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Laurance Johnston, Ph.D.

Sponsor: Institute of Spinal Cord Injury, Iceland



1) Methylprednisolone

2) Sygen® or GM-1 Ganglioside

3) Thyrotropin-Releasing Hormone

4) Gacyclidine

5) Neotrofin

6) Minocycline

7) Cethrin

8) Tacrolimus

9) Lipitor (Atorvastatin)

10) Erythropoietin

11) Nogo

12) Ibuprofen

13) Riluzole

14) Taxol

1) Methylprednisolone (MP), a synthetic glucocorticoid steroid, is often administered soon after injury and many assume it is a post-injury standard of care, though many scientists are now challenging that assumption. This use is based on a foundation of animal studies and key clinical studies in humans. MP minimizes post-injury neurological damage by inhibiting, in part, lipid peroxidation, a key process that mediates secondary damage to the injured cord (Click on thumbnail illustration below (From Spinal Cord Medicine Principles and Practice, 2003, p 780))

There have been a number of MP-focused clinical trials, including two key multi-center, randomized, double-blind, placebo-controlled, clinical trials: National Acute Spinal Cord Injury Study 2 (NASCIS 2) and NASCI 3. An earlier NASCIS 1 study of MP generated no significant results.

In NASCI 2, 162 acutely injured patients received a MP bolus of 30 mg per kilogram of body weight followed by infusion of 5.4 mg per kilogram per hour for 23 hours. These patients were compared to 171 patients given placebo (Bracken et al, N Engl J Med, 322, 1990). Motor and sensory function was assessed at admission and after six weeks and six months. The investigators concluded that patients treated with MP within eight hours of injury had improved neurological recovery. Side effects included GI bleeding, wound infections, and delayed healing. The study also evaluated a second drug naloxone, which did not improve neurological function.

Before the results were published in a professional journal, the US National Institutes of Health disseminated them through announcements and faxes to emergency-room physicians and the news media. Though this was done to help the acutely injured as soon as possible, it essentially created a standard of care before other experts could critically evaluate the results.

MP Treatment Regimen (Click on thumbnails)

NASCIS 3 compared the efficacy of a 24-hour MP dose with a 48-hour dose of MP or the non-glucocorticoid tirilazad, which was included to ascertain if it had MP’s effectiveness without possessing MP’s steroid-related side effects (Bracken et al, JAMA 277(2), 1997). Based on the results of the previous NASCIS 2 study, all 499 acutely injured subjects were initially given 30-mg/kg dose of MP within eight hours of injury. Then, patients were randomized to receive 1) a 5.4-mg/kg infusion of MP for 24 hours, 2) the same dose for 48 hours, or 3) 2.5 mg/kg of tirilazad every six hours for 48 hours.

Follow-up assessments were again carried out at six weeks and six months.  The investigators concluded that if MP is initially administered within three hours of injury, the regimen should be continued for 24 hours; if initiated three to eight hours after injury, the regimen should be continued for 48 hours. Patients treated with tirilazad for 48 hours had comparable improvement to the patients treated with the 24-hour MP regimen. MP-associated side effects were greater in patients treated for 48 hours.

Controversy: A growing number of critics believe that MP has been promoted as a standard of care for acute injury based on results obtained through the use of questionable statistical procedures. Simply stated, the NASCIS 2 study showed little if any statistically significant benefits from high-dose MP, and modest benefits were only demonstrated in a patient subgroup when study data was micro-analyzed in a challenged post-hoc fashion.

This controversy is not insignificant. For example, a survey of participants at a 2001 Annual Canadian Spine Society meeting indicated: “75% of respondents were using MP either because everyone else does or out of fear for failing do so.”

The Canadian Spine Society and the Canadian Neurosurgical Society commissioned an expert review of the available MP data, which concluded that there was insufficient evidence to support the use of MP as a treatment standard or guideline, although there is weak clinical evidence to support its use as a treatment option. The two societies adopted these recommendations (see website for Canadian Association of Emergency Physicians: www.caep.ca/002.policies/002-01.guidelines/steriods-acute-spinal.htm).

Some of the published articles that challenge the use of MP as a treatment standard include, but are not limited to, the following:

1) Dr. Shanker Nesathurai (Massachusetts, USA) stated that neither NASCIS 2 or 3 convincingly demonstrated MP’s benefits. “There are concerns about the statistical analysis, randomization, and clinical benefits… Furthermore, the benefits of this intervention may not warrant the possible risks.” (J Trauma 45, 1998)

2) Dr. Deborah Short and colleagues (United Kingdom) extensively reviewed the scientific literature to evaluate the evidence in support of MP’s use (Spinal Cord, 38, 2000). They concluded: “The evidence produced by this systematic review does not support the use of high-dose methylpredinisolone in acute spinal cord injury to improve neurological recovery. A deleterious effect on early mortality and morbidity cannot be excluded by this evidence.”

