diffusion across lipid membranes of the BBB
- Heroin has to acetyl groups added to morphine molecule making it 100x more lipid soluble - produces more rapid onset of action
- Once within the brain metabolised to morphine, which only slowly leaves the brain
Increase permeability of BBB
- Increased permeability my be due to disease or induced by vasoactive compounds (such as bradykinin and histamine) to enhance drug delivery
- Delivery of chemotherapeutic agents into the brain
- Delivery of certain antibiotics enhanced by inflammation in meningitis
'Prodrug' to Utilise BBB Transport Mechanisms
- Prodrugs which cross the BBB may be used which are subsequently metabolised in the brain to active compounds
- The neurotransmitter dopamine cannot cross the BBB
- The precursor L-DOPA is transported across the BBB by facilitated diffusion where it is subsequently converted to dopamine
- It is used in Patients with Parkinson’s disease, in which there is a dopamine deficiency of the substantia nigra
'Trojan Horse' Delivery to Utilise BBB Transport Mechanisms
- A monoclonal Ab (Mab) acts as a molecular Trojan horse to deliver drugs across the BBB
- A drug pharmaceutical is genetically fused to the MAb
- The MAb acts against receptors on cells of the BB such as the insulin receptor leading to transport across the cell via transcytosis
- Early clinical trials for specialist treatments
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