Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 5 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - CNS and Neurological Disorders
- Sprache: Englisch
Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology.
The fifth volume of this series features reviews that cover the following topics:
-drug treatment for spinal cord injury
-action tremors
-natural products for Alzheimer’s disease treatment
-non pharmacological approaches towards pain management
-biosensors for detecting neurodegenerative diseases
-NMDA receptor targeting
-alkaloid antidepressants
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Veröffentlichungsjahr: 2017
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Frontiers in Clinical Drug
Research - CNS and
Neurological Disorders
(Volume 5)
Edited by
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
Frontiers in Clinical Drug Research - CNS and Neurological Disorders presents the recent developments for the treatment of central nervous system (CNS) and nerve disorders. The book is a valuable resource for pharmaceutical scientists, postgraduate students and researchers seeking updated and critical information for devising research plans in the field of neurology. The chapters are written by eminent authorities in the field. The contents of this volume represent exciting recent researches on spinal cord injury, essential tremor, alzheimer’s disease, pain management, neurotransmitters and neurodegenerative diseases, NMDA receptors, and plant alkaloids as antidepressants.
I hope that the readers will find these reviews valuable and thought provoking so that they may trigger further research in the quest for the new and novel therapies against CNS disorders.
I am grateful for the efforts made by the editorial personnel, especially Mr. Mahmood Alam (Director Publications), and Mr. Shehzad Naqvi (Senior Manager Publications) at Bentham Science Publishers.
List of Contributors
Drug Treatment for Spinal Cord Injury
Jason H. Oh*,Hiroyuki Yoshihara*Abstract
Spinal cord injury (SCI) is a devastating event that often leads to profound disability. Traditionally, the treatment for such injury consisted of steroids, spinal decompression and stabilization surgery, and physical therapy. Despite all these treatments, however, prognoses for meaningful functional recovery remained grim. Recently, laboratory-based advancements in our understanding of central nervous system injuries at the cellular and molecular levels have ushered in new drug treatment strategies for neuroprotection and regeneration following SCI. Emerging strategies include pharmacotherapy to reduce spinal cord ischemia, cellular excitotoxicity, demyelination, and free radical-mediated peroxidation and ensuing cell death. In this chapter, we review traditional avenues of drug therapy following traumatic SCI including methylprednisolone, naloxone, and monosialotetrahexosyl (GM-1) ganglioside. We also discuss pharmacotherapy options currently under investigation for the treatment of SCI, with attention given to those that are actively under human clinical trials: riluzole, minocycline, Rho protein antagonist, magnesium chloride in polyethylene glycol formulation, granulocyte colony stimulating factor (G-CSF), and fibroblast growth factor (FGF), and lithium. Far more work remains to be done to further characterize the efficacy, safety, and practicability of these pharmaceutical therapies.
EPIDEMIOLOGY
According to the United States National Spinal Cord Injury Center, spinal cord injury (SCI) affects approximately 40 per million people per year in the US,
accounting for an incidence of approximately 12,500 new cases of survivable SCI per year [1]. The total number of people currently living with SCI in the US is estimated to be between 240,000 to 337,000. Traumatic SCI was historically the affliction of young people, with an average age of onset of 29 years old in the 1970s; currently, the average age at injury is 42 years old. There is a strong predilection for male gender, with men accounting for 80% of new SCI cases. Motor vehicle accidents account for a plurality of new cases at 38%. Falls from height account for an additional 30%, and violence (particularly gun violence), sporting accidents, and miscellaneous causes account for the remainder. Slightly more than half of all SCI cases are at the level of the cervical spine, with the remainder of cases distributed between the thoracic, thoracolumbar, and lumbar spine (including the cauda equina and the exiting nerve roots in the lumbar spine). The average lifetime costs directly attributable to SCI have been estimated to be as high as $4.7 million for a young person with tetraplegia; this figure does not account for indirect costs such as lost wages and other productivity [1].
PATHOPHYSIOLOGY
SCI is initiated with a primary phase of injury, characterized by mechanical disruption of axons by an abnormal force from the spinal column, followed by a delayed secondary phase of injury, which is mediated by inflammation, vascular injury, and excitotoxicity [2].
In the primary phase of SCI, the most typical mode of injury is a compressive insult to the spinal cord that can cause shearing, laceration, or traction injury to the axons [3]. Complete cord transection is rare; usually, there are at least some intact (but potentially demyelinated) axons left in continuity at the subpial rim [4]. Since animal models have demonstrated that there is some potential for clinical recovery with the preservation of even as few as 5-10% of the original axons, it is hoped that even a profoundly spine-injured patient may be able to recover some function with timely neuroprotective measures [5].
