Spinal Cord Injury: Secondary Damage

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NECROSIS AND APOPTOSIS

In severe spinal damage, necrosis is seen all around the area of injury. Most researchers at first thought that all of the cellular death was due to necrosis, which is uncontrolled cell death; a large-scale injury will uncontrollably kill many cells in the injured region due to the infliction. However researchers have recently seen that both necrosis and apoptosis lead to the ultimate demise of many cells. Necrosis seems like it is an obvious and imminent by-product of a spinal cord injury, and any injury for that matter. For a major spinal cord injury, not only are cells killed by the injury itself but also because of glutamate excitotoxicity and the excess flow of sodium ions into the cell via the AMPA receptor, which leads to an osmotic imbalance and ultimately to uncontrollable swelling and bursting. But what about apoptosis? Studies have shown that apoptosis and necrosis processes may run parallel to each other. In an experiment, necrosis via excitotoxicity led to the death of many of the cells in a rat's cerebral cortex, because of the spilling-out of powerful regulatory chemokines. However, when a glutamate antagonist was used to halt necrosis excitotoxicity led the cell to apoptosis. More research needs to be done to more clearly define the interactions between cell necrosis and cell apoptosis.

Apoptosis is a major end-result of the preliminary secondary damages, such as glutamate excitotoxicity and the bombardment of Ca²⁺ into the cell through the NMDA receptor and also the effect of the free radical peroxynitrate on the nerve growth factor. Apoptosis, or programmed cell death, is a normal biological function of organisms, used to eliminate damaged cells and in the developing nervous system, used to eliminate unused neuronal connections. However, because of several processes, apoptosis can become rampant and lead to the programmed death of otherwise healthy cells. Apoptosis begins with the activation of a family of proteins known as caspases. Caspases break down normal cellular substrates that are used for such functions as cytoskeleton formation and DNA repair. There are five stages of apoptosis that researchers have identified: activation, propagation, commitment, execution, and death. Until the death stage, the proteins that function at each stage can be inhibited so that apoptosis does not take place. Otherwise, the cell will go through the stages that lead to its ultimate demise. Apoptosis is characterized by the condensation of the genetic material and the shrinking of the cytoskeleton, which leads to the shrinking of the entire cell. The plasma membrane undergoes changes, which can be seen under the microscope by locating "blebs," or blisters in the plasma membrane. While undergoing changes, the plasma membrane releases signal proteins that activate microphages, which phagocytose, or engulf, the dead cell. The engulfing of the dead cell by the microphage prevents the spilling out of dangerous byproducts such as free radicals, which is normally seen in necrosis.

Apoptosis and necrosis both contribute to the abnormal cell death and the dysfunction after the trauma, but apoptosis is seen more in milder cases of spinal cord trauma. At the original site of injury, apoptosis occurs about eight hours after the injury in glial cells. A second wave of apoptosis comes about seven days after the injury in the oligodendrocytes of the white matter and the effect is much broader, expanding far away from the original location of the injury. Knowing the timetable of apoptosis gives us a better idea of the importance of immediate therapeutic intervention.

Because there are specific proteins that work at each stage of apoptosis, inhibitors of these certain proteins can act to halt the rampant apoptosis that may take place after a spinal cord injury. Studies have shown that rats that have had spinal cord injuries were able to retain some hind limb movement with an apoptosis protein inhibitor treatment for a month. Studies have suggested that by blocking the cell death program, a larger window for treatment is created and the extent of secondary damage can be moderately lessened.

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AXON DAMAGE

Of all of the secondary effects that contribute to the overall damage that takes place after the initial injury, axon damage is possibly the most detrimental to the victim. The damage to the axons causes most of the symptoms associated with a severe spinal cord trauma. The major axon damage is not seen right after the initial spinal cord injury; it is seen hours later. Normal axonal transport is impaired due to the constriction of the axons caused by the initial damage. The constriction leads to disruption in the flow of important molecules and also leads to axonal swelling. The swollen axons have been called "reactive swellings" or "retraction balls." These swollen axons impede the axonal transport of neighboring axons, setting off a cascade of axonal damage.

Changes in the cytoskeleton of the axon appear to play a major role in the disruption of axonal transport. Calpain, mentioned earlier for its role in apoptosis, might play a role in a cytoskeleton structure deformation, which in turn disrupts transport. Even axons that do not have a major change in ion permeability also may be damaged by axon swelling. In this case neurofilaments become misaligned, thereby restricting transport down the axon.

Damaged axons have several consequences in the spinal cord. Axons that are disconnected from their cell body disintegrate in a process known as orthograde degeneration. This degeneration begins two to three days after the injury. In a few weeks, all of the axonal debris is cleared away by macrophages. Primary, or retrograde degeneration, also occurs. This is where an attached axon degenerates starting at the point of injury and working toward the cell body. All of the degeneration of axons has major effects on the victim who incurred the spinal cord injury, including some of the major symptoms of the injury, such as paralysis and loss of sensation in the extremities.

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EFFECTS OF SECONDARY DAMAGE

Depending on where the injury takes place, the major symptoms of the spinal cord injury are paralysis and loss of sensation at or below the level of the injury. Loss of bowel and bladder control may occur because the nerves required for normal bowel and bladder functioning run through the spinal cord and may be damaged by gross spinal cord damage. The same can be said for the sexual dysfunction that may accompany the injury. Autonomic dysreflexia is a major symptom of spinal cord injuries. This occurs because autoregulatory organs, such as the heart, gastrointestinal tract, and the glands, are controlled by autonomic nerves. If these nerves become damaged, than the autoregulation of these organs becomes disrupted. Irritation to these areas causes an exaggerated response from the autonomic nerves, which may lead to the excessive release of the neurotransmitter norepinephrine. The symptoms that come with the excessive release of norepinephrine include sweating, nausea, headache, anxiety and goose bumps below the injury, and can even lead to death. Other symptoms of spinal cord injury are mentioned in other sections.

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