Spinal Cord Injury: Drug Treatment

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Thyrotropin-releasing hormone

Anti-inflammatories and antioxidants are not the only possible drug therapies for spinal cord injury. Besides inflammation and lipid peroxidation, other processes related to the primary injury can be harmful. One is ischemia, or dangerously low levels of blood flow, to which the spinal cord is especially vulnerable. The flow chart at left, from Basic Neurochemistry, shows the chain of events that leads to excitotoxicity (see Secondary Damage) and thus neuronal damage. While ischemia is detrimental in and of itself, it also can lead to edema, which is swelling caused by excessive fluid in the tissue.

Endorphins are opioids released in response to injury and may be partially responsible for ischemia. Researchers have pursued therapies that would inhibit this harmful effect of endorphins. Naloxone is a drug that block opioid receptors and is most commonly used to treat opiate overdoses; it was found that by preventing endorphin-receptor interaction, naxolone also promotes blood flow to the spinal cord after contusion, or bruising. This discovery inspired investigations of thyrotropin-releasing hormone and similar compounds.

Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus of the brain. It causes the synthesis and release of thyroid-stimulating hormone, which stimulates the thyroid to secrete hormones. However, TRH can act throughout the body on opioid receptors as well, blocking the binding of endorphins. In this manner, TRH has been able to improve recovery from spinal cord injury in lab animals. TRH may also work by blocking other substances involved in secondary damage, including toxins that cause neuronal cell death.

Ceylan et al. (1991) observed that the average blood pressure of rats with spinal cord injury quickly increased after being given TRH; these results suggest that the hormone increases blood flow to the spinal cord. The study also found that administration could begin as late as 24 hours after the initial damage and still be significantly beneficial.

The positive effects of TRH do no stop with fighting ischemia. After spinal cord compression, motor and sensory systems recover faster with TRH treatment, and neuron disintegration decreases.

However, because it is active throughout the body, TRH may not be specific enough to be especially useful as a neuroprotective. Scientists have modified the TRH molecule in hopes of creating more effective compounds. Advantages of these analogs include that they fight edema and that they last for longer periods of time. YM14673 specifically may promote new axonal growth as well. Unfortunate, though, is that not all analogs improve neurological recovery like TRH does. TRH and some of its analogs are shown below, from Horita (1998). Analogs modified at the C-terminus (on the left end of the molecule) improved neural function, but those altered at the N-terminus (on the right end) failed to do so in animal models.

Preliminary trials of TRH have found that patients have no adverse reactions to the treatment. Additionally, Pitts et al. (1995) observed that treatment was beneficial, though the test group was quite small. Results suggest, however, that further investigation is both warranted and potentially advantageous. While TRH analogs have not yet been tested on humans, scientists are working towards doing so in the future.

Researchers are interested not only in TRH and analogs of the molecule, but also in cyclo-his-pro, the metabolic product of TRH. The body quickly metabolizes TRH; therefore it is effective for only a short period. Cyclo-his-pro, however, still prevents neuronal cell death, but only in cell cultures. Therefore, scientists have been working with a class of molecules structurally related to cyclo-his-pro: cyclic dipeptides. Recently, Faden et al. (2004) created a series of these compounds, several of which were found to stop neuronal cell death in live animals. This direction, while just emerging, has many possibilities.

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SYGEN AND CALCIUM-CHANNEL BLOCKERS

Gangliosides are molecules that are integrated into the cell membrane of neurons in the brain and spinal cord. One in particular, GM1 (marketed as Sygen) has anti-excitotoxicity properties. Besides fighting excitotoxicity, it seems to be involved in regeneration, though by what mechanism we do not yet know.

In the early 1990s, the Maryland GM1 ganglioside trial found that after one year, patients experienced greater neurological function than those receiving placebo. Treatment began within 72 hours of the insult and lasted for three days. (Incidentally, the results of the Second National Spinal Cord Injury Study were not yet known, and patients also received a dose of methylprednisolone prior to the Sygen therapy.)

