Anatomy 101: What happens after injury
Topics:
Cavitation
Following an injury to the spinal cord, several things happen. First the spinal cord, which contains the neurons and axons that allow the brain and body to communicate, is injured, crushing or damaging the axons at the site of the injury. This is followed by a series of events that occur days to weeks after the initial insult. The neurons that are injured at the impact site, burst and release molecules that over excite the surrounding neurons resulting in a spreading wave of cell death, this is called excitotoxicity. The end result of which is a large hole around the injury site, the process of creating this hole is called cavitation. The hole, or cyst, fills with fluid and becomes a barrier for axons trying to regrow into the injury site. Scientists working on cavitation are exploring ways to decrease the amount of excitotoxicity and secondary cell death, as well as ways to create a bridge through the cyst so that axons can grow through the injury site.
Cell Death
Cells of the body, including neurons, can die in 2 ways, necrosis or apoptosis. Necrotic cell death occurs through injury or accident, while apoptotic cell death occurs when the cell actively commits suicide. With necrosis, the injured cell bursts open pouring the contents of the cell into the extracellular space. This is a problem because what is inside a cell is toxic to other cells. The contents of the necrotic cell may cause other cells to burst as well. This is frequently the case in traumatic spinal cord injury. Cells at the injury site explode due to mechanical insult, releasing toxic substances that cause their neighbors to burst. This spreading wave of cell death, called secondary cell death, can result in much more tissue damage than was caused by the original traumatic impact.
With apoptosis, the cell dies a more orderly death. Either because the cell has been compromised in some way, represents a threat to surrounding tissue or because it is old, a chemical reaction within the cell is initiated that results in death. In the end, the cell breaks into pieces that the body recognizes as debris and cleans up. With apoptosis, other cells in the area are not in danger. Apoptosis is a hot area in science right now. It is becoming clear that this process is a regular event for cells and is in fact critical during development and for maintaining normal tissue. Apoptotic cells can be recognized by a characteristic pattern of morphological, biochemical and molecular changes, which can be measured in the laboratory.
Secondary Cell Death and Excitotoxicity
There is a period of time, lasting from hours to days, after a traumatic spinal cord injury, during which tissue damage continues in a process called "secondary cell death". Blocking this cell death could reduce the extent of functional impairment after spinal cord injury. One mechanism that is thought to contribute to this secondary cell death is "excitotoxicity", caused by release of an excitatory nerve cell signaling compound, called glutamate, from damaged nerve cells. Glutamate is a critical molecule, a neurotransmitter, in the brain and spinal cord, but un-controlled release of glutamate, as occurs following a spinal cord injury, kills nerve cells as well as the cells that form the insulating myelin sheath (oligodendrocytes).
Normally, glutamate released by nerve cells is kept in check because astrocytes, a type of neural support or glial cell, have a pump called a "transporter" that removes excess glutamate. It turns out that injured neurons produce and release a chemical called "reactive oxygen", which damages the glutamate transporter in astrocytes setting off a cycle that results in a cascade of neuron death-astrocyte damage-more neuron death, and so forth.
- A. As glutamate is released at the end of the axon, some goes to the next nerve cell and some gets taken up by the astrocyte.
- B. Glutamate release by injured neurons causes them to produces reactive osygen, which dames the glutamate transporte in astrocytes.
- C. A cycle begins where more glutamate outside causes the neuron to make more reactive oxygen species, which causes more damage to the glutamate transporter, causing damage to all the neurons in its neighborhood
- D. ...
Immune Response
The central nervous system is generally walled off from the rest off the body by the blood-brain barrier, and so few immune system cells are normally found in the brain and spinal cord. After injury, however, immune system cells come running into the injury site. Unfortunately, some of the cells that come into the injury site immediately after the injury, specifically destructive T cells and macrophages, do quite a bit of harm. We now know that the destructive T-cells are actually recruited or called into the injury site by another molecule, called a chemokine. Research suggests that up to 70% of the damage seen after a spinal cord injury may be due to the body's own immune system response. Moreover, if the chemokine that recruits the T cells into the injury site is blocked, there is significant tissue sparing.
Another immune function that is seen after injury is inflammation, and a process called the "complement cascade" is one means by which inflammation can cause cells like neurons and oligodendrocytes (myelin makers) to die. Complement does this through the formation of the 'Big Mac', or membrane attack complex (MAC). Only this MAC doesn't include french fries and a coke. Instead, this MAC makes a hole in the cell, which impairs the cell's ability to regulate normal events necessary for its survival. If enough MACs are formed on the surface of the cell, the cell dies.
Usually it is invading cells, like bacteria and viruses, that are attacked by complement created MAC. However, after spinal cord injury, many damaged but surviving neuronal and glial cells of the spinal cord are 'tagged' for removal even though it is possible that these cells could recover and function again. This process also involves the complement system, which 'tags' or marks debris for removal and activates cells of the immune system (called microglia) to do the cleanup. So, the complement cascade could contribute to mechanisms, like neuronal degeneration and demyelination, that disconnect the brain from the spinal cord after injury.
Astrogliosis or Scar Formation
The spinal cord and brain are fairly isolated from the rest of the body by the blood brain barrier. After an injury, this barrier is compromised and cells from outside the central nervous system can move in. One function of certain types of astrocytes is to repair or restore the blood brain barrier. They do this by creating a scar around the injury site. The scar, however, creates several problems for regeneration. It is not only a physical barrier to nerve cells trying to regrow, literally as wall, it also gives off chemical stop signs that inhibit axonal regeneration. Recent research has shown that the scar is not limited to immediately around the cavity that forms at the impact site. Astrocytes near the injury site also infiltrate and wrap around remaining neurons.
Demyelination
While loss of neurons in critical to loss of function, oligodendrocyte death also plays a major role in functional loss after spinal cord injury. Neurons need the insulating substance, myelin, made by oligodendrocytes to send messages. Research has demonstrated that in contusion injuries, the most common injury seen in humans, there are often small numbers of spared axons on the very edges of the injury site. However, these axons are typically demyelinated; they have lost their insulation and can no longer send messages, they are "naked". It turns out that demyelination is a progressive condition following spinal cord injury and in rodents can continue for months to years after injury.
