Cerebrospinal fluid CSF

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Introduction

• Cerebrospinal fluid (CSF)
• What is it?
• What does it do?
• Disorders
• The Blood Brain Barrier (BBB)
• What is it?
• What does it do?
• Disorders

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Cerebrospinal Fluid

• Fills the spaces in the brain and spinal cord
• Acts as a cushion or shock-absorber
• Provides appropriate local environment
• Medium of exchange

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Cerebrospinal Fluid

• Fills the spaces in the brain and spinal cord
• Acts as a cushion or shock-absorber
• Provides appropriate local environment
• Medium of exchange

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CSF

• FORMATION
• 70 from choroid plexus
• 30 from around cerebral vessels and
• along the walls of the ventricles
• Secretory Activity of Epithelial Cells
• Evidence
• Expose Lat. Ventricles ? Flow of fluid
• Catheter into the 3rd ventricle ? can collect
  fluid
• CSF Content in Man 130 -150 mls of which30 mls
  in ventricular system rest in subarachnoid space

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Composition

• Filtration and diffusion from bloodBut CSF not
  simply an ultrafiltrate of Plasma
• Facilitated diffusion (carrier molecules) e.g.
  Glucose, Amino Acids
• Active Transport (ATP dependent)e.g. Ma K
  ATPase

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CSF Composition
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Ionic Composition of CSF Plasma
Ultrafiltrate(mM/Kg H2O)
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CSF Composition v Plasma
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CSF Disorders

• If Pressure/volume drops (e.g. spinal tap)
• ? Headache
• If pressure/volume increases (e.g. drainage
  blocked, hydrocephalus)
• ? Severe brain damage/retardation

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CSF Disorders

• If Pressure/volume drops (e.g. spinal tap)
• ? Headache
• If pressure/volume increases (e.g. drainage
  blocked, hydrocephalus)
• ? Severe brain damage/retardation

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Morphological Barrier

• Capillary Endothelium cells of the brain
  capillaries have TIGHT JUNCTIONS not
  FENESTRATIONS as other capillaries
• This limits access to molecules with MW
  greater than 2000

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Factors Regulating PassageAcross BBB

• LIPID SOLUBITLITY
• High Lipid Solubility ? Greater Access
• DEGREE OF IONISATION
• Drugs ionised at physiological pH (7.4) ? Less
  access
• Drug pKa value pH at which 50 of drug
  molecules are ionised
• DEGREE OF PLASMA PROTEIN BINDING
• In bound state too large to cross BBB

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Factors Regulating PassageAcross BBB

• LIPID SOLUBITLITY
• High Lipid Solubility ? Greater Access
• DEGREE OF IONISATION
• Drugs ionised at physiological pH (7.4) ? Less
  access
• Drug pKa value pH at which 50 of drug
  molecules are ionised
• DEGREE OF PLASMA PROTEIN BINDING
• In bound state too large to cross BBB

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Glucose Transport

• Facilitated transport of monosaccharides
• Specific to D-glucose (L-glucose and fructose are
  not transported
• Competitive 2-deoxyglucose gt glucose gt 3.0
  methyl glucose gt mannose
• Not metabolised in brain
• Labelled form used as a marker of cell activity
  in PET

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Amino Acid Transport

• FACILITATED TRANSPORT COMPETITIVE CARRIER SYSTEM
• i.e. large neutral amino acids compete for the
  same carrier system

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Amino Acid Transport

• Readily Transported Virtually Excluded
• Phenylalanine ) Alanine
• Leucine ) Large Proline
• Tyrosine ) Glutamic Acid
• Isoleucine ) neutral Aspartic Acid
• Tryptophan ) GAB (? -amino butyric acid)
• Methionine ) amino Glycine
• Valine )
• Threonine ) acids
• Histidine )

L-DOPA
ESSENTIAL AMINO ACIDS TRANSMITTER AMINO
ACIDS TRANSPORTED NOT TRANSPORTED Transmitter
Precursor Amino Acid Amino Acid Synthesised from
glucose metabolites
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Metabolic Barriers

• Endothelial cells, rich in certain metabolic
  enzymes, e.g. Monoamine Oxidase (MAO)
• Unable to use DOPAMINE to treat Parkinsons
  Disease because
• Ionised at pH 7.4
• Metabolised by MAO
• Use precursor L-DOPA PERIPHERAL DOPA
  DECARBOXYLASE INHIBITOR
• L-DOPA enters CNS as unionised at pH 7.4
• Inhibitor prevents conversion of L-DOPA to
  dopamine outside the brain
• Inhibitor does not enter CNS as ionised at pH
  7.4

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BBB Disorders

• Tumours
• Leaky BBB
• Increased nutrients, increased growth
• Infiltration
• Infection
• Increased antibiotic permeability
• Ischaemia
• Cellular damage
• Increased water, oedema

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Non Barrier Regions

• Areas where capillaries with tight junctions
  replaced by normal fenestrated endothelia.
• Peptides and small organic mols can cross
• Post-pituitary
• Median eminence Oxytocin, Vasopressin
• Area postrema
• chemoreceptor zone vomiting
• Organum vasculosum of the lamina terminalis
  (OVLT)
• Angiotensin II receptors
• Subfornicular organ
• Angiotensin II receptors

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Summary

• Differences between plasma and CSF
• Morphological features tight junctions
• Active transport
• Role of choroid plexus arachnoid villi
• Some drugs enter brain others excluded
• Lipid solubility/degree of ionisation
• Facilitated transport L-glucose/some amino
  acids
• Non Barrier Regions