In the secondary phase of SCI, a constellation of factors including ischemia, inflammation, dysvascularity, excitotoxicity, and oxidative stresses can contribute to ongoing neuronal and glial cell death by a combination of necrosis and apoptosis [2]. In addition to direct and indirect promotion of cell death, these processes affecting the microenvironment of the injured spinal cord may also inhibit local cell regeneration and remyelination [6]. The secondary phase of SCI can be further categorized into subphases that are roughly based upon time elapsed from initial injury: these are the immediate, acute, subacute, intermediate, and chronic stages of SCI. The phases on SCI are summarized below in Table 1.
The immediate phase of SCI occurs within the first two hours of injury and is characterized by neuronal and glial cell death associated with the clinical picture of spinal shock [7, 8]. Cell death is caused by necrosis secondary to mechanical rupture of cell membranes, ischemia, hemorrhage, and subsequent edema [5]. During the immediate phase, the inflammatory cascade is initiated with the upregulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-beta [9]. Furthermore, the levels of extracellular glutamate rise to potentially excitotoxic levels [10]. In general, medical treatment strategies are not effective in addressing the physiological changes associated with the immediate phase of SCI because of the time required to transport a spine-injured patient to a trauma center and make the relevant diagnoses.
The acute phase of SCI follows the immediate phase and continues to about 48 hours post-injury. The acute phase is characterized by cord ischemia [11], which in turn is correlated with acute changes in the permeability of the blood-spinal cord barrier (BSCB). The source of cord ischemia in this critical period is the subject of ongoing research and is likely multifactorial secondary to systemic hypotension in combination with local microvascular disruption and local interstitial edema [12]. Inflammatory cytokines and chemokines released in the immediate and early acute phases are believed to contribute to lability in the permeability of the BSCB [13]. In rat models, BSCB permeability reaches a maximum at about 24 hours post-injury and gradually declines back to pre-injury levels by about 2 weeks post-injury [14]. The porous BSCB allows for the infiltration of neutrophils into the CNS lesion, where they produce cytokines and chemokines as well as matrix metalloproteinases (MMPs), superoxide dismutase, and myeloperoxidase [15]. The neutrophils are followed by monocytes after about 48 hours post-injury. These colonize the lesion and differentiate into macrophages, which in turn produce glutamate, TNF-alpha, IL-1, IL-6, and prostanoids [16]. These inflammatory mediators have both neuroprotective and neurotoxic, proinflammatory effects.
Free radicals play an important role in the acute phase of SCI. The reactive oxygen and nitrogen species that are produced by immune cells, or as a direct byproduct of ischemia and reperfusion injury, have been noted to peak at approximately 12 hours post-injury and remain persistently elevated for one week in animal models [15]. Hall [17] discussed the manner in which free radicals such as peroxynitrite interact with high iron concentrations in the central nervous system (CNS) to induce intracellular lipid peroxidation (LP). LP, in turn, has several deleterious effects that exacerbate SCI: it disrupts cellular ionic homeostasis by contributing to intracellular sodium and calcium ion accumulation, it interferes with mitochondrial function, it enhances glutamate-mediated excitotoxicity, and it impairs microvascular perfusion by inducing damage to microvascular endothelium, enhancing platelet-leukocyte adhesion, and promoting the formation of microemboli. Free radical species are also known to contribute directly to neuronal apoptosis from experimental animal models [18].
Disruption of ionic homeostasis, especially sodium and calcium, propagates cellular losses through positive feedback-loop production of more free radical species, mitochondrial dysfunction, and calpain activation [19]. Ensuing increases in the levels of extracellular glutamate contributes to rising intracellular sodium and calcium ion concentrations via the N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptorsfollowed by intracellular acidosis, cytotoxic edema, and excitotoxic cell death [20].
The cumulative effect of the abovementioned changes during the acute phase of SCI leads to neuronal cell death primarily through cell necrosis, though apoptosis also plays a role [21]. Glial cell death occurs in parallel, though apoptosis tends to take a more dominant role.
The subacute phase of SCI follows the acute phase, lasting from 2 days post-injury to 2 weeks post-injury. This phase is characterized by an initial wave of astrocyte necrosis followed by hypertrophy and repopulation; these astrocytes tend to conglomerate into a large glial scar that forms a biochemical barrier for neuronal regeneration [2, 22]. In addition to its inhibitory mechanical properties, the glial scar produces inhibitory molecules such as chondroitin sulfate proteoglycans that further slow the process of neuronal regeneration [23].
The intermediate phase of SCI follows the subacute phase and lasts for approximately 6 months post-injury. In this time period, the glial scar continues to evolve and produce reactive gliosis. Some axonal sprouting has been observed during the intermediate phase in rat models [24]. More research still needs to be done to establish whether this axonal sprouting can be correlated with clinically meaningful functional recovery.
Finally, the chronic phase of SCI lasts from 6 months post-injury through the remainder of the patient’s life. As the scar becomes fully mature, a cyst can develop within the spinal cord lesion as neuronal cells continue to die by Wallerian degeneration, and the ensuing necrotic and apoptotic debris is resorbed [25]. Like the glial scar, this cyst presents a mechanical barrier to neuronal regeneration [26]. Relatively few medical modalities have been proposed to assist in functional recovery for the chronic phase. Instead, physical rehabilitation measures typically predominate, with an emphasis on preserving and expanding the function of the surviving axons through neuroplasticity.
