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Introduction

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. Cerebrospinal Fluid. Fills the spaces in the brain and spinal cord Acts as a cushion or shock-absorber

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Introduction

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  1. 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

  2. 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

  3. 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

  4. 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 which:30 mls in ventricular system rest in subarachnoid space

  5. 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

  6. CSF Composition

  7. Ionic Composition of CSF & Plasma Ultrafiltrate(mM/Kg H2O)

  8. CSF Composition v Plasma

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

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

  11. 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

  12. 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

  13. 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

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

  15. Amino Acid Transport FACILITATED TRANSPORT COMPETITIVE CARRIER SYSTEM i.e. large neutral amino acids compete for the same carrier system

  16. Amino Acid Transport Readily Transported Virtually Excluded Phenylalanine ) Alanine Leucine ) Large Proline Tyrosine ) Glutamic Acid Isoleucine ) neutral Aspartic Acid Tryptophan ) GAB (ﻻ -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

  17. Metabolic Barriers • Endothelial cells, rich in certain metabolic enzymes, e.g. Monoamine Oxidase (MAO) • Unable to use DOPAMINE to treat Parkinson’s 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

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

  19. 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

  20. 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

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