3) Dr. W.P. Coleman et al (Maryland, USA) strongly criticized both NASCIS 2 and 3 for methodological weaknesses and the lack of data that could be critically reviewed by others (J Spinal Disord 13(3), 2000). For example, they stated: “The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public…These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.”

4) Dr. R.J. Hurlbert (Alberta, Canada) concluded: “The use of methylprednisolone administration in the treatment of acute SCI is not proven as a standard of care, nor can it be considered a recommended treatment. Evidence of the drug's efficacy and impact is weak and may only represent random events. In the strictest sense, 24-hour administration of methylprednisolone must still be considered experimental for use in clinical SCI. Forty-eight-hour therapy is not recommended.” (J Neurosurg 93(1 suppl), 2000)

5) In perhaps one of the most potentially damning criticisms, Dr. Tie Qian and colleagues (New Jersey, USA) suggested that high-dose MP therapy may damage muscles through acute corticosteroid myopathy (ACM) and that functional improvement attributed to MP may merely be due to the recovery of muscle damage caused by this extremely high dose of MP (Med Hypothesis 55, 2000). The investigators noted that under the NASCI 3 clinical protocol, a 75-kg acutely injured individual could receive nearly 22 gm of MP, which is the “highest dose of steroids during a 2-day period for any clinical condition.”

6) In a recent report, Qian and colleagues (Florida, USA) assessed the possibility that high-dose MP could cause ACM-related muscle damage (Spinal Cord, 43, 2005). Specifically, five acutely injured patients who received the high-dose MP treatment regimen were compared with three control patients, who did not meet the requirements for MP treatment (i.e., 2 gunshot injuries and 1 arrived at hospital 8 hours after injury). ACM was assessed by muscle biopsy and electromyography (EMG). Muscle biopsies indicated that four of the five MP-treated patients had muscle damage consistent with ACM. EMG studies supported these findings. In the controls, muscle biopsies were normal, and EMG’s did not suggest myopathy. The investigators concluded that “the improvement of neurological recovery showed in NASCIS may be only a recording of the natural recovery of ACM, instead of any protection that MP offers to the injured spinal cord.”

7) Studies carried out in rats by Dr. Y. Wu et al (USA) further documented the muscle-damaging nature of MP when used as a treatment after SCI. In this study, rats were experimentally injured at the thoracic T9-T10 level and treated with either MP or a placebo control. Seven days after injury, both body and muscle weight was significantly reduced in the MP-treated rats compared to controls. The investigators concluded that MP caused substantial muscle atrophy both above and below the the level of injury.

8) Dr. Yasuo Ito et al (Japan) compared the outcomes of patients who had been administered high-dose MP as part of their acute-injury care to those who had been identically treated but without MP. Specifically, between 2003 and 2005, all patients with cervical injuries were treated with the standard high-dose MP protocol. The following two years, all similarly injured patients were treated without MP. Other than MP administration, treatment was the same in both groups. The MP-treated group included 38 patients (30 men; 8 women) with an average age of 55 years. The non-MP treatment group included 41 patients (33 men; 8 women) averaging 60-years old.

Neurological improvement was observed in 45% and 63% of MP-treated and non-MP-treated patients, respectively. In other words, MP-treated patients apparently fared worse. In addition to less improvement, the MP-treated patients had a significantly greater incidence of pneumonia. Specifically, 50% of the MP-treated patients developed pneumonia compared with only 27% of the non-MP-treated patients. The investigators concluded that they “found no evidence supporting the opinion that high-dose” MP “administration facilitates neurological improvement in patients with spinal cord injury.” They also added that MP “should be used under limited circumstances because of the high incidence of pulmonary complications.”

9) In a 2011 published study, Dr. M. Aomar Millan and colleagues (Spain) retrospectively compared the outcomes of acutely injured patients treated with MP with patients not treated with the drug between 1997 and 2007. Using the ASIA impairment scale described in the appendix, neurological function was measured at ICU admission and discharge. No statistically significant differences in neurological recovery were noted between the groups. In addition, the MP-treated patients had more medical complications, such as hyperglycemia (i.e., high blood sugar) and gastrointestinal bleeding.

10) In 2012, Dr. P. Felleiter and associates (Switzerland) published the results of a retrospective study which compared the neurological outcomes of two groups of patients with SCI treated at different times. In the earlier time period (2001-2003) in which MP-treatment prevailed, 96% of 110 patients received MP. In contrast, reflecting the concerns about MP use that emerged over time, only 23% of of the later group (2008-2010) of 116 patients received MP. Given the large difference in the numbers treated with MP, one would expect much more improvement in the earlier group if MP had substantial effectiveness. Unfortunately, this was not the case. Although the earlier MP-emphasizing group had slightly improved neurological outcomes compared to the later group, the difference was not statistically significant.



“There are three kinds of lies: lies, damned lies, and statistics,” Mark Twain

2) Sygen® or GM-1 Ganglioside: Like MP discussed above, the degree of effectiveness of Sygen® or GM-1 ganglioside (click on thumbnail) for promoting neurological recovery after acute SCI depends on statistical interpretation. Sygen is the trade name (Fidia Pharmaceutical Corporation) for a naturally occurring GM-1 ganglioside, a complex glycolipid (see figure) found in abundance in central-nervous-system cell membranes.