DRUG THERAPIES
In this section, we discuss individual drug therapies for the treatment of SCI. Drugs with completed human randomized trials (RCTs) are reviewed first, and organized by chronological order from oldest to newest. Drugs without completed human RCTs will be discussed at the end, again in chronological order. Table 2 summarizes those treatments that have completed human RCTs.
Methylprednisolone
Methylprednisolone is a corticosteroid that is administered intravenously in its sodium succinate form (MPSS) (Fig. 1). Its proposed mechanism of neuroprotection is immunomodulatory, reducing the rate of infiltration of immune cells through the BSCB by inhibiting the process of lipid peroxidation (Fig. 2) during the acute phase of injury. It has also been observed to reduce TNF-alpha and nuclear factor kappa B activity [27].
Methylprednisolone is the most widely studied drug therapy for SCI, having been tested in three large, well-designed double-blind, randomized control trials named the National Acute Spinal Cord Injury Studies (I, II, III) [28-30].
NASCIS I sought to establish the role of MPSS as a neuroprotective agent by testing its efficacy in low and high dose protocols for incomplete acute SCI patients who were able to initiate treatment within 48 hours of injury. The drug was administered as either a 100mg or 1000mg loading dose followed by 25mg or 250mg boluses, respectively, administered every 6 hours thereafter for 10 days. Due to ethical concerns at the time of study design, there was no placebo control group. Outcome measures included gross motor function as well as sensibility to pinprick and light touch, and patients were followed for one year post-injury. The results of the study were that there was no significant difference appreciated between treatment groups on the basis of neurological improvement – however, there was a notable increase in the incidence of infectious adverse events in the high-dose subset [28]. Understandably, the results of NASCIS I tempered enthusiasm for MPSS administration and the drug saw considerably less widespread clinical use in the months following its publication.
Fig. (1)) Molecular structure of methylprednisolone. Fig. (2)) Protective effects of inhibition of lipid peroxidation.However, follow-up animal studies performed by Hall et al. [31] subsequently found that even the “high-dose” arm of the NASCIS I study had used steroid concentrations that were well below the required threshold for clinically effective neuroprotection. In response, the NASCIS II trial was designed to compare the effectiveness of truly high-dose MPSS (given as a 30mg/kg bolus followed by a 5.4mg/kg/hr infusion for the following 23 hours] as compared against placebo and the opioid receptor antagonist naloxone [32]. Patients received their initial treatment no more than 12 hours post-injury, and each individual’s time to initial treatment was recorded to further subcategorize the effectiveness of each subset. Initial review of the NASCIS II data revealed that there was no significant difference between treatment arms in the 6-week, 6-month or 1-year outcomes of all trial participants. However, subsequent subgroup analysis revealed a statistically significant improvement in motor and sensory function up to 1 year post-injury in those patients that received MPSS within 8 hours of injury.
With the publication of the NASCIS II 1992 subgroup analysis, high-dose administration of MPSS became the de facto standard of care for SCI patients within 8 hours of their injury in the US. However, there was a substantial number of clinicians who remained skeptical of MPSS treatment, citing the poorly standardized manner of data collection in the NASCIS II trial (particularly the lack of a functional outcome measure] and a suspicion for selection bias considering the retrospective nature of determining clinical relevance in the sub-8-hour administration arm. A follow-up study was conducted in Japan by Otani et al. [33] that confirmed the effectiveness of MPSS if administered within 8 hours of injury; however, this study was also criticized for low sample sizes, a short 6-month follow-up period, and continuing concerns regarding adverse effects of high-dose corticosteroid administration.
Finally, the NASCIS III trial was designed to refute some of the above critiques. The outcome measures were changed to ASIA scores in combination with a functional independence measure (FIM). All patients received a 30mg/kg bolus of MPSS followed by one of three subsequent treatment strategies: 1) MPSS 5.4mg/kg/hr infusion for 24hr; 2) MPSS 5.4mg/kg/hr for 48hr; and 3) tirilazad mesylate (TM, a synthetic glucocorticoid with inhibitory effects on lipid peroxidation with fewer adverse effects than traditional glucocorticoids) at doses of 2.5mg/kg administered every 6hr for 48hr. Analysis of the NASCIS III data revealed that patients who received their initial MPSS bolus within 3 hours of injury benefited from 24hr MPSS administration but did not receive any additional benefit thereafter. Patients who received their initial treatment within 3-8 hours of their injury did show significant improvement with 48hr MPSS administration.
The potential adverse effects of high-dose corticosteroids have been well documented in the medical literature and include infectious sequelae such as wound infections, pneumonia, sepsis, and death, as well as gastrointestinal complications such as peptic ulcer disease and ensuing hemorrhage [34]. In addition, it is unclear whether the anti-inflammatory effects of steroids such as MPSS have deleterious effects on neuronal regeneration and axonal sprouting in the subacute and intermediate phases on injury. It is likely that these delayed harmful effects offset any clinical benefits of MPSS administration, thereby leading to the clinical ineffectiveness of MPSS given more than 8 hours post-injury [3].
