RESEARCH ARTICLE

Recent advances in the pharmacologic treatmentof spinal cord injury

April Cox & Abhay Varma & Naren Banik

Received: 3 February 2014 /Accepted: 10 April 2014# Springer Science+Business Media New York 2014

Abstract A need exists for the effective treatment of individ-uals suffering from spinal cord injury (SCI). Recent advancesin the understanding of the pathophysiological mechanismsoccurring in SCI have resulted in an expansion of new thera-peutic targets. This review summarizes both preclinical andclinical findings investigating the mechanisms and cognatepharmacologic therapeutics targeted to modulate hypoxia,ischemia, excitotoxicity, inflammation, apoptosis, epigeneticalterations, myelin regeneration and scar remodeling.Successful modulation of these targets has been demonstratedin both preclinical and clinical studies with agents such asOxycyte, Minocycline, Riluzole, Premarin, Cethrin, and ATI-355. The translation of these agents into clinical studies high-lights the progress the field has made in the past decade. SCIproves to be a complex condition; the numerous pathophysi-ological mechanisms occurring at varying time points sug-gests that a single agent approach to the treatment of SCI maynot be optimal. As the field continues to mature, the hope isthat the knowledge gained from these studies will be appliedto the development of an effective multi-pronged treatmentstrategy for SCI.

Keywords Spinal cord injury . Neurodegeneration .

Inflammation . Estrogen . Regeneration .Myelin

Introduction

The first known documented case of SCI has been dated to2500 years BCE. During that era, SCI was considered “anailment not to be treated” (Donovan 2007). Tremendous ad-vances have been made in the field since this ancient begin-ning; however, a panacea for spinal cord injury remains elu-sive. Extensive bench research has lead to a better understand-ing of the pathophysiology of SCI, thereby uncovering poten-tial therapeutic targets. Novel therapeutics showing promise inpreclinical models of SCI have been translated into clinicaltrials. In addition to advancements in the pharmacologicaltreatment of spinal cord injury there is now a growing fieldof non-pharmacological interventions such as: stem cell trans-plantation, gene therapy, RNAi, electrical stimulation, etc.However, these topics will not be reviewed herein. This re-view will provide a brief historical overview, followed by asummary of the mechanisms and pharmacological therapeu-tics studied over the past decade; therein a particular emphasisis placed on mechanistic studies highlighting neuroprotectionand regeneration of the spinal cord.

Historical overview

The concept that SCI was an “ailment not to be treated”reflects the long-lasting belief that the catastrophic na-ture of the injury and lack of regenerative capacity ofthe spinal cord made the injury medically futile to treat.Over the course of the last 4,000+ years, treatment forspinal cord injury was centered on surgical interventionsto stabilize and decompress the spine (Donovan 2007).Only in the second half of the 20th century did scien-tists begin using pharmacologic interventions.

A. Cox (*) :N. BanikDepartment of Neurosciences,Medical University of South Carolina,96 Jonathan Lucas ST. MSC606, Charleston, SC 29425, USAe-mail: coxaa@musc.edu

A. VarmaDepartment of Neurosurgery, Medical University of South Carolina,96 Jonathan Lucas ST. MSC606, Charleston, SC 29425, USA

Metab Brain DisDOI 10.1007/s11011-014-9547-y

The first randomized clinical trial investigating a phar-maceutical agent in SCI was initiated in 1979 when theNational Acute Spinal Cord Injury Study I (NASCIS)investigated the efficacy of the synthetic glucocorticoidsteroid methylprednisolone in SCI (Bracken 1992).Glucocorticoid steroids are potent anti-inflammatory andimmunosuppressant drugs, and in the first known publi-cation investigating steroids in spinal cord injury, re-searchers found that treatment with a high dose of glu-cocorticoid steroid (dexamethasone) significantly im-proved the functional recovery in a dog model of SCI(Ducker and Hamit 1969). These preclinical findings,along with findings from many additional studies, weretranslated into this seminal clinical trial in 1979.NASCIS I was followed by two subsequent studies,NASCIS II and NASCIS III, both investigating dosesand timing of methylprednisolone treatment after SCI(Bracken et al. 1984, 1990, 1997). The reported findingsof these trials have led to wide off-label use of methylpred-nisolone in acute SCI. However, these studies have fallenunder intense scrutiny and have not resulted in FDA approvalof methylprednisolone treatment in acute SCI.

The largest randomized clinical trial ever conducted in SCIinvestigated the efficacy of monosialotetrahexosylgangliosidesodium (GM-1), proprietary name Sygen. GM-1 is aganglioside (complex glycolipid predominant in plasmamembrane) that through unknown mechanisms can elicitneuroprotective effects in SCI by promoting neural out-growth, repair and regeneration (Geisler et al. 1991). As

with the NASCIS trials, there is controversy over thepotential effectiveness of this therapeutic. The GM-1study failed to report statistically significant efficacy ina clinical setting (Geisler et al. 2001). Due to lack ofefficacy, the current guidelines published by theAmerican Association of Neurological Surgeons(2013), do not recommend treatment with either corti-costeroids or GM-1 ganglioside.