Animal studies suggest that GM-1 exerts a neuroprotective effect and promotes regeneration after injury. In the acute injury phase, it prevents further cell death and injury by lessening the consequences associated with the injury-induced over-release of excitatory neurotransmitters, which, in turn, over-stimulates their receptors.   In the chronic injury phase, GM-1 promotes the expression of nerve growth factors. In addition to SCI, clinical trials suggest that GM-1 provides benefits in cases of stroke and Parkinson’s disease.

Again, like MP, GM-1’s use to treat acute SCI was the focus of two important clinical trials. In the first, Dr. Fred Geisler et al. (Maryland, USA) randomized patients to receive an intravenous 100-mg dose of GM-1 or placebo within 72 hours of injury (average 48 hours) and continuing for 18 to 32 days (N Eng J Med, 324, 1991). Of the 34 subjects, 23 had cervical injuries and 11 thoracic injuries; and 32 were men. Because all patients were recruited at one center, the procedural variability was inherently less than it would be in multi-center trials.

All patients were given 250-mg dose of MP upon admission and thereafter 125 mg every six hours for 72 hours. This MP dose was much less than that used in the NASCIS-2 study, whose results were not known during this GM-1 study.

Follow-up assessments were carried out twice a week for the first 4 weeks and at 2, 3, 6, and 12 months using the Frankel scale (grade A [complete], B, C, D & E [normal motor functioning]) and the ASIA motor score (0 = complete quadriplegia; 100 = normal motor function).

At one-year, there was statistically significant functional improvement in the GM-1 treated patients compared to controls. For example, in the placebo group, 13 patients stayed in the same grade, 4 improved one grade, and 1 improved two grades. In contrast, in the GM-1-treated group, 8 stayed in the same grade, 1 improved one grade, 6 improved two grades, and 1 improved three grades. In addition, GM-1 treated patients had a statistically significant improvement in the ASIA motor score.

In the second, six-year GM-1 trial, Giesler and colleagues randomized 760 patients recruited from 48 North-American SCI centers into low-dose GM-1 (331 patients), high-dose GM-1 (99 patients) and placebo (330 patients) treatment groups (Spine, 26(24S), 2001). The groups were further subdivided into six subgroups,using 1) injury severity (grade A, B, and combined C+D) and 2) cervical or thoracic injury.  

All patients initially received the NSCIS-2 MP-dosing regimen (i.e., the high dose; not the low dose used in the earlier GM-1 study). GM-1 treatment was not initiated until MP treatment was completed, on average 55 hours after injury. The low-dose GM-1 regimen consisted of an initial 300-mg loading dose followed by 56 days (i.e., 8 weeks) of a 100-mg/day; the high-dose doubled these amounts. Enrollment into the high-dose treatment group was terminated early on.

Follow-up assessments were performed at 1, 2, 4, 6, and 12 months. The study’s pre-defined primary measurement of GM-1 efficacy was the proportion of patients at 6 months with “marked recovery,” defined using various SCI-assessment scales. A secondary efficacy measure included the time course of marked recovery and other established measures of spinal cord function.

Study results were mixed and depended on the time of assessment. For example, although the GM-1-treated group did not have a statistically significant greater number of patients with “marked recovery” at 6 months (i.e., study’s primary efficacy measure), it had statistically significant greater recovery at the end of the two-month dosing period, suggesting that GM-1 accelerates recovery that is obtained. The drug appeared to enhance ASIA motor, light touch, and pinprick scores, as well as bowel function, sacral sensation, and voluntary anal contraction. Finally, GM-1 appeared to exert greater effects on individuals with incomplete injuries.

Although statistical significance was not shown for the pre-defined, primary endpoint, the investigators, nevertheless, believed that GM-1 is “active in SCI, somehow: in some respect, using some regimen, and in some group of patients.” The possibility was suggested that MP and GFM-1 may have antagonistic actions, and, as such, the much higher, NSCIS-2-mandated MP dose administered in the second GM-1 trial may have diminished GM-1’s beneficial effects.  

3) Thyrotropin-Releasing Hormone (TRH) is a three amino-acid peptide (glutamic acid-histidine-proline) produced in the brain’s hypothalamus. In spite of its molecular simplicity, TRH influences diverse biological function through affecting the secretion of a variety of hormones, including thyroid hormone, prolactin, growth hormone, vasopressin, and insulin; and the neurotransmitters noradrenaline and adrenaline.

Experimental studies in a animal models indicate that TRH improves long-term motor recovery after acute, apparently by minimizing some of the biochemical and physiological processes that mediate secondary injury.