The standardized use of MPSS remains a subject of fierce debate among clinicians. Although the NASCIS studies have been the most complete clinical trials to date regarding any drug therapy for SCI, their therapeutic level of evidence is only grade III due to the abovementioned flaws in study design, data presentation, and data analysis. Other studies have since emerged that frankly contest the efficacy of MPSS administration, such as a 2015 study by Evaniew et al. [35] that found no significant benefit from NASCIS-II protocol MPSS administration compared to placebo when matching patients based upon anatomical level and severity of injury. Furthermore, critical reviews concerning the clinical application of MPSS administration have found that there is still ongoing confusion regarding the indications for treatment, as well as instances of overtreatment resulting from fear of litigation [36]. Officially, the American Academy of Neurological Surgeons’ (AANS) current clinical practice guidelines have concluded that there is insufficient evidence to support the use of MPSS as anything other than a treatment option, with a pointed reminder that the evidence of harmful side effects of high-dose MPSS administration has historically been far more consistent than evidence of clinically significant benefit.
Naloxone
The opioid peptide, dynorphin A, is released endogenously in response to traumatic SCI [3]. In addition to providing pain relief, the dynorphins in high concentrations produce a paradoxical hyperalgesia and allodynia. Furthermore, prolonged elevations in dynorphin-derived peptides have been found to be directly neurotoxic, and associated activation of the kappa-type opioid receptor has been noted to reduce blood flow to the spinal cord [37]. Initial animal models investigating the use of the nonselective opioid receptor antagonist naloxone (Fig. 3) for SCI demonstrated improved spinal cord electrophysiology as well as reduced edema, free radical generation, and allodynia with naloxone administration.
Fig. (3)) Molecular structure of naloxone.Naloxone was subsequently used in NASCIS II as an independent treatment arm, administered as an intravenous 5.4 mg/kg bolus followed by 4 mg/kg/hr infusion for 23 hours. Although there was no statistically significant benefit over placebo in primary outcomes, secondary analysis showed that there was significantly increased recovery below the level of injury in patients who had received naloxone within 8 hours of injury [38]. Despite these promising findings, more human research has yet to be performed to assess naloxone’s clinical utilization potential.
Monosialotetrahexosylganglioside
The gangliosides are a group of glycosphingolipids with sialic acid moieties that are found in the membranes of nervous tissue [39]. In vertebrates, gangliosides are found most predominantly in the cellular plasma membrane of central nervous system cells. They are found in varying concentrations depending on the type of nervous tissue (i.e., white matter vs. gray matter) and location (i.e., brain cortex vs. brain stem vs. spinal cord). Although their function is still under investigation, prior basic science studies have demonstrated that exogenous administration of these compounds can promote neurite outgrowth in vitro. In vivo animal studies have shown that ganglioside administration can potentiate neurotrophic effects. The proposed mechanism for the neuroprotective effects of gangliosides is that they may block the formation of nitric oxide and other reactive oxidative species, thereby reducing toxic effects to the injured spinal cord during the acute phase of injury. Human studies have previously been conducted investigating the efficacy of ganglioside administration for the treatment of stroke and peripheral neuropathy, with promising results [40, 41].
In 1991, Geisler et al conducted the Maryland monosialotetrahexosylganglioside (GM-1) Study to determine GM-1’s clinical impact in patients with cervical and thoracic SCI (Fig. 4) [42]. Patients within 72 hours of injury were recruited for the study and given either 100 mg of GM-1 or placebo via daily intravenous administration for 18 to 32 total doses. The subjects were followed for a year with successive Frankel scale and American Spinal Cord Injury Association (ASIA) score assessments. There was a statistically significant increase in clinical improvement in the GM-1 treated patients, with the caveat that significant improvements were only seen in the lower extremities. Based on these findings, it was proposed that GM-1 may improve the survival and function of damaged white matter tracts passing through the level of injury; however, there is no evidence to suggest that GM-1 has any significant impact on the gray matter at the zone of injury. It was noted, with some excitement, that GM-1 demonstrated benefit even when administered 48hr post-injury. Moreover, there were no adverse reactions documented as a result of the drug administration, fueling ongoing interest in further research.
Fig. (4)) Molecular structure of monosialotetrahexosyl (GM-1) ganglioside.The Maryland study was followed by the Sygen GM-1 study: a multi-center, prospective, double-blind randomized and stratified trial that enrolled 797 cervical or thoracic SCI patients in total [43]. All patients were initially managed with MPSS as per the NASCIS II protocol, and then were split into one of three treatment arms: 1) placebo, 2) low dose GM-1 (300mg loading dose followed by 100mg daily for 56 days), or 3) high dose GM-1 (600mg loading dose followed by 200mg daily for 56 days). The outcome measures were the modified Benzel Classification and ASIA motor/sensory scores, with reassessments at 4, 8, 16, 26, and 52 weeks. The primary efficacy assessment of the trial was called “marked recovery” and defined as an improvement in two functional grades by week 26 of the study.
