| Home |
| Quick Facts |
| Cells of the Spinal Cord |
| Impulse Transmission |
| Physiology of the Spinal Cord |
| Effects of SCIs |
| Initial Treatment of SCIs |
| Recent Advances in SCI Research |
|
|
|
Current research into the methods of treating spinal cord injuries is focused in two areas. The first involves primary intervention strategies to reduce nerve degeneration that promptly follows injury. The other involves finding treatments that will promote nerve regeneration and reconnection of the spinal cord across the lesion (2). Whereas sensory axons in mature humans can regenerate following injury, axons in the central nervous system cannot (24). In order for normal functions to return following a spinal cord injury, the axons must survive, regrow, reconnect with their target cells, and follow the paths of normal development. There are three reasons why this does not happen in the adult central nervous system: neurons die, axons do not have the ability to initiate or maintain growth, and the environment of the injured area is not conducive to regeneration (5, 23). The inability of the central nervous system to allow cell regrowth is due to the presence of inhibitory signals and the lack of growth promoting signals. These signals can come from cells, extracellular matrix, or other molecules that diffuse into the injury. Myelin is one substance that greatly contributes to the axons inability to regrow (5). Whereas myelin does not prevent axonal regrowth in young neurons and in the peripheral nervous system, it prevents axonal regrowth in the adult central nervous system. Neurons lose the ability to regrow because of two factors: the development of myelin, and the axonal response (inability to regrow) associated with it. During spinal cord injury both the axon and the myelin surrounding the axon are damaged. Axonal regeneration is prevented due to its exposure to substances secreted from myelin and the inhibitory substances related to the myelin membrane. After the glial scar forms, axons completely lose the ability to cross the lesion and reconnect with target cells.
Scientists have discovered two approaches that could allow the neuron to regenerate and reconnect with its target cells. The first involves trying to prompt the neuron into a "young" state in which it would not be inhibited by the environment of the adult central nervous system. A study by Neuman and Woolf showed that neurons having axons in both the peripheral and central nervous system have the ability to regrow following a lesion in the central nervous system if a lesion was produced one or two weeks before in the peripheral nervous system. The theory behind this is that the peripheral nervous system conditioned the central nervous system so that it would no longer be affected by the inhibitors in the environment following injury (11). In their experiment the injured fibers either grew through the lesion or they traveled around the lesion. They showed, however, that regrowth after complete lesion of the dorsal cord can take place in the inhibitory environment that results from the injury. They attribute this enhanced regenerative ability to increased growth capacity (11). The second approach to regeneration and reconnection involves obstructing the myelin related substances that prevent neuron regeneration (5). Nogo and myelin-associated glycoprotein (MAG) are two molecules shown to inhibit axonal regeneration. When growing axons are exposed to Nogo their growth cone breaks down. The Schwab laboratory demonstrated that IN-1, a monoclonal antibody against CNS myelin, enhanced axonal regrowth both on a culture of myelin and also in vivo (11). When IN-1 secreting cells were transplanted at the same time that the lesion was created, many axons grew rather long distances and in some cases regained its function (11). While the transplantation induced the long-distance growth of some axons, 90-95% of axons showed no growth at all. This indicates that there are inhibitors in addition to Nogo that prevent axons from regrowing. MAG is another powerful growth inhibiting molecule. It prevents axonal regeneration in vivo, and it is probable that any release of MAG from myelin at the injury site contributes to the axons inability to regrow (11). It is likely that in addition to Nogo and MAG, there are other myelin associated growth inhibitors (5,11). In tests where an animals own immune system was induced to make antibodies against all myelin associated molecules, the extent of regrowth was greater than when specific antibodies were used, but the regrowth was still restricted suggesting that other factors contribute to the prevention of regeneration (5). It is also probable that effects of these substances are not additive, but that the presence of one is enough to prevent regeneration. The best approach in devising ways to aid axonal regrowth is to inhibit the effects of all of the substances simultaneously (11).