In 1995, Dr. Lawrence Pitt and colleagues (California, USA) reported the results of treating 20 acutely injured patients with TRH recruited over a two-year period from 1986–1988 (J Neurotrauma 12(3), 1995). The patients were subdivided into four groups: 1) complete and incomplete injuries and 2) in a double-blind fashion, TRH- or placebo-treated groups. The treatment groups were dosed with 0.2 mg/kg intravenous bolus of TRH followed by an hourly infusion of the same dose for six hours.

Patients were examined at various follow-up periods up using 1) motor and sensory scales in which 0 corresponded to no movement and 5 normal power, and 1 corresponded to no sensation and 3 normal sensation; and 2) a 1-10 Sunnybrook scale in which 1 represented complete motor and sensory loss, and 10 represented normal motor and sensory function.

At the four-months before patient attrition started compromising the study, the TRH-treated group with incomplete injuries demonstrated improved functional recovering using the aforementioned scales. However, no improvement was noted in the TRH-treated group with complete injuries. The investigators emphasize that results must be interpreted with caution due to the small sample size.

Unfortunately, in spite of the pilot-study’s positive results and many promising animal studies, no further work in humans with SCI appears to have been carried out. TRH efforts are now focusing on traumatic brain injury.

4) Gacyclidine: Dr. Alain Privat and colleagues (Montpellier, France) have studied the effectiveness gacyclidine in minimizing neurological damage after acute SCI. Basically, after injury, cells lyse, releasing excitatory amino acids, such as glutamate, which soon reach toxic concentrations. Through interactions with receptors on neighboring cells, excessive glutamate will initiate a neurotoxic biochemical cascade. Animal studies suggest that antagonists that block these receptors will exert a neuroprotective influence by inhibiting this cascade. Gacyclidine is one of these antagonists.

Privat’s study recruited over 200 patients, a relatively large clinical trial for SCI. Most subjects were treated within three hours of injury and once again in the following four hours. Although analysis of the study results indicated no statistically significant difference between the gacyclidine and placebo-treated groups, data suggested that subjects who 1)received the highest drug dose functionally improved, and 2) sustained cervical injuries had the most improvement.

5) Neotrofin®: NeoTherapeutics (Irvine, California) sponsored clinical trials examining the effect of Neotrofin (also called AIT-082 or leteprinim) on several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and SCI. Neotrofin is a purine analog that can be taken orally, and due to its relatively small size, able to cross the blood-brain barrier, a prerequisite for any drug that targets central nervous system (CNS) disorders.

Animal studies indicate Neotrofin reduces neurological damage and improves walking after acute injury in rats (Middlemiss, et al. Soc Neurosci Abstr, 25, 1999). Evidence suggests that Neotrofin stimulates the production of neurotrophic factors, such as nerve growth factor and protects neurons from glutamate-induced cell death (see previous section). Studies in mice indicate that the drug also stimulates the proliferation of CNS stem cells, which given the increasing number of SCI-related stem-cell programs may have important implications.

In 2001, NeoTherapeutics started the recruitment of an intended 30-40 patients with complete SCI one to three weeks after injury (i.e., sub-acute injury phase) at four SCI centers: Thomas Jefferson University (Pennsylvania), Craig Rehabilitation Center (Colorado), Rancho Los Amigo (California), and Gaylord Hospital (Connecticut). Patients orally consumed a twice daily 250-mg dose of Neotrofin for 12 weeks.

Unfortunately, few, if any, study results have been reported. After Neotrofin failed to demonstrate a statistically significant effect in late-stage clinical trials for Alzheimer’s disease, the nearly broke NeoTherapeutics reorganized into Spectrum Pharmaceuticals with an emphasis on cancer drugs.   

6) Minocycline: A broad-spectrum antibiotic in the tetracycline group, minocycline is often used to treat acne and rosacea. Compared to other tetracyclines, minocycline is eliminated more slowly from the body, and, hence, exerts a longer physiological effect.

Studies in animal models of acute SCI indicate that minocycline minimizes the secondary neurological damage that occurs soon after injury. For example, University of Calgary researchers have shown that acutely injured, minocycline-treated mice recover more hind-limb function and strength compared to untreated mice. In addition, minocycline reduced the size of the injury-site lesion and promoted the survival of axons through the injury site (Wells JE, et al, Brain, 126(7), 2003). Harvard University (Teng YD et al, Proc Natl Acad Sci, 101(9), 2004) and South Korean investigators (Lee SM et al, J Neurotrauma, 20(10), 2003) have also demonstrated similar neuroprotective effects in rats.

Minocycline mediates its neuroprotective effects through a number of mechanisms, including minimizing the destructive, post-injury immune response and the release of cytochrome c. Although cytochrome c is a key cell-respiratory protein essential for cell life, when it is released, it initiates a metabolic cascade triggering cell death.

Based on the results of these animal studies, Dr. R. John Hurlbert, Dr. Steven Casha, and colleagues (Canada) have initiated a randomized, double-blind, placebo-controlled, phase-1 and -2 studies evaluating minocycline administered within 12 hours of injury. Sixty subjects with injuries at or above the thoracic T11 level are to be cumulatively recruited. The minocycline will be intravenously administered in twice-daily doses for seven days. Control subjects would receive a saline infusion. The patients will be followed for a two years using a variety of assessments, including ASIA motor and sensory scores, the Quality-of-Life Assessment, and the Functional Independence Measure.