Geisler et al. (2001) performed a multicenter trial to test the efficacy of Sygen and observed motor and autonomic recovery in patients who received the anti-excitotoxin. In almost all cases, the results were stastically significant. They also observed that Sygen had the most positive effects for patients who had only partial or mild injuries; those with complete injury did not benefit as greatly from the treatment. However, all patients did show improvement by the end of the therapy.

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Calcium-channel blockers prevent excitotoxicity caused by ischemia. (See the flow chart in the segment on TRH, above.) By directly inhibiting the entrance of Ca²⁺ into neurons, calcium-channel blockers are able to prevent apoptosis. (For more information on excitotoxicity and apoptosis, see Secondary Damage.)

One drug that works by blocking calcium channels is nimodipine. Although it has been shown to increase spinal cord blood flow after primary injury, it has little influence on tissue and functional recovery. In fact, it causes hypotension, which seems to exacerbate the damage caused by ischemia.

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NEW RESEARCH AND SOLUTIONS

Research on anti-inflammatories and antioxidants is taking new directions. Some scientists are investigating the role integrins play in inflammation. Others are looking to the endogenous antioxidant glutathione for answers.

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Neutrophils are the first immune cells to arrive at the site of injury, and they are responsible for the production of free radicals; macrophages arrive later, but are similarly involved in inflammation and oxidative damage. (Secondary Damage discusses this more.) Integrins guide these two types of leukocytes to the damaged tissue by helping them exit the blood vessel. The figure below, from the Hospital Practice website, illustrates this. By using antibodies, scientists have found that they can inhibit the presence of these immune cells at the site of injury. One such integrin is CD11d of the CD18 family, and it is located on the surfaces of both neutrophils and macrophages. While its precise function in spinal cord inflammation is not clear, it is known to be involved in the infiltration of neutrophils and macrophages into spinal cord injuries.

Prompted by this knowledge, Saville et al. (2004) investigated the possibility of blocking CD11d with an antibody to treat spinal cord injury; they compared the efficacy of the antibody to that of methylprednisolone by administering each on the same time schedule over the course of the first two days following the insult. The study found that antibody therapy, in addition to improving motor and autonomic recovery and reducing chronic pain, increased the amount of tissue spared from secondary damage. Furthermore, the antibody to CD11d prevented neutrophils from entering the injury without inhibiting macrophages from entering later. (Macrophages do mediate positive healing processes.) This is an important discovery, as it may lead to an alternative to methylprednisolone, which nearly eliminates the presence of macrophages. Saville and colleagues also observed that in rats treated with methylprednisolone, the number of neutrophils remained high for a week after injury; this was not the case in rats given the antibody. The results of this experiment suggest there exist many novel anti-inflammatories, especially in the form of antibodies.

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Glutathione is an antioxidant that is produced by the body. (It also participates in preventing ischemia, regulating genes, synthesizing proteins and other important functions, but the discussion here will be limited to its antioxidant effects.) After spinal cord injury, the balance of glutathione is disrupted, and it cannot exert its protective actions.

Because glutathione cannot easily enter cells, direct administration is not an option. Therefore, scientists have developed reduced glutathione monoethyl ester, which is easily transported across the cell membrane. Guizar-Sahagun et al. (2005) compared glutathione monethyl ester, methylprednisolone, and control. During the first two weeks of treatment, similar improvements in motor recovery were observed in rats from every group. After that, however, those who received glutathione monethyl ester showed greater recovery than those receiving methylprednisolone and vehicle; the latter two groups were experienced similar improvements. These findings too encourage further investigation.

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While pharmaceutical treatments continue to improve for patients of spinal cord injury, the majority of patients suffer devastating injuries. For these patients to fully experience the benefits of scientists' discoveries, a greater degree of consistency must be established among treatment centers. More over, there is a paucity of data on the drugs described in this section; more clinical trials are needed not only to establish which therapies are most beneficial, but to point out holes in our current understanding of spinal cord injury so that new directions can be explored.

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