Immediate pharmaceutical intervention is essential to improve the chances of recovery for patients of spinal cord injury. There are three main categories of drugs for these patients: anti-inflammatories, antioxidants, and anti-excitotoxins. Anti-inflammatories act against immune system responses, antioxidants prevent oxidation, and anti-excitotoxins fight excitotoxicity. These three processes damage the spinal cord tissue, and are explained in Secondary Damage.
Within each of these three categories, a number of drugs exist. Methylprednisolone is the most prominent anti-inflammatory, though it also acts as an antioxidant. Lazaroids are also antioxidants. Anti-excitotoxins include thyrotropin-releasing hormone, Sygen, and calcium-channel blockers. Ongoing research is being conducted to improve current drug therapies, as well as to find new and more effective pharmaceutical options.
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Inflammation is a process that generally promotes the healing of an injury. It does so in part by delivering additional immune cells and molecules to the injured site. Unfortunately, these inflammatory cells produce free radicals, which modify molecules necessary for proper cell function in the spinal cord. Free radicals are chemical substances with an unpaired electron and therefore very reactive. They can cause lipid peroxidation, an irreversible chain reaction that damages neurons and blood vessels cells by destroying their lipid bilayer (cell membrane). In the picture to the right the red particles are oxygen free radicals, shown destroying the lipid bilayer (Source: http://www.lef.org/magazine/mag2006/jun2006_report_sod_01.htm). The section on Secondary Damage provides more information about the damaging effects of immune responses on the spinal cord.
Because, however, secondary damage occurs during the hours following the initial trauma, anti-inflammatory therapy can help decrease the effects of an injury. Currently, the standard anti-inflammatory given to patients who have just suffered a spinal cord injury is methylprednisolone, a corticosteroid. Corticosteroids are synthetic versions of glucocorticoids, a family of hormones involved in the regulation of immune responses.
First, it is important to understand how corticosteroids work to reduce inflammation. Their natural counterparts, glucocorticoids, bind to receptors located inside the cell nucleus. The hormone-receptor complex then acts as a transcription factor, which controls the transcription of DNA. When bound to a receptor, glucocorticoids promote the transcription of genes, or they very occasionally suppress such transcription. The figure below, from Basic Neurochemistry 6th Ed., illustrates this process.
The anti-inflammatory actions of methylprednisolone are mediated through this type of receptor interaction, and they include reducing the period and intensity of inflammation, inhibiting white blood cells from recognizing foreign chemicals, and preventing the destruction of pathogens. To have such protective effects, corticosteroids must be given at very high doses; these doses also intensify the harmful effects of glucocorticoids (discussed later) because such large amounts of substance do no naturally occur.
Interesting, though, is that the receptor-mediated anti-inflammatory actions of methylprednisolone seem to be secondary to its role as a neuroprotective. Its greatest effects appear to result specifically from its antioxidant action, specifically its ability to combat lipid peroxidation. The healing effects of this action are summarized in the flow chart below from Hall (2003). Methylprednisolone integrates itself into the structure of the lipid bilayer, making the cell membrane more rigid and thus preventing the movement of lipid peroxyl radicals within it.
Limitations exist, however, to the effectiveness of methylprednisolone. First, to exert its neuroprotective effects, it must be constantly administered intravenously in high doses of 30 mg/kg. Secondly, because lipid peroxidation sets in quickly and can last at least from 24 to 48 hours, immediate and continued treatment is necessary.
Risks must be considered as well regarding methylprednisolone. Problems arise as a result of the high dose, and they are most prominent in treatments extending beyond 24 hours, the time limit determined by the Second National Spinal Cord Injury Study. Such complications include pneumonias, pressure sores, bleeding in the gastrointestinal system, and the formation of blood clots in veins. Concern has also arisen that the current method of methylprednisolone treatment may cause myopathy, or muscle weakness, and it is supported by a preliminary study by Qian, et al (2004).
Other side effects simply result from the fact that methylprednisolone is a corticosteroid. For instance, there is a small margin of error between effective and unsafe doses, as well as a small frame of time after the injury for effective treatment to be initiated; beyond 8 hours, it is detrimental to begin treatment because, ironically, the anti-peroxidation action of methylprednisolone can slow down the removal of peroxidized lipids and thus exacerbate the damage. Most notable, though, is that corticosteroids may inhibit neuronal regeneration by interfering with neurotrophins. The section on Regeneration has more information on regenerative processes and neurotrophins.
However, conflicting studies hinder our understanding of whether methylprednisolone actually interferes with regeneration. Hayashi et al. (2000) reported that the corticosteroid does prevent regenerative growth. On the other hand, a study by Nash et al. (2002) investigated the effects of methylprednisolone on the efficacy of transplanted ensheathing cells, which promote axon growth in the central nervous system, and found that the ensheathing cells still functioned properly. Cell transplant is one of several therapies currently being studied and is explained more in Regeneration.
Methylprednisolone is clearly a controversial method of treatment for acute spinal cord injury. In fact, it has not been approved in the United States for treatment of spinal cord injuries. Although it has many positives, it is difficult to ignore the negatives. Though some current research is trying to determine exactly those pros and cons, many scientists are working to develop safer and more effective pharmaceutical treatments.
Because the effectiveness of methylprednisolone is not notably due to glucocorticoid receptor-mediated anti-inflammatory actions, and because dangers are associated with those actions, researchers developed a family of antioxidants that also prevents lipid peroxidation, but without the corticosteroid-related side effects. These drugs are known as lazaroids and were created by modifying the methylprednisolone molecule. The chemical structures of methylprednisolone and a lazaroid are shown below, adapted from Hall & Springer (2004).
Lazaroids work against lipid peroxidation in two ways. The first is by the same manner as methylprednisolone: they incorporate themselves into the cell membrane and thereby stop the chain of destructive reactions set off by peroxyl radicals. Their second mechanism of action is to scavenge peroxyl radicals, stabilizing the molecules that set off the chain.
Tirilazad was chosen to be developed for clinical trials. It was found to be as effective as a 24-hour treatment of methylprednisolone when treatments were begun within three hours of injury. Additionally, research could find no evidence that tirilazad has any side effects even after extended administration, suggesting that it may be a safer option than methylprednisolone in cases where therapy needs to continue after 48 hours. However, it is important keep in mind that these results are not definitive.
It is also important to note that the FDA has not approved tirilazad for spinal cord injury treatment. This is due in part to the fact that it has been tested only against another unapproved drug, methylprednisolone. For tirilazad to become a treatment option, it will have to be compared to placebo, which will occur only if determined to be ethically appropriate.
Other lazaroids too are under investigation. Compound U-74500A offers especially exciting possibilities since it is in fact more effective than tirilazad. Iron radicals catalyze, or speed up, some peroxidation reactions; U-74500A can interact with these iron radicals. In effect, it can remove not only the peroxyl radicals that cause lipid peroxidation, but also the radicals that increase rate at which the harmful process occurs. Tirilazad, on the other hand, cannot interact with iron radicals. Lazaroids and other antioxidants will continue to be investigated as important possible treatments of acute spinal cord injury.
High dose vitamin therapy has just recently begun, though the results of a preliminary study by Liao and Song (2004) on high dose vitamin C do not seem promising; they found that while vitamin C effectively prevents lipid peroxidation, it does not do so and well as methylprednisolone. Research regarding vitamin E is equally unfruitful; Koc et al. (1999) found that although it greatly reduced lipid peroxidation, vitamin E was not as effective as either methylprednisolone or tirilazad.