Phase II results were reported in 2012. The study included 27 minocycline-treated patients (22 men and 5 females) and 25 placebo-treated controls. Average age of the minocycline patients was 41, and their injury cause was motor vehicle accidents (14), sport injuries (6), work accidents (5), and falls (2). Sixteen and 11 had cervical and thoracic injuries, respectively. Among other measurements, neurological function was periodically assessed for up to a year using ASIA motor scores. After three months of evaluations, minocycline-treated patients averaged six points more of motor recovery than controls. The effects of minocycline treatment seemed more robust for those with cervical injuries. Specifically, minocycline-treated patients with cervical injuries averaged 14 points more motor recovery than controls, a difference that approached statistical significance. In contrast, those with thoracic injuries accrued minimal benefit. The investigators concluded: “The minocycline regimen established in this study proved feasible, safe, and was associated with a tendency towards improvement across several outcome measures.”

Dr. R. John Hurlbert

Dr. Steven Casha

7) Cethrin® Based on a foundation of research by Dr. Lisa McKerracher et al (Canada), BioAxone/Alseres Pharmaceuticals has initiated clinical trials evaluating Cethrin in patients with acute SCI.   Animal studies indicate that SCI stimulates the production of  Rho, a molecule that inhibits axonal growth and regeneration, and initiates a physiological cascade that results in the death of nearby neuronal cells (a process called apoptosis). Cethrin apparently blocks these adverse effects, restoring regenerative potential and preventing cell death.

The initial clinical trial was designed to test Cethrin’s safety and pharmacokinetics at various dosing regimens, and did not include the control subjects necessary to determine overall effectiveness. The drug was administered an average of 53 hours after injury at the time of spinal-stabilization/decompression surgery, a procedure often done relatively soon after injury. As the surgery is being completed, Cethrin was applied on the membrane covering the spinal cord using a sealant to keep it in place. The drug penetrates through the membrane to the underlying neuronal tissue.

As reported in 2011, 48 subjects were recruited at nine clinical sites in the United States and Canada. Thirty-two had thoracic injuries (mean age 34) and 16 had cervical injuries (mean age 41). All subjects (40 men, 8 women) had ASIA-A complete injuries (most complete on a scale ranging from ASIA-A to ASIA-E representing total recovery). In addition to assessing recovery by this impairment scale, motor-function gains were periodically followed for a year. Of the 48 subjects initially enrolled, 35 completed the study.

Overall, the results suggested that patients with cervical injuries accrued greater benefit from Cethrin treatment. Specifically, although only 6.3% of subjects with thoracic injuries improved two levels to ASIA-C functioning (i.e., some sensory and motor recovery) after one year, 31% of those with cervical injuries did so. In one of the dosing regimens, improvements were especially impressive, with 66% improving to ASIA-C.  Two subjects with cervical injuries and one with a thoracic injury improved three levels to ASIA-D.  For the sake of comparison, historical data suggests that less than 10% of individuals with cervical injuries would spontaneously improve two or more grades.

Using a scale ranging from 0 to 100, motor scores on average improved 18.6 points for subjects with cervical injuries compared with historical data suggesting only a 10-point improvement is likely after a year. Again, one dosing regimen appeared especially effective with a 27-point improvement. In contrast, little motor improvement was noted in subjects with thoracic injuries.

Alseres Pharmaceuticals has indicated their intention to initiate a much larger study, which will recruit 200 subjects with cervical C5-7, ASIA-A complete injuries.

8) Tacrolimus & Minocycline: Although available details are scant, investigators at Riyadh Armed Forces Hospital, Saudi Arabia have initiated a clinical trial assessing the effectiveness of tacrolimus and minocycline in reducing neurological damage after acute SCI. Minocycline is discussed above. Tacrolimus (also called FK506) is an antibiotic originally obtained from soil bacteria. It is primarily used to 1) suppress the immune system to minimize rejection of transplanted organs and 2) topically to treat eczema. Animal studies suggest that it exerts a neuroprotective effect that may be greater than the currently widely used methylprednisolone (Exp Neurol 1998; 154(2); Exp Neurol 1999; 158(2); Exp Neurol 2002; 177(1); & J Neurosci Res 2005; 81(6)). Tacrolimus inhibits calcineurin, an enzyme found in neurons and lymphocytes (white blood cells).  This inhibition apparently prevents lymphocyte activation, in turn attenuating the destructive, post-injury immune process.

9) Lipitor (Atorvastatin): A cholesterol-lowering medicine belonging to the statin-drug group, Lipitor (trade name for atorvastatin) is one of society’s most widely used and profitable drugs. By inhibiting the liver’s enzymatic production of a cholesterol precursor, it lowers cholesterol levels.  Animal and clinical studies suggest that Lipitor or related statins exert a neuroprotective and anti-inflammatory influence for various neurological disorders, including MS, Alzheimer’s disease, stroke, and SCI.