One approach to blocking all myelin related inhibitors was tested by Huang et al. They 'vaccinated' mice against myelin inhibitors three weeks before injury to induce the production of antibodies against the inhibitors. Three weeks after injury 50% of the immunized mice showed considerable axonal regrowth, while the control immunized group showed no regrowth (11). As compared to the studied performed by Schwab and colleagues using IN-1 injections, myelin-immunized mice regrew more axons and the distance of regrowth was up to two-thirds of the spinal cord compared to one-forth. One major question concerning myelin injection is whether or not the antibodies have to be present along the entire path while the axon regrows, or if their initial presence and their presence across the lesion and through myelin inhibitors is enough to allow regrowth. Work performed by Silver's group, indicates that antibodies are needed only across the lesion site where the inhibitors are present. As Davies and colleagues demonstrated in 1997, undamaged myelin is permissive to axonal regrowth. It is therefore possible that if the antibodies were present where the axon encounters the myelin inhibitors, the axon could transverse the lesion and continue its growth outside the myelin. The glial scar also creates anther barrier to axonal regrowth. Whereas axons are able to regrow if they do not come in contact with damaged myelin, axonal growth ceases when it reaches the glial scar. Although it is not known exactly what molecules impede regrowth, some possible molecules include: developmental growth cone inhibitory guidance cues, such as semaphorin 3A and EphB3; extracellular matrix molecules such as the proteoglycans versican, brevican, phosphacan, and neurocan, and some adhesion molecules such as tenascin-R (5). One possible approach to aid axon regeneration is the transplantation of peripheral nerves and Schwann cells (19, 24). Schwann cells are the glial cells in the peripheral nervous system that foster nerve regeneration (19, 24). In addition to supplying guidance tubes for regenerating peripheral axons, they produce cell-adhesion molecules, and molecules of extracellular matrix (19). They also produce many neurotrophic factors, which improve nerve regeneration by guaranteeing survival, providing growth cues, and encouraging cells to produce substances needed for growth (5). Implantation of Schwann cells aids in axonal regeneration by supporting and guiding the growing axon and giving them neurotrophic support. They link each side of the lesion with living cells thus guiding the axons during regeneration (24). They may even foster axonal sprouting. Martin et al showed that the best time for Schwann cell implantation is immediately following the cord lesion because this improves cell survival and reduces the scar tissue (19, 24).
Neurons in the olfactory mucosa are the only neurons that are born after birth and that continue to divide throughout adult life (19). Olfactory ensheathing cells are specialized glial cells of the olfactory mucosa that maintain axonal growth from the mucosa to the olfactory bulbs. Like Schwann cells, olfactory ensheathing cells continue to divide throughout life, but unlike Schwann cells, which are confined to the peripheral nervous system, olfactory ensheathing cells can enter the central nervous system by guiding olfactory axons to their target destinations in the olfactory glomeruli. They are the only glial cells known to be able to travel across the boundary between the peripheral and the central nervous system (10). Ramón- Cueto and colleagues recently demonstrated that implantation of olfactory ensheathing cells after complete spinal cord transection could restore both structure and function to the injured animal. Their study, in which adult rats with complete spinal cord transection received transplantations of olfactory ensheathing cells, showed the greatest amount of recovery as compared to other transplantation studies using Schwann cells, astrocytes, microglia, macrophages, and fibroblasts. The transplantation of olfactory ensheathing cells resulted in the recovery of proprioception and light touch, the ability to support body weight, voluntary hind limb movement, plantar paw placement, as well as the long-distance regeneration of motor axons through the transection site (28). Transplantation of olfactory ensheathing cells could be an advantageous repair strategy for humans because the cells can be obtained from and possibly transplanted from adult donors (28). Most of the current research surrounding spinal cord regeneration deals with the best methods to improve axon growth. Although axon regrowth is important, it alone will not lead to functional recovery. The essentials for functional recovery include recognition of and reconnection to targets, reenervation of neurons and their pathways, and the recovery of functional synapses (5). |
||||||||||||||
|
|