There were several interesting observations noted at the Sygen study’s conclusion. First, the high-dose GM-1 arm was discontinued relatively early in the trial because of markedly higher mortality, thus casting doubt on the previously touted “safety” of GM-1 proposed by the Maryland study. Second, the primary study outcome was ultimately negative: there was no statistically significant difference between study arms in the proportion of patients that achieved marked recovery at the six-month time period. However, secondary subgroup analyses found that patients in both the low-dose and high-dose GM-1 arms demonstrated a more accelerated recovery within the first three months of treatment [43]. Third, the patients included in the placebo arm of the Sygen trial failed to display the same levels of neurological improvement as their equally-treated counterparts in the NASCIS II and III trials, thus calling into question the legitimacy of the NASCIS findings.
As with MPSS, the clinical application of GM-1 remains the subject of some debate. Because the only positive effects of GM-1 in the Sygen study could only be appreciated based on secondary analysis, the current AANS guidelines recognize GM-1 as a treatment option when used in combination with NASCIS II/III protocols; however, there is no recommendation in favor of its routine use [44].
Thyrotropin Releasing Hormone
Thyrotropin releasing hormone (TRH) is a tripeptide best known for its role in regulating thyroid hormone homeostasis via its effects on the pituitary gland (Fig. 5). In addition to this important function, TRH may also protect against secondary neurological injury in SCI. Dumont et al. [45] hypothesized that TRH can provide neuroprotection by antagonizing the effects of endogenous opioids, platelet activating factor, peptidoleukotrienes, and excitatory amino acids. In a rat model of SCI, Hashimoto and Fukuda [46] found that the daily subcutaneous administration of TRH for 7 days, initiated either 24hr or 7 days following injury, resulted in improved neurologic function.
Fig. (5)) Molecular structure of thyrotropin releasing hormone.In 1995, Pitts et al. [47] reported the results of a Phase I/II study of TRH in human SCI in which they had recruited 20 patients with complete or incomplete SCI who were able to receive initial treatment within 12 hours of injury. The subjects in the experimental group received an initial bolus of 0.2mg/kg TRH followed by an infusion of 0.2mg/kg/hr for 6 hours. Saline infusion was administered to the control group. The patients were followed for 4 months and evaluated with NASCIS standard motor/sensory scales as well as the Sunnybrook scale. The patients with incomplete SCI who received TRH treatment had statistically significant improvements in all outcome measures as compared to those in the placebo group. No significant difference in outcomes was appreciated among the complete SCI patients. Criticisms against this study included the small sample sizes and the relatively large amount of variability within the placebo-treated incomplete SCI group. No follow-up human trials of TRH have yet been initiated.
Tirilazad
Tirilazad mesylate (TM) is a type of “lazaroid”, or 21-aminosteroid (Fig. 6): a synthetic glucocorticoid analog that has been proposed to provide neuroprotection in cases of SCI without incurring the harms associated with systemic glucocorticoid receptor activation. Hall [48] proposed three mechanisms of neuroprotection: 1) antioxidation; 2) preservation of endogenous vitamin E; and 3) neuronal cell membrane stabilization via inhibition of iron-dependent lipid peroxidation.
Fig. (6)) Molecular structure of tirilazad.Intermittent IV infusion of tirilazad was one of the treatment arms of NASCIS III following the global loading bolus of 30mg/kg MPSS, and it was found to be as effective as 24hr administration of MPSS [49]. However, since its superiority was never established over a placebo control group, and since it did not demonstrate clinical superiority over MPSS, TM and other lazaroids have not been adopted into clinical practice.
Nimodipine
Continuing on the therapeutic strategy of preventing acute and subacute-phase SCI secondary to calcium ion-mediated excitotoxicity, direct calcium channel blockade has been investigated. In 1989, Fehlings et al. [50] proposed that the L-type calcium channel blocking agent nimodipine may reduce excitotoxicity-mediated cell damage as well as vasospasm-induced local cellular ischemia (Fig. 7). In a rat model of SCI, they found that administration of nimodipine with dextran improved spinal cord blood flow and axonal function. A subsequent baboon study by Pointillart and Petitjean [51] confirmed that nimodipine administration improved neurologic outcomes on the basis of somatosensory evoked potentials as compared to placebo.
