Neuron Response to Injury

• Neurons are particularly vulnerable to injury, due to their:
  • High metabolic rate
  • Small capacity to store energy
  • Lack of regenerative ability
  • Axons being very dependent on the cell body.
    • Axons cannot make their own protein as they have no Nissl substance.
    • The cell body produces the axon's protein and disposes of its waste.
    • Death or damage of the cell body causes axon degeneration.

• There are four ways in which neurons may react to insult:
  1. Acute Necrosis
  2. Chromatolysis
  3. Wallerian Degeneration
  4. Vacuolation

Acute Necrosis

• Acute necrosis is the most common neuronal response to injury.
• Causes of actue necrosis include:
  • Ischaemia
    • Diminution of the blood supply causes a lack of nutrients and oxygen, inhibiting energy production. A decrease in the levels of ATP leads to:
      1. Failure of the Na⁺/K⁺pumps, causing cell swelling and an increase in extracellular potassium.
      2. Failure to generate NAD required for DNA repair.
  • Hypoxia
  • Hypoglycaemia
  • Toxins, such as lead and mercury

Laminar Cortical Necrosis

• Laminar cortical necrosis refers to the selective destruction of neurons in the deeper layers of the cerebral cortex.
  • These neurons are the most sensitive to hypoxia.
• The laminar cortical pattern of acute necrosis occurs in several instances:
  1. Ischaemia
     • For example, seizure-related ischaemia in dogs.
  2. Polioencephalomalacia in ruminants
     • Also called cerebrocortical necrosis or CCN.
  3. Salt poisoning in swine
  4. Lead poisoning in cattle
• It is most likely that gross changes will not be seen. When they are visible, changes may be apparent as:
  • Oedema
    • Causes brain swelling, flattened gyri and herniation
  • A thin, white, glistening line along the middle of the cortex.
    • In ruminants, this fluoresces with UV-light.
• Ultimately the cortex becomes necrotic and collapses.

View images courtesy of Cornell Veterinary Medicine

Chromatolysis

• Chromatolysis is the cell body’s reaction to axonal insult.
• The cell body swells and the Nissl substance (granular cytoplasmic reticulum and ribosomes found in nerve cell bodies) disperses.
  • Dispersal of the Nissl substance allows the cell body to produce proteins for rebuilding the axon.
• IT IS NOT A FORM OF NECROSIS.
  • It is an adaptive response to deal with the injury.
  • It can, however lead to necrosis.
• Seen, for example, in grass sickness in horses (equine dysautonomia).

View images courtesy of Cornell Veterinary Medicine

Wallerian Degeneration

• Wallerian degeneration is the axon’s reaction to insult.
• The axon and its myelin sheath degenerates distal to the point of injury.
• There are several causes of wallerian degeneration:
  • Axonal transection
    • This is the "classic" cause
  • Vascular causes
  • Inflamatory reactions
  • Toxic insult
  • As a sequel to neuronal cell death.

View images courtesy of Cornell Veterinary Medicine

The Process of Wallerian Degeneration

1. Axonal Degeneration
   • Axonal injuries initially lead to acute axonal degeneration.
     • The proximal and distal ends separate within 30 minutes of injury.
   • Degeneration and swelling of the axolemma eventually leads to formation of bead-like particles.
   • After the membrane is degraded, the organelles and cytoskeleton disintegrate.
     • Larger axons require longer time for cytoskeleton degradation and thus take a longer time to degenerate.
2. Myelin Clearance
   • Following axonal degeneration, myelin debris is cleared by phagocytosis.
   • Myelin clearance in the PNS is much faster and efficient that in the CNS. This is due to:
     • The actions of schwann cells in the PNS.
     • Differences in changes in the blood-brain barrier in each system.
       • In the PNS, the permeability increases throughout the distal stump.
       • Barrier disruption in CNS is limited to the site of injury.
3. Regeneration
   

   Neuronal vacuolation. Image courtesy of BioMed Archive
   • Regeneration is rapid in the PNS.
     • Schwann cells release growth factors to support regeneration.
   • CNS regeneration is much slower, and is almost absent in most species.
     • This is due to:
       • Slow or absent phagocytosis
       • Little or no axonal regeneration, because:
         • Oligodendrocytes have little capacity for remyelination compared to Schwann cells.
         • There is no basal lamina scaffold to support a new axonal sprout.
         • The debris from central myelin inhibits axonal sprouting.

Vacuolation

Neuronal vacuolation. Image courtesy of BioMed Archive

• Vacuolation is the hallmark of transmissible spongiform encephalopathies.
  • For example, BSE and Scrapie.
• Vacuolation can also occur under other circumstances:
  • Artefact of fixation
  • Toxicoses
  • It may sometimes be a normal feature.