Secondary damage is the damage that occurs at the cellular level following the initial trauma. There are two main ways that secondary damage occurs. Apoptosis and necrosis, two types of cell death, take place because of byproducts of normal intercellular responses two the trauma, such as the immune system response and the increase in glutamate activity. What is more traumatic and implicated in the severe symptoms of an acute spinal cord injury is the neuronal damage that impedes transport of neurotransmitters to and from the central nervous system. Both the cell death and the neuron damage take place over a few days following the initial damage. It is important to understand the timeline of secondary damage so that damage and the resulting symptoms can be minimized. Much of the immediate treatment depends on the knowledge of the intercellular consequences that take place after the spinal cord injury.
- Immune System Response
- Oxidative Damage
- Excitotoxicity
- Necrosis and Apoptosis
- Axon Damage
- Effects of Secondary Damage
IMMUNE SYSTEM RESPONSE
The immune system response to a spinal cord injury begins with the entrance of neutrophils into the central nervous system about twelve hours after the injury. Neutrophils are a type of leukocyte (white blood cell) that act as the body's first line of defense and play a key role in the inflammatory response. About three days after the injury, T-cells enter the spinal cord. Helper T-cells and macrophages release regulatory messenger proteins called cytokines, which regulate normal biological functioning, such as cell growth, inflammation, and tissue repair. Some cytokines have a detrimental effect however; they may induce cell apoptosis, or programmed cell death. Neutrophils and macrophages, another type of leukocyte, also have the detrimental effect of producing free radicals that cause oxidative damage on cells. Oxidative damage leads to DNA damage. These detrimental effects will be discussed in later sections.
OXIDATIVE DAMAGE
Oxidative damage occurs because of excess free radicals in the
cell due to neutrophil signaling, or more indirectly through excitotoxicity,
the excess release of glutamate and necrosis. Free radicals are a normal
byproduct of metabolic processes and are also produced in the immune response,
as they are implicated in much of the intercellular killing of pathogens and
also the execution of host cells programmed for death. However an excessive
amount of free radicals can harm normal cells as well. Superoxides are oxygen
molecules with an extra electron and are found in normal antioxidant defenses.
Superoxides can also bind to hydrogen peroxide, which is normally found in the
cell, and form hydroxyl radicals. Both of these free radicals are extremely
reactive because of the extra electron. Because of their ability to give away
extra electrons, the damage caused by the free radicals is called oxidative
damage. Free radicals have been thought to induce forms of cancer by mutating
the cell's DNA, causing changes in the cell cycle that lead to uncontrollable
cell production. Free radicals also lead to membrane lipid peroxidation, which
causes a reduction in membrane permeability. This in turn disrupts the electron
transport chain portion of the metabolic process. Because free radicals are
important in normal biological functioning yet are harmful to the cell when in
excess, there are a number of enzymes which reduce the number of free radicals
to a healthy amount. One of these enzymes is called superoxide dismutase, which
is abundant in the spinal cord and throughout the central nervous system.
However, because of consequences of secondary damage, such as necrosis,
excitotoxicity and neutrophil signaling, free radicals are in such a high
quantity that the enzymes cannot clear enough of them away and cell damage
occurs.
Nitric oxide is thought to play a role in the immune response. It facilitates the relaxation of smooth muscle and the vasodilation of the blood vessels. This allows for neutrophils to bombard the injured spot. However, as a byproduct nitric oxide reacts with superoxide to produce peroxynitrate, which can diffuse much faster then the other free radicals and can therefore lead to more cellular damage. Peroxynitrate inactivates many of the antioxidant defenses such as superoxide dismutase so that the free radicals can cause even more damage. It also interacts with certain growth factors such as nerve growth factor (NGF) and mutates it so that it accelerates apoptosis instead of inhibiting it, which is NGF's normal function.
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Although not
completely understood, severe central nervous system injury leads 
to
elevation in the levels of excitatory amino acids, especially glutamate. The excessive release of glutamate
leads to a chain of events that is called excitotoxicity. NMDA receptors, which
are located on neurons, are opened when glutamate binds to it (along with a
brief depolarization event of the cell), allowing calcium ions (Ca2+)
to flood into the cell. Ca2+ ions trigger many different biological
processes. These ions trigger many biological processes through the activation
of calcium-binding proteins such as calmodulin. Calcium-bound calmodulin
activates protein kinases, which in turn activate other proteins by
phosphorylating them. Another Ca2+-binding protein is calpain, which
leads to some of the detrimental effects of excitotoxicity. Calpain has been
implicated as playing a key role in the activation of apoptosis. Because of the
excessive release of glutamate, unwarranted amounts of Ca2+ ions
enter into the cell through the NMDA receptor, leading to the activation of too
much calpain, which leads unwarranted apoptosis.
Glutamate also binds to the AMPA receptor, a glutamate activated (Na+) channel. When the AMPA channel is opened, Na+ floods into the neuron. The entrance of Na+ into the neuron leads to an osmotic imbalance and water, which can permeate through the plasma membrane, will fill up the cell and cause swelling. The excess swelling then leads to necrosis and a spilling out of powerful regulatory proteins.
Excitotoxicity can lead to apoptosis and necrosis because of an excessive influx of ions into the cell. Calcium ions have also been implicated in another detrimental effect. Mitochondria actively sequester calcium within the cell. Mitochondria are the metabolic powerhouses of the cell; they produce much of the cellÍs energy through oxidation. However excess calcium ions can lead to the production of excess free radicals, which causes oxidative damage. The process of oxidative damage will now be explained.
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