Drs. Avtar and Inderjit Singh and colleagues (South Carolina, USA) have carried out several studies indicating that Lipitor minimizes neurological damage in rats with an experimental contusion injury (i.e., comparable to the sort of injury observed in most humans).  In the first study, rats treated before and after injury with Lipitor recovered more hind-limb function than control animals (J Neurosci Res. 79(3), 2005). 

A more recent study showed that this neuroprotective effect was also observed when the rats were given Lipitor only after injury, a finding, of course, needed if the drug is to have any real-world applicability. Specifically, rats were given oral doses of Lipitor two, four, or six hours after injury followed thereafter by a once daily dose. Compared to controls, Lipitor-treated rats regained considerable recovery in hind-limb function, with the earlier treated rats regaining the most.

Apparently, Lipitor helped preserve the blood-spinal-cord barrier after injury, which, in turn, limited the infusion into the injury site of inflammatory molecules that cause function-compromising secondary damage. Overall, there was more tissue sparing in Lipitor-treated rats, including less 1) degeneration of neuronal axons, 2) degradation of the conduction-promoting, axon-insulating myelin sheath,  3) scar-forming gliosis (the production of a dense complex of neuronal support cells called glia in the injury area), and 4) neuronal cell death through apoptosis (below)

Lipitor also suppresses the injury-induced expression of Rho (see discussion above), a molecule that inhibits axonal growth and regeneration, and initiates a physiological cascade that results in the death of nearby neuronal cells.

Dr. M.A. Dery and colleagues (Canada) have studied Lipitor’s influence on neuronal cell apoptosis and recovery of locomotion in rats with SCI. As discussed elsewhere, apoptosis is a form of secondary cell death in which a programmed sequence of events leads to cell elimination. In this study, rats were injected with either a Lipitor or a saline solution intraperitoneally (i.e., into the body cavity) two hours after injury experimentally produced by contusion, a type of injury similar to that frequently observed in humans with SCI. Four hours post-injury, Lipitor-treated rats had 20% fewer neuronal cells dying through apoptosis compared to controls, and apparently as a consequence, four weeks after injury, they demonstrated greater recovery of locomotion.

10) Erythropoietin (EPO): EPO (Epogen®) is a glycoprotein growth hormone produced by the kidney that stimulates the bone-marrow production of red blood cells. In a feedback fashion, decreases in blood-oxygen levels trigger EPO synthesis, which, in turn, results in the creation of more oxygen-carrying red blood cells. EPO has been primarily used in the treatment of kidney disease, in which EPO production has been compromised, and cancer to ameliorate the side effects of chemotherapy- or radiation-induced anemia. Because of EPO’s ability to promote oxygenation, endurance athletes have used the drug as a blood-doping agent to obtain a competitive advantage.

More recently, it has been shown that EPO is also created by the CNS and exerts a neuroprotective influence for a variety of neurological disorders, including stroke, head injury, and SCI. In the case of SCI in animal models, a number of interacting physiological mechanisms may mediate EPO-influenced neuroprotection: Specifically, EPO

bulletblocks injury-related cell death called apoptosis;
bulletprevents injury-related hypoxia in which limited oxygen reaches the spinal cord;
bulletinhibits the damage caused by excitotoxins, amino acids which, when elevated by injury, damage neighboring neuronal cells;
bulletreduces injury-site inflammation;
bulletrestores post-injury vascular integrity, enhancing blood flow and, in turn, tissue oxygenation;
bulletenhances neuronal regeneration through the stimulation of stem cells to produce new neurons and support cells.

Given EPO’s well-documented neuroprotective effect in injured animals, Italian investigators have initiated a multicenter clinical trial comparing the effectiveness of EPO with methylprednisolone (MP, discussed previously) for treating acute SCI. The study intends to recruit 100 subjects at Italian SCI centers within eight hours of injury and randomize them to receive either MP or EPO. All subjects must have more complete ASIA A-B injuries (i.e., the most neurologically complete injuries; see appendix). Relative improvement will be periodically measured over three months using this ASIA-impairment scale, as well as assessments evaluating neuronal conduction (i.e., electrophysiology), spasticity, pain, and functional autonomy.

11) Anti-Nogo: Since the 1980’s, Dr. Martin Schwab and colleagues (Switzerland) have been investigating factors that inhibit neuronal regeneration after injury and, in turn, the blocking of these factors as a means to promote functional recovery. His research was based on the findings by others, which showed that usually regeneration-reluctant, spinal-cord neurons are able to grow when placed in the peripheral-nervous-system (PNS - nerves outside of the brain and spinal cord). These findings suggested that a CNS environmental factor inhibited neuronal regeneration which did not exist in the PNS. Schwab demonstrated the factor was associated with CNS myelin, the insulating material surrounding neurons. CNS and PNS myelin are dissimilar, generated by different cells called oligodendrocytes and Schwann cells. The CNS oligodendrocyte-derived myelin possesses a protein dubbed Nogo that repels the growth cones of neuronal axons attempting to regenerate. To negate this inhibition, Schwab’s team developed an antibody that complexes with Nogo, hence, neutralizing or blocking Nogo.

