CNS Response to Injury - Pathology

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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.

Neuron Response to Injury

Glial Cell Response to Injury

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

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.