Fig. (7)) Molecular structure of nimodipine.In 1996, Pointillart et al. [52] went on to conduct a human study including 106 complete and incomplete SCI patients that were split into four treatment arms: 1) NASCIS II MPSS protocol; 2) nimodipine administered at 0.015mg/kg/hr for 2 hours followed by 0.03mg/kg/hr for 7 days; 3) combination of MPSS and nimodipine as above; and 4) placebo. The study subjects also underwent early decompression and stabilization surgery in addition to their medical treatment. Primary outcomes at one year follow-up were negative – although each treatment group experienced statistically significant improvement from baseline, no benefit was seen from any pharmacological intervention (including “standard” NASCIS II MPSS treatment). These results have been criticized for the relatively low powering of the study, but no further human trials of nimodipine have yet been performed.
Gacyclidine
Following acute spinal cord injury, the sudden rise in intracellular sodium levels via voltage-gated sodium channels triggers the profuse extracellular release of glutamate, an excitatory neurotransmitter [10]. Glutamate activates postsynaptic and NMDA receptors, contributing to Na+ and Ca2+ influx into the postsynaptic cells. Axonal edema and neuronal cell death quickly follow. Glutamate antagonism was initially perceived as a difficult therapeutic strategy since systemic administration of conventional anti-glutamatergic agents such as Selfotel has been complicated by severe cognitive adverse effects, including hallucinations, memory loss, and agitation in prior human stroke and brain injury studies [53].
Interest in direct NMDA antagonism for the treatment of SCI was renewed with the development of the noncompetitive NMDA receptor antagonist, gacyclidine (GK-11, Beaufour-Ipsen Pharma), in the 1990s (Fig. 8). Rodent studies showed that administration of gacyclidine was associated with improved functional, histological, and electrophysiological recovery in rats after spinal cord contusion, and these benefits were realized with significantly fewer adverse effects than with the older, competitive NMDA antagonists [54]. Tadie et al. [55] performed a double-blinded Phase II human randomized control trial on over 200 patients in which the study participants received two bolus injections of either 0.005mg/kg, 0.01mg/kg, or 0.02mg/kg of gacyclidine within 2 hours of injury; these were compared against a placebo group. Although overall recovery at one year was not statistically significant in between groups, there were trends noted toward earlier motor recovery as well as toward better overall recovery in the subset of patients that had suffered incomplete cervical injuries. Despite conjecture that statistical significant might have been achieved with a larger study, no additional human trials on gacyclidine have yet been conducted.
Fig. (8)) Molecular structure of gacyclidine.Lithium
For decades, lithium has been used as a mood-stabilizing agent in the treatment of depression and bipolar disorder. It has also been used against Alzheimer’s disease and Huntington’s disease with good effect. Lithium has many physiologic effects, some of which have been implicated for its role in neuroprotection. Its inhibition of glycogen synthetase kinase-3-beta (GSK3β), an enzyme that activates various nuclear factors including nuclear factor of activated T-cells (NFAT) and Wnt/β-catenin [56]. Furthermore, lithium upregulates neurotrophic factors such as brain-derived neurotrophic factors (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT3) [57]. Lithium also inhibits glutamate-mediated excitotoxicity, upregulates antiapoptotic intracellular genetic regulators such as Bcl-2, and downregulates proapoptotic factors such as p53 and Bax. In a 2007 study, Su et al. [58] found that treatment with lithium improved survival, proliferation, and differentiation of neural progenitor cells that had been implanted into injured rodent spinal cords. It also reduced the rate of microglia and macrophage activation, suggesting that it has an immunomodulatory role as well.
In 2007, Wong et al. performed a Phase I clinical trial of lithium administration on 20 chronic SCI patients [59]. These subjects, all of whom were beyond 12 months of injury, were treated with 6 weeks’ duration of oral lithium carbonate titrated to attain a serum lithium level of 0.6-1.2mmol/L. Although there was a relatively high incidence of minor adverse events (predominantly nausea and vomiting), no severe adverse events were noted. This study was succeeded by a Phase II study by Yang et al. [60], in which 40 chronic SCI patients received the same 6-week duration of oral lithium therapy and were compared against placebo for a 6 month follow-up period. The primary outcome parameters measured in the study included functional outcome measures, neurological classification scales, and visual analog pain scales. There were no significant differences in functional or neurological classification improvement between the experimental and control groups at 6 months; however, there was a significant improvement in pain reduction in the lithium-treated group. Larger scale trials have yet to be performed to assess lithium’s potential for SCI treatment.
Minocycline
Minocycline is a tetracycline antibiotic that has most often been used for the treatment of acne in humans (Fig. 9) [61]. Yong et al. [62] proposed that minocycline may have neuroprotective properties based upon the reduction of excitotoxicity, matrix metalloproteinase inhibition, mitochondrial stabilization, antioxidation, and calcium regulation. Stirling et al. [63] added that minocycline may be particularly well-suited for SCI treatment since it can cross the BSCB with a relatively long half-life, and may have anti-inflammatory properties. In addition, Kobayashi et al. [64] found that minocycline may inhibit harmful gliosis in M1 microglia. In a rodent model of cervical SCI, minocycline treatment reduced apoptosis of astrocytes and microglia, improved microglial density, and retarded the rate of corticospinal tract dieback; these findings were associated with an overall improvement in functional recovery [65]. There have been several proposed mechanisms for minocycline’s inhibition of apoptosis. Teng et al. [66] found that minocycline treatment reduces the rate of cytochrome c release from mitochondria; cytochrome c activates pro-apoptotic caspases. Another mechanism proposed by Yune et al. [67] focuses on p38 mitogen-activated protein kinase (p38MAPK), an enzyme found in microglia that becomes activated via phosphorylation upon spinal cord trauma. The activated p38MAPK forms pro-nerve growth factor (pro-NGF), which in turn promotes oligodendrocyte apoptosis. The researchers found that minocycline administration reduces the phosphorylation of p38MAPK and thereby reduces the downstream rate of oligodendrocyte apoptosis.