As a crude analogy, visualize the Nogo-growth inhibitors as burrs sticking to your clothing unless they are so filled with lint that they fall away. Essentially, the anti-Nogo antibodies represent the molecular lint that preferentially sticks to the Nogo burrs, keeping them from attaching to struggling growth cones. These regenerating cones can now move forward in the spinal cord with less inhibitory drag.

In several SCI animal models, including rats and primates, Schwab and colleagues have shown that anti-Nogo antibodies promote functional recovery. This recovery is apparently due to not only the regeneration of injury-affected neurons but the stimulation of sprouting in neurons bypassing the injury site. Based on these experiments, the Swiss company Novartis in collaboration with Schwab has initiated preliminary clinical trials in humans injured within 10 days of treatment. 

12) Ibuprofen: Even though ibuprofen’s SCI-treatment potential has only been explored in animal models (like Lipitor discussed above), this drug is included in this discussion because its widespread consumption makes it much easier candidate to be considered for SCI applications.  Marketed under many brand names (e.g., Advil, Motrin, etc), ibuprofen is categorized as a non-steroidal anti-inflammatory drug (NSAID – like aspirin). The drug works by inhibiting the production of prostaglandins, which mediate inflammation.

As is the case with both Cethrin and Lipitor summarized before, ibuprofen blocks the injury-triggered production of Rho.  Again, Rho is a protein that inhibits axonal growth and regeneration, and initiates a physiological cascade that ultimately results in the death of nearby neuronal cells (a process called apoptosis).

Dr. Shuxin Li and colleagues (USA) have shown that by blocking Rho, ibuprofen stimulates the growth of not only neurons grown in culture but within the injured spinal cord (31).  Specifically, subcutaneous injection (via mini-pump) of ibuprofen into rats with experimental SCI stimulated considerable axonal sprouting. Compared to untreated control animals, ibuprofen-treated rats regained additional walking ability. The investigators concluded that “ibuprofen promotes a remarkable locomotor functional recovery, even when delivered 1 week after trauma. The axon growth-promoting effect and the common use of ibuprofen in patients raise the high possibility that” it may be an effective SCI treatment.

Dr Stephen Strittmatter et al (USA) confirmed and extended these findings. Specifically, pumps implanted under the skin in rats with an experimental contusion injury delivered ibuprofen for 28 days starting three days after injury. When adjusted for weight, the ibuprofen dosing in these rats was comparable to that consumed by many humans on an ongoing basis. The investigators showed that ibuprofen 1) not only blocks the Rho-regeneration inhibitor discussed above, but also a myelin-associated glycoprotein that hinders neuronal outgrowth; 2) stimulates the sprouting of some, but not all, types of axons; and 3) protects and spares spinal-cord tissue at the injury site. Compared to controls, more ibuprofen-treated rats were able to walk; twice as many were able to support their weight with their hind limbs. This function-restoring effect persisted well after ibuprofen treatment had been discontinued, indicating that it was due to a persistent change in neuronal anatomy or function and not just a transient drug effect.

13) Riluzole: Dr. Robert Grossman (USA) and colleagues at several North American SCI centers have initiated a preliminary clinical trial evaluating the safety and pharmacokinetics (i.e., how a drug is metabolized by the body) of treating 36 patients with SCI with riluzole. Patients with C4-T12 level injuries will be administered 50 milligrams of the drug twice a day for two weeks starting within 12 hours of injury. In addition to the safety and pharmacokinetic focus, a preliminary assessment of functional outcomes will be undertaken for the sake of planning a more comprehensive, phase-II efficacy study.

Riluzole exerts neuroprotection through several mechanisms, including 1) limiting the post-injury influx of damaging sodium ions into neurons by blocking the channels through the membrane by which the ions enter or 2) inhibiting the injury-triggered release of certain excitatory amino-acid neurotransmitters, which at excessive levels are neurotoxic.

Numerous clinical trials have targeted riluzole’s ability to treat a wide-range variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis, schizophrenia, Parkinson’s Disease, Tourette syndrome, depression, etc.

The SCI-focused clinical trial is based on a foundation of promising animal studies, including the following:

1) Dr. J.M. Stutzmann et al. (France) evaluated the effects of 10 days of riluzole treatment in rats with thoracic injuries generated by spinal cord compression. Compared to controls, riluzole-treated rats recovered more function, demonstrated improved nerve conduction through the injury site, and had less tissue damage at the injury site.

