Neurological Barriers by yurtgc548


									The Blood-Brain Barrier

   Structure & Function

          Learning Objectives

1. understand how the blood-brain barrier
   (BBB) was discovered
2. list the BBB protective functions & limitations
3. explain a major drawback of the BBB in
   treating brain disorders
4. describe the physical and chemical
   components of the BBB
5. identify substances that can cross the BBB
   into the brain and substances that cannot
6. indicate how the BBB can be damaged
 Discovery of the BBB
• More than 100 years ago it was
  discovered that when a particular
  blue dye was injected into the
  blood- stream of an animal, tissues
  of the whole body EXCEPT the
  brain and spinal cord turned blue.
• To explain this phenomenon, the
  investigators suggested that a
   prevented some materials from
  leaving the brain capillaries and
  actually entering the brain tissue.
Selective Filtration Process

• BBB strictly limits transport of
  some substances into the brain
  through both physical barriers and
  chemical processes.
• Keeps many substances out
  of the brain, including complex
  chemicals and large biomolecules.
         Protective Functions of BBB

1. Protects the brain from some "foreign”
   substances in the blood that may cause
   injury (pathogens, foreign proteins).
2. Protects the brain from hormones and
   certain neurotransmitters that are
   designed to work in other parts of the body.
3. Maintains a relatively constant
   environment in the brain by limiting free
   flow of substances into this critical organ.
Critical Drawbacks of BBB
   -- Sometimes Fatal --
  • Very few medications can
    cross the BBB; therefore it is
    difficult to deliver therapeutic
    drugs to the brain.
  • Immune cells (T- and B- cells)
    cannot enter the brain to fight
    infection either . . .
  • For these reasons, BBB
    presents a major challenge to
    tx of many brain disorders
    Composition of Blood Brain Barrier
• Physical barrier– molecule size limitation
  – endothelial cells line brain capillaries
    This “inner lining” has very tight cell junctions
  – layer of fatty glia on outside of capillaries
    This “outer covering” of capillaries is highly lipid
  – ependymal cells (glia) line brain cavities
    Tight cell junctions between CSF and brain
• Chemical factors-- solubility & “charge”
  – Lipid layers exclude hydrophilic substances
  – Also limit molecules w/ high electrical charge
  Layers Composing
Physical Barrier of BBB
   • Tight fitting endothelial cells
     line the “inside” of blood
     vessels in the brain.
     Pale blue layer, Fig.1
   • Basement membrane of
     endothelial cells is
     “complete”. Black layer, Fig.1
   • The “end-feet” of astrocytic
     glia (astrocytes) cover the
     “outside” of blood vessels in
     brain. Bright blue layer, Fig.1
                Another View: Tight Cell Junctions

                                                       Ependymal cells
Endothelial cells                                       line brain cavities
   “inner lining”                                          (tight fitting)
of brain capillaries
    (tight fitting)
                                                         Fatty glia cells
                                                         “outer covering”
                                                             of brain

                Diagram: Brain Capillary & Lining of Brain Cavity
        Lipid Layer: Astrocytic Glia
• Astrocyte end-feet form part of BBB
• Cover 85% of brain capillary surfaces
• Highly lipid composition (2+ lipid layers)
Brain Capillary
 “inner lining”    Ependymal
   Glia Cells      flow via CFS
 Brain Capillary
“outer covering”
    Difference Between
Brain & Somatic Capillaries

  Somatic Capillary Bed
Somatic Capillary, Many Pores

                     Brain Capillary, No Pores
                   --longitudinal section in brain tissue--

Endothelial cells, inner
lining of brain
capillaries, are packed
tightly together—no

    Layer of lipid
 material, composed
  of fatty glia cells,
  cover almost all
  capillaries in the
    (glial sheath)
          Side-by-Side Comparison
         Brain & Somatic Capillaries

Brain Capillary with BBB    Somatic Capillary, Many Pores
   Essentially “No Pores”
             Chemical Aspects of BBB
• Chemical/ metabolic barrier: Limits entry of
  certain kinds of substances
   – small, fat soluble substances cross easily
   – water soluble substances cannot cross
   – large molecules cannot cross BBB
   – substances with high bioelectrical charges
     cannot cross the BBB
   – small neutral molecules and small electrolytes
     (low charge) can cross more easily
  – Examples of common electrolytes, next page
           Major Electrolytes in the Body

                    Small Electrolytes can cross BBB
•   sodium (Na+)
•   potassium (K+)
•   chloride (Cl-)
•   calcium (Ca2+)
•   magnesium (Mg2+)
•   bicarbonate (HCO3-)
•   phosphate (PO42-)     Notice low charges of these small
                            ions & anions (+/- 1 to +/- 2)
•   sulfate (SO42-)
           Cell Membrane Solubility
Phospholipid Bi-layer favors Fat Soluble Substances

           Fatty Inside layers—fat soluble

               Outer layers—water soluble
Nature of Electrical Charges

• Attraction and Resistance
              Characteristics of
          Substances that Cross BBB

• With very few exceptions substances must
  meet all of the following criteria to cross the
  BBB and enter the brain:
       small molecules, low molecular weight

       non-ionic (neutral) or low electrical charge

       fat soluble (lipophilic/hydrophobic)
          Molecular Size and BBB
• Size limit to cross BBB = 500 daltons
• Reference substances:
     water molecule = 18 daltons
     insulin molecule = 5000 daltons
     viruses = millions of daltons
     bacteria = much larger than viruses

   99% of medical drugs are > 500 daltons!
         Substances that Cross BBB
•   blood gases (O2, CO2 , carbon monoxide)
•   blood sugars (D-glucose, D-hexose)
•   Electrolytes (Na+, K+, Cl-, etc.)
•   some amino acids
•   small molecule drugs (alcohol, caffeine,
    nicotine, morphine, heroin, cocaine, etc.)

• However, large carrier molecules required
  to deliver medications, cannot cross BBB.
         Solubility BBB & Cell Membranes
Small fat soluble molecules more easily cross
Phospholipid bi-layers & the Blood-Brain Barrier
•   barbiturates        •   morphine
•   librium             •   cocaine
•   valim               •   marijuana
•   halcion             •   nicotine
•   xanax               •   alcohol
•   opium               •   amphetamine
•   heroin              •   methamphetamine
      Materials that do NOT easily Escape
     Brain Capillaries and Enter Brain Tissue
•   Microorganisms
•   Large molecules
•   Molecules that are not very lipid soluble
•   Molecules with a high electrical charge
•   Hormones that work outside the CNS
•   T-cells and B-cells of the immune system
•   Drugs bound to plasma proteins (99%)
Damage to the BBB
              Hypertension
              Dehydration
              Microwaves
              Radiation
              Brain edema
              Inflammation/fever
              Ischemia
              Poisoning
              Brain infection
              Tumors
              Head injury
CAUTION: BBB in infants is not fully developed,
     from birth to about 1 or 2 years of age.
          Circumventricular Organs
         The Necessary “Loop-hole”

• There are several special areas of the
  brain where the BBB is weak.
• This allows substances to cross into
  these small specialized areas of the
  brain somewhat freely.
• These areas allow the brain to “sample”
  and monitor the makeup of the blood in
  the entire body and therefore regulate it.
                  Next Topic
      Neurotransmitter Life Cycle
1. Synthesis of NTs from precursors
2. Storage of NTs in vesicles
3. Release of NTs into synaptic space
4. Actions at post-synaptic receptor
5. Reuptake by pre-synaptic neuron
6. Metabolism/degradation of NTs
7. Regulation of NT Synthesis & Release
   via autoreceptors on pre-synaptic neuron

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