While progress certainly has been made through clinicaltrials over the last 30 years, the need for effective pharmaco-logical intervention in acute SCI remains. The drug that hasbeen most extensively clinically evaluated, methylpredniso-lone, functions primarily as an immunosuppressant and anti-inflammatory in the setting of acute SCI. Since these earlydays of SCI research and clinical testing, it is now acceptedthat inflammation is only one of many pathophysiologicalmechanisms in SCI. Through the use of animal models, ithas been demonstrated that SCI is marked by a primary injury,that results from the mechanical trauma, followed by a moreinsidious phase referred to as secondary injury (Tator andFehlings 1991). The secondary injury cascade begins withinseconds of the primary injury and results in further tissuedamage, cell death, inflammation, Wallerian degenerationand glial scarring. Considerable progress has been made tounravel the complex molecular signals that drive secondaryinjury. These mechanisms, along with their cognate therapeu-tic approaches, will be discussed in the following three broadcategories: acute, intermediate, and chronic mechanisms ofsecondary injury.

Metab Brain Dis

Acute mechanisms

Hypoxia & ischemia One of the first pathophysiologicalchanges to occur immediately following a traumatic SCI isdisruption of blood flow with resultant hypoxia to the injuredtissue. The mechanical trauma results in disruption of cellmembranes, vasospasm, hemorrhage, and loss of microvascu-lature necessary to supply spinal cord tissue with oxygen andother vital nutrients. The loss of both oxygen and nutrients tothe spinal cord immediately following injury triggers thesubsequent secondary injury with influx of Ca+, calpain andcaspase activation, glutamate excitotoxicity, and inflamma-tion. Hypoxia, therefore, contributes to the expansion of theprimary lesion (Tator and Fehlings 1991; Tator and Koyanagi1997). Pharmacological agents that have the capacity to re-store oxygen and nutrients to the damaged region of the spinalcord have been an area of research interest. One such com-pound that has been studied is Oxycyte (a new generationperfluorocarbon), an oxygen carrier that can be intravenouslyinjected to increase oxygen availability in damaged tissue.Oxycyte treatment in a rat model of moderate-severe contu-sion spinal cord injury significantly increased oxygen satura-tion and reduced apoptotic cell death with better tissue andmyelin preservation, respectively (Yacoub et al. 2013;Schroeder et al. 2008). Additionally, it has been shown in aswine model of decompression sickness Oxycyte treatmentreduced spinal cord lesion size (Mahon et al. 2013). Oxycytemay be suitable as an adjunctive therapy in the treatment ofSCI; Oxycyte treatment ideally should begin at the earliestpossible time point following an acute injury to lessen thedetrimental cascade triggered by hypoxia.

The mechanical trauma from the initial injury will causemassive disruption in both macro and micro vasculature thatwill disrupt blood flow to the spinal cord and result in ische-mia. Numerous studies have reported that ischemia contrib-utes to the subsequent neuronal degeneration and loss ofmotor function in SCI (Anthes et al. 1995; Muradov andHagg 2013; Tator and Koyanagi 1997). Ischemia, unlikeSCI, can be studied as a single entity to provide some enlight-enment about the contribution it plays in the complex networkof mechanisms driving secondary injury. Researchers haveattempted to determine what role ischemia plays in SCI usinga model of focal ischemia in the spinal cord to investigateeffects on axonal degeneration. Focal ischemia alone has beenreported to cause both loss of sensory axons and death ofoligodendrocytes (Muradov et al. 2013); these findings sug-gest that restoration of blood flow should be of utmost impor-tance in the treatment of SCI.

In addition to triggering cell death, ischemic injury alsoactivates microglia, the resident macrophages of the CNS.Inhibition of microglial activation has been shown to elicitneuroprotective effects (Cho et al. 2011). Activation of thetoll-like receptor 4 on microglia may be a potential

mechanism for microglial activation in the setting of ischemicinjury (rodent aortic occlusion model) (Bell et al. 2013). Asresearch continues to further elucidate the exact signalingmechanisms of ischemia that trigger the activation of microg-lia, additional pharmacological targets may be identified.Activated microglia are primary drivers of both innate andadaptive immune response through the release of pro-inflammatory cytokines and chemokines (Schomberg andOlson 2012) and will be discussed in more detail in theinflammation section of this review.

Excitotoxicity Excitotoxicity is a pathological state in whichhigh levels of the excitatory neurotransmitter glutamate resultsin toxicity or death to neurons (Doble 1999). Immediatelyfollowing spinal cord injury, the levels of glutamate can rise toexcitotoxic threshold levels (Liu et al. 1991). Glutamate bindsone of three receptors, N-Methyl D-Aspartate (NMDA),Alpha-amino-3-hydroxy-5-methylisoxazoleproprionate(AMPA) or Kainate; the binding of glutamate will modulateCa+ influx into the cell thereby regulating Ca+ homeostasisand downstream signaling cascades (Mehta et al. 2013).Given the potential critical role the NMDA receptor plays inmediating CA+ influx, it has been an attractive pharmacolog-ical target for many years now. The NMDA receptor antago-nist, MK-801, was reported to attenuate numerous inflamma-tory markers in a mouse model of SCI (Esposito et al. 2011).Although MK-801 cannot be used in SCI patients due totoxicity