2) Dr. Xiaojun Mu and associates (USA) treated rats with a T10-level contusion injury with riluzole, methylprednisolone (MP- discussed above), or a combination of the two. Riluzole was intraperitoneally administered (i.e., into the body cavity) two and four hours after injury and thereafter daily for a week. MP was intravenously administered just two and four hours after injury. Neuroprotective potential was assessed by evaluating 1) recovery of hind-limb function, 2) tissue sparing at the injury site, and 3) the amount of myelinated axons, an indication of functional neurons. Given study constraints, only the combined MP/riluzole treatment was shown to improve hind-limb function and spare injury-site tissue.

3) Drs. Gwen Schwartz and Michael Fehlings (Canada) treated injured rats with intraperitoneal doses of riluzole and several other similar acting drugs. The drugs were administered 15 minutes after an experimental injury produced by clipping the exposed spinal cord at the C7-T1 region. After hindlimb function was evaluated weekly for six weeks, the animals were sacrificed and the degree of tissue sparing anatomically examined. Functional recovery and tissue sparing was significantly enhanced in riluzole-treated animals. The investigators concluded that “Riluzole should be considered an important therapeutic candidate for this form of CNS trauma.”

4) Dr. Ozkan Ates and colleagues (Turkey) treated injured rats with riluzole or other neuroprotective agents.  A single drug dose was intraperitoneally administered immediately after an experimental contusion injury was produced at the T7-10 level. Various scales were used weekly for six weeks to assess motor-function recovery. In addition, anatomical and biochemical assessments of injury site damage were carried out. Compared to saline-dosed controls, riluzole-treated rats 1) recovered more motor function, 2) had smaller injury-site lesions, and 3) had less lipid peroxidation, a biochemical process which mediates secondary neurological damage to the injured cord.

5) Dr. Patrick Kitzman (USA) examined whether riluzole can reduce SCI-generated tail spasticity in rats. The spinal cords of the rats were transected at the sacral S2 level, a type of injury which consistently produces spasticity in tail muscles. The animals were treated for three days with either a saline placebo solution or two different riluzole dosages. Depending upon the dose, riluzole-treated animals had less tail spasticity.

14) Taxol: Originally isolated from the bark of the Pacific Yew tree, Taxol is a drug used to treat a variety of cancers, including lung, ovarian, breast, and head and neck cancers. Animal research indicates it may be also beneficial for SCI. Because of its extensive use as a cancer treatment, much is already known about Taxol’s interactions with the human body. In theory, such understandings should accelerate its consideration as a SCI treatment.

Microtubules: Through stabilizing key structural components within the cell called microtubules, Taxol interferes with the division of cancer cells and, hence, slows tumor growth. Microtubules are, so to speak, the protein “girders” that help create cell infrastructure and, depending upon how these girders are assembled, fate. Basically, Taxol stabilizes this infrastructure by strengthening girder connections with additional rivets in the form of molecular bonds. In the case of cancer, these rivets prevent the cells from assuming the more malleable structure required for cell division and, in turn, tumor growth. As discussed below, with SCI, Taxol stabilizes microtubule structure after injury in a way that increases the regenerative potential of damaged neuronal axons.

Growth Cones vs. Retraction Bulbs: Considerable animal research evaluating Taxol’s regenerative influence on neurons has been carried out by Dr. Frank Bradke and colleagues (Germany and USA). Much of their research has focused on a damaged neuron’s propensity to develop either a growth cone or retraction bulb after injury. Generally, regenerating neurons, especially those in the regeneratively inclined peripheral nervous system (i.e., outside the brain and spinal cord), have a growth cone at their axonal tips. This cone contains an abundance of the physiological machinery and substrates necessary for axonal elongation. In contrast, damaged central-nervous-system neurons usually form non-regenerating swellings called retraction bulbs at the tip of their axonal stumps - essentially the non-growing equivalent of growth cones.

A key difference between growth cones and retraction bulbs involves the degree of microtubule assembly. When assembled in parallel bundles, microtubules are the backbone of axonal shafts with growth cones. They lay the tracks for 1) bringing in needed molecules, cellular structures, and energy supplies to the rapidly advancing growth cone and 2) helping to push the axon forward. In contrast, retraction-bulb microtubules are disorganized; rather than a backbone, it’s more like a “collection of unconnected vertebra” that can’t support growth.

If microtubule structure is experimentally destabilized in a growth cone, it becomes more like a refraction bulb, and, as a consequence, axonal growth stops. On the other hand, Taxol-induced microtubule stabilization reduces retraction-bulb formation after CNS injury. After Taxol treatment, the axonal endings now resemble growth cones and are better able to push through the inhibitory, environmental gauntlet characteristic of the injury-site scar.

Scar Reduction: In an article published in the prestigious Science Magazine, Bradke et al provided evidence that in addition to microtubule stabilization, Taxol reduces scarring after SCI. Specifically, the investigators demonstrated that Taxol treatment reduces the amount of regeneration-inhibiting substances that accumulate at the injury-site scar. As a result, the environmental gauntlet that the axon must pass through to reach its target has been diminished. Specifically, the number of axons making it through increased five fold after Taxol treatment, and, as a result, treated animals with SCI regained 3.4-times more ambulatory ability than controls.