CNS Response to Injury - Pathology

Introduction

• The CNS is composed of two major cell types:
  1. Neurons
  2. Glial cells, which include:
     • Astrocytes
     • Oligodendrocytes
     • Microglial cells
     • Ependymal cells
     • Choroid plexus epithelial cells
• The response to injury varies with the cell type injured.

General CNS Responses to Injury

Ischaemic Damage

• The CNS is particularly sensitive to ischaemia, because it has few energy reserves.
• The CNS is protected by its bony covering.
  • Despite offering protection, the covering also makes the CNS vulnerable to certain types of damage, for example:
    • Damage due to fractures and dislocation.
    • Damage due to raised intracranial pressure.
      • Raised intracranial stimulates a compensatory increase in blood flow, further raising intracranial pressure. This stimulates a further increase in blood flow, and the cycle continues until intracranial pressure is so high that blood flow is impeded.
        • The result of this is ischaemia.
• Survival of any cell is dependent on having sufficient energy.
  • Ischaemia causes cell death by impeding energy supply to cells.
    • Cells directly affected by ischamia die rapidly.
      • For example, those suffering a failure of pefusion due to an infarct.
    • Neurons surrounding this area of complete and rapid cell death exist under sub-optimal conditions and die over a more prolonged period.
      • This area of gradual death is known as the lesion penumbra.
      • There are several mechanisms implicated in cell death in the penumbra:
        1. Increase in intracellular calcium
        2. Failure to control free radicals
        3. Generation of nitrogen species (e.g NO and ONOO) are the main damaging events.

Oedema

• There are three types of cerebral oedema:
  1. Vasogenic oedema
     • Vasogenic oedema follows vascular injury.
     • Oedema fluid gathers outside of the cell.
     • This is the most common variation of cerebral oedema.
  2. Cytotoxic oedema
     • Cytotoxic oedema is due to an energy deficit.
       • The neuron can’t pump out sodium and water leading to swelling within the cell.
  3. Interstitial oedema
     • Associated with hydrocephalus.
     • This type of cerebral oedema is of lesser importance.
• One serious consequence of oedema is that the increase in size leads to the brain trying to escape the skull.
  • This causes herniation of the brain tissue.
  • The most common site of herniation is at the foramen magnum.
    • The medulla is compressed at the site of the respiratory centres, leading to death.

Demyelination

• Demyelination is the loss of initially normal myelin from the axon.
• Demyelination may be primary or secondary.

Primary Demyelination

• Normally formed myelin is selectively destroyed; however, the axon remains intact.
• Causes of primary demyelination:
  • Toxins, such as hexachlorophene or triethyl tin.
  • Oedema
  • Immune-mediated demyelination
  • Infectious diseases, for example canine distemper or caprine arthritis/encephalitis.

Secondary Demyelination

• Myelin is lost following damage to the axon.
  • I.e. in wallerian degeneration

Vascular Diseases

• Vascular diseases can lead to complete or partial blockage of blood flow which leads to ischaemia.
  • Consequences of ischaemia depend on:
    1. Duration and degree of ischaemia
    2. Size and type of vessel involved
    3. Susceptibility of the tissue to hypoxia
• Potential outcomes of vascular blockage include:
  • Infarct, and
  • Necrosis of tissue following obstruction of its blood supply.
• Causes include:
  • Thrombosis
    • Uncommon in animals but may be seen with DIC or sepsis.
  • Embolism. e.g.
    • Bone marrow emboli following trauma or fractures in dogs
    • Fibrocartilaginous embolic myelopathy
  • Vasculitis, e.g.
    • Hog cholera (pestivirus)
    • Malignant catarrhal fever (herpesvirus)
    • Oedema disease (angiopathy caused by E.coli toxin)

Malacia

• Malacia may be used:
  • As a gross term, meaning "softening"
  • As a microscopic term, meaning "necrosis"
• Malacia occurs in:
  • Infarcted tissue
  • Vascular injury, for example vasculitis.
  • Reduced blood flow or hypoxia, e.g.
    • Carbon monoxide poisoning, which alters hemoglobin function
    • Cyanide poisoning, which inhibits tissue respiration

Excitotoxicity

• The term "excitotoxicity" is used to describe the process by which neurons are damaged by glutamate and other similar substances.
• Excitotoxicity results from the overactivation of excitatory receptor activation.

The Mechanism of Excitotoxicity

• Glutamate is the major excitatory transmitter in the brain and spinal cord.
  • There are four classes of postsynaptic glutamate receptors for glutamate.
    • The receptors are either:
      • Directly or indirectly associated with gated ion channels, OR
      • Activators of second messenger systems that result in release of calcium from intracellular stores.
    • The receptors are named according to their phamacological agonists:
      • NMDA receptor
        • The NMDA receptor is directly linked to a gated ion channel.
        • The ion channel is permeable to Ca⁺⁺, as well as Na⁺ and K⁺.
        • The channel is also voltage dependent.
          • It is blocked in the resting state by extracellular Mg⁺⁺, which is removed when membrane is depolarised.
        • I.e. both glutamate and depolarisation are needed to open the channel.
      • AMPA receptor
        • The AMPA receptor is directly linked to a gated ion channel.
        • The channel is permeable to Na⁺ and K⁺ but NOT to divalent cations.
        • The receptor binds the glutamate agonist, AMPA, but is not affected by NMDA.
        • The receptor probably underlies fast excitatory transmission at glutamatergic synapses.
      • Kainate receptor
        • Kainate receptors work in the same way as AMPA receptors, and also contribute to fast excitatory transmission.
      • mGluR, the metabotropic receptor
        • Metabotropic receptors are indirectly linked to a channel permeable to Na⁺ and K⁺.
        • They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca⁺⁺ stores.
        • The physiological role ot mGluR is not understood.

• Under normal circumstances, a series of glutamate transporters rapidly clear glutamate from the extracellular space.
  • Some of these transporters are neuronal; others are found on astrocytes.
• This normal homeostatic mechanism fails under a variety of conditions, such as ischaemia and glucose deprivation.
  • This results in a rise in extracellular glutamate, causing activation of the neuronal glutamate receptors.
• Two distinct events of excitiotoxicity arise from glutamate receptor activation:
  1. The depolarisation caused mediates an influx of Na⁺, Cl^- and water. This give acute neuronal swelling, which is reversible.
  2. There is a rise in intracellular Ca⁺⁺.
     • This is due to:
       • Excessive direct Ca⁺⁺ influx via the NMDA receptor-linked channels
       • Ca⁺⁺ influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
       • Release of Ca⁺⁺ from intracellular stores.
     • The rise in neuronal intracellular Ca²⁺ serves to:
       • Uncouple mitochondrial electron transport and activate nitric oxide synthase and phospholipase A, leading to generation of reactive oxygen and nitrogen species which damage the neurone.
       • Activats a number of enzymes, including phospholipases, endonucleases, and proteases.
         • These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
• Excitotoxicity is, therefore, a cause of acute neuron death.