Fig. (9)) Molecular structure of minocycline.Minocycline has already been the subject of some human studies relating to its usefulness in other neurological disorders such as stroke, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and schizophrenia [68-71]. These have shown relatively low rates of adverse events, though there have been some instances of drug-induced lupus with prolonged use. Casha et al. [72] executed a Phase I/II randomized control trial involving a total of 52 patients with complete or incomplete cervical or thoracic SCI who received either low dose minocycline, high dose minocycline, or placebo. Subjects in the low dose arm of the study were given the previously published “maximum allowable” dose of minocycline, 200mg every 12 hours, for seven days. The high dose subjects were given an initial bolus of 800mg followed by successive doses tapered by 100mg each 12 hours until 400mg; the 400mg dose was carried through until the end of 7 days. They found that there were no significant adverse events attributable to minocycline at either dosing level, though there was one instance of asymptomatic elevation in liver enzymes in one of the patients in the high-dose arm. Although there was no statistically significant difference in functional recovery after 1 year, secondary analyses suggested a trend toward improved outcomes among the incomplete cervical SCI patients that received minocycline treatment. This trend was not statistically significant, possibly due to inherent lack of power in the initial study design. Phase III research is ongoing.
Magnesium
Magnesium is an NMDA receptor antagonist that can offset the NMDA receptor overstimulation caused by high glutamate levels in acute SCI. By doing so, it can help to prevent the massive intracellular calcium influx that leads to excitotoxic cell damage and death [73]. Consequently, it protects the integrity of the BSCB, reduces lipid peroxidation, and promotes functional recovery. Although the amount of raw magnesium chloride required to attain therapeutic levels in the CNS by systemic administration would be toxic, a polyethylene glycol (PEG)-associated formulation has been developed. In rodent SCI models, the PEG-associated MgCl demonstrated improved neuroprotection and superior motor function recovery as compared to placebo [74].
MgCl-PEG was evaluated in Phase I human trials in 2009 and found to generate no adverse effects [75]. Phase II trials are currently underway.
Fibroblast Growth Factor
Fibroblast growth factors (FGFs) are another agent for SCI treatment. Basic FGF (FGF-2) has previously been shown to increase neural stem cell and progenitor cell proliferation [76] and decrease cell death rates in excitotoxic conditions [77]. FGF-2 also enhances functional recovery in SCI by neuroprotection, stimulation of angiogenesis, and inhibition of cavitation [78]. Furthermore, treatment with FGF-2 appears to reduce BSCB permeability in SCI models, thereby reducing the rates of immune cell infiltration, cytokine production, glial scar formation, and astrogliosis in rodent models [79-81]. FGF also appears to have promise for the treatment of chronic SCI, as rodent models of complete spinal cord transection have demonstrated benefit from FGF directly impregnated alongside peripheral nerve bridge grafts [82].
Wu et al. [83] performed an uncontrolled human clinical trial with acidic FGF (FGF-1, closely related to FGF-2) in which the compound was surgically administered to SCI lesions at an average of 26 months post-injury, with additional FGF-1 spinal injections given 3 months and 6 months post-operatively. Over the 24 month follow-up period, study enrollees demonstrated improved ASIA sensorimotor scores and functional independence measures. No significant adverse events were reported. Although the study suffered from lack of control and possible confounding due to concomitant physical rehabilitation protocols, Phase II research on both FGF-1 and FGF-2 are ongoing.
Rho Protein Antagonist: BA-210
Rho is an intracellular GTPase whose activation of the Rho-associated kinases (ROCKs) leads to actomyosin contraction, growth cone collapse, neurite retraction, and eventual neuronal cell death. Rho is activated by various myelin-associated debris including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate glycoproteins, which are commonly expressed by the glial scar [84]. Several Rho antagonists have been studied for the potential promotion of axonal regeneration and prevention of cell death in SCI (Fig. 10). The most promising of these is C3 transferase (C3), an enzyme derived from Clostridium botulinum. C3 has been studied in animal models of optic nerve injury and SCI, and has been shown to increase long-distance axonal regeneration and improve motor function; it also reduces the rate of cellular apoptosis [85, 86].
Fig. (10)) Role of Rho inhibition in cellular signal transduction for neuroprotection.One of the clinical challenges encountered with C3 is relatively low cellular permeability. To address this, a more-permeable variant of C3 called BA-210 was developed. Epidural administration routes are used to bypass the BSCB [87]. Fehlings et al. [88] executed a multicenter Phase I/II study using BA-210 to treat a total of 48 complete (ASIA A) cervical or thoracic SCI patients. BA-210 was used as an adjunct in combination with decompression surgery performed within 7 days of injury; the compound was impregnated onto a fibrin-mediated delivery system and directly administered onto the dura mater overlying the spinal cord lesion at the time of surgery. The drug was believed to diffuse locally into the spinal cord in a dose-dependent manner, with relatively low rates of release into the systemic circulation. Although this study was relatively small and did not include a control group, the results were promising: over 30% of cervical SCI patients improved to at least an ASIA grade C after 1 year, and there were no major adverse events associated with drug administration. It is important to note that BA-210 is one of the only compounds reviewed in this chapter that relies upon direct surgical administration to achieve therapeutic efficacy. Therefore, its indications and scope of use are currently limited to those spine-injured patients who are indicated for surgical treatment. BA-210 is currently under further investigation with a Phase IIb/III double-blinded, placebo-controlled RCT.
Granulocyte Colony Stimulating Factor
Granulocyte colony stimulating factor (G-CSF) is an endogenously produced glycoprotein named for its roles in the promotion of neutrophil differentiation and the inhibition of neutrophil apoptosis [89]. In addition to these functions, G-CSF also has important neuroregulatory functions. G-CSF is expressed in large quantities on microglia, where it promotes the expression of the phenotype markers Arg 1 and CD206 as well as various neurotrophic factors [90]. Due to its relatively small size (19.6 kDa), G-CSF is able to cross the BSCB under normal physiological conditions [91]. G-CSF also has a neuroprotective role through the inhibition of inflammatory cytokines including TNF-alpha, IL-1-beta, and nuclear factor kappa B. Rodent models have demonstrated that G-CSF can also inhibit neuronal and oligodendrocytic apoptosis, and that it promotes angiogenesis [92].
Takahashi et al. [93] performed a Phase I/IIa human clinical trial in which 16 cervical and thoracic SCI subjects within 48hrs of their injury received daily intravenous injections of either 5 or 10 microg/kg/day for 5 days. The drug was well tolerated at both dosing levels, and significant improvements were seen in ASIA scores in the 10 microg/kg/day group, especially for injuries at the cervical levels. This work was built upon by the same group as 28 more patients were recruited to receive the 5-day regimen of 10 microg/kg/day [94]. All the data were retrospectively compared to the outcomes of 34 similar patients who had received standard-of-care MPSS treatment. Based upon this retrospective analysis, G-CSF appeared to promote improved functional recovery with fewer adverse events as compared to MPSS. However, a prospective randomized control trial to directly compare G-CSF against MPSS has yet to be conducted.
Riluzole
Derangement of sodium ion homeostasis in the zone of SCI is an important mediator of secondary cell death. Increasing concentrations of intracellular sodium are associated with reversal of function of sodium/calcium antiporters, leading to pathologic influx of calcium intracellularly. In order to prevent this toxic progression, Rosenberg et al. [95] initially investigated the use of tetrodotoxin, a voltage-gated sodium channel blocker, in rat models of SCI. They found that there were significantly lower axonal losses with tetrodotoxin administration.
Since tetrodotoxin is extremely toxic, the benzothiazole anticonvulsant sodium channel blocker, riluzole, is currently under investigation for potential use in human models of SCI (Fig. 11). Riluzole has already been Food and Drug Administration (FDA)-approved in the US for the treatment of ALS, and previous animal studies have demonstrated its neuroprotective properties via its modulation of glutamate release by preventing over activation of sodium channels (Fig. 12) [96, 97]. Riluzole is also believed to stimulate neurotrophic factor expression [98]. Other rodent studies with riluzole have demonstrated improved functional recovery, reduced CNS cavitation [99], and increased preservation of white matter, mitochondrial function, and motor neurons as measured by somatosensory-evoked potentials [100].
Fig. (11)) Molecular structure of riluzole.The Riluzole in Spinal Cord Injury Study (RISCIS) is an ongoing multicenter clinical trial designed to test the safety and efficacy of riluzole in humans. The Phase I portion of the study involved 36 subjects and found that there were no serious adverse events associated with the administration of 50mg of riluzole administered every 12 hours for 14 days, with first administration within 12 hours of injury in cervical and thoracic SCI patients. Within the first 90 days of the Phase I trial, there were some improved functional improvements noted especially within the cervical SCI subgroup treated with riluzole [101]. Phases II and III of RISCIS are ongoing.
Fig. (12)) Role of riluzole in reducing glutamate-mediated cellular excitotoxicity.Table 3 below reviews the mechanism of action and most advanced level of human trial for all drugs discussed in this section. They are listed in chronological order based upon date of their first trials in human subjects.
