by Marion Murray, PhD
The Problem: Acute Injury Kills Neurons
During embryonic and early postnatal development, neurons in the Central Nervous System (CNS: brain and spinal cord) employ an active genetic program to drive growth of axons and formation of specific patterns of connections with other neurons. Neurons of the Peripheral Nervous System (PNS), whose axons innervate muscle or autonomic ganglia, can readily regenerate axons even in the adult and thus retain the capacity to restore functional connections.
Diagram of spinal cord following an injury. A bruising injury induces hemorrhage and cell death. The epicenter is characterized by necrotic cell death and the lesion expands (secondary injury) into the surrounding region, with additional cell death due to apoptosis. Ultimately the area of injury is surrounded by a dense glial scar. The injury destroys some axons, and damages others, leading to demyelination. Cut axons often retract (die-back). Some axons are usually spared by a contusion injury.
As we know, however, injuries to the adult CNS are not repaired. The reasons for this failure are becoming clear. The mature spinal cord does not provide a favorable environment for repair because of the presence of molecules that prevent axonal elongation and because neurons have lost much of the ability to grow axons. The initial injury directly destroys neurons, by a process called necrosis, and this is followed by an inflammatory reaction, the secondary injury, which expands the injury site over the next few days. During this period, axons spared by the original injury may be damaged and, as a process called apoptosis (a-puh-TOE-sis)-also known as programmed cell death or induced cell suicide—is triggered, additional neurons may die.
Neurons that die are not replaced, axons that are damaged do not regenerate, and the functions that these neurons and axons mediate are lost. The injury site is then walled off by a dense scar, formed by astrocytes, that provides an additional barrier to repair. Finally, even if growth of injured neurons could be achieved, would the pathfinding signals be available that will enable them to restore the original pattern of connections?
These impediments to repair may seem overwhelming, but what laboratory research has achieved over the last decade is an understanding of the mechanisms by which each of these processes act and, more importantly, how to intervene in the destructive processes and promote the reparative ones. Paradoxically, some of the factors that contribute to the inability of damaged CNS to repair itself are normal protective processes that, if countered, can promote repair. Treatment: Limit the Lesion
Neurons that are directly damaged by the injury and that die through necrosis can probably not be saved. The reason that neurons in the surrounding area die is because an intracellular suicide pathway (apoptosis) is activated; this is probably nature’s way to eliminate damaged neurons. Many of the cells that are vulnerable to apoptosis can be saved by providing molecules, e.g., growth factors or antiapoptotic molecules, that block the suicide pathway and thus permit the cells to survive. This has the effect of diminishing the expansion of the injury and of rescuing neurons that may retain function. Diminishing the extent of the secondary injury also increases survival of axons that pass near the lesion and provides the promise of greater recovery through these spared axons.
Treatment: Improve The Environment
In the adult, the spinal cord contains many molecules that prevent axons from growing; this is probably a mechanism that ensures that the pattern of connections formed during development are maintained throughout life. Among these molecules are those found associated with myelin sheath that surrounds many axons. Several of these molecules have been identified and methods of neutralizing their activity have been developed. The damaged spinal cord is even less hospitable to growth and that is because of the scar that develops around the injury; the scar probably acts to seal off damaged tissue from healthy tissue. Blockade of myelin inhibitors or dissolution of the scar have been shown to allow damaged axons to grow and, in animal experiments, is associated with improved function.
Treatment: Energize The Neuron
In the developing CNS, axons grow long distances to find their appropriate targets. This is because the developing CNS has a rich source of trophic factors, molecules that stimulate growth, and because the intracellular machinery in the developing neuron is biased in favor of axonal extension. In the mature CNS, the amount of trophic factor present is much reduced and the intracellular machinery of the neuron has become biased in favor of preventing axonal growth. Laboratory studies have begun to reveal which trophic factors need to be applied and what pharmacological treatments can reverse the intracellular bias to one which once again can promote axonal growth. These treatments are beginning to show promise in restoring some connections and therefore some functions.
Treatment: Make A New Spinal Cord
A spinal injury that severs connections between the brain and the spinal cord prevents voluntary control of walking, bladder, bowel and sexual functions and can result in neuropathic pain. While restoring the connections to those that existed before the injury remains a distant goal, it is possible that establishing new connections may permit some communication between brain and spinal cord, and thus some improvement in function.
An alternative to trying to modify the environment and to energize the surviving neurons and axons is therefore to attempt to create a new spinal cord. One way is to transplant cells into the injury site. These transplantation procedures can act to fill the injury site with cells which can provide a potential bridge for growing axons. If the transplanted cells secrete appropriate molecules, e.g. trophic factors, they can also prevent apoptosis and encourage axonal growth. The presence of growth promoting cells in the injury site can also diminish scar formation.
The search is on for the most effective cell type to transplant. A particularly appealing source is neural precursor cells, a form of stem cell, that, when transplanted into an injury site, can develop into both neuronal and glial cells and thus repopulate the injury site with normal spinal cord cells. Transplanted cells that develop into neurons can establish new circuitry with the host that may allow re-establishment of connectivity. Transplanted cells that become oligodendroglia can form myelin sheaths around host axons that improves function.
Treatment: Train The Spinal Cord
It is also possible to modify the connectivity of the spinal cord below the lesion by certain kinds of structured activity. This activity- dependent plasticity appears to be a form of learning in which repeated patterns of neuronal activity elicited by repetitive movements can change the spinal circuitry to emphasize the trained patterns. In laboratory experiments, animals with spinal transsections can, through training, develop some aspects of locomotor patterns that are similar to normal locomotion.
Combinations of Treatments
While what we have learned is very encouraging, we need to recognize that most of the improvements in axonal growth or in function have been only incremental. It is also clear from the last decade of inquiry that there are many factors that operate independently to prevent spinal cord repair and recovery. The effort now is to develop the appropriate combinations of treatments that treat each of these factors. These experiments are being done in laboratories around the world.
Marion Murray, PhD, is professor of Neurobiology and Anatomy at Drexel University in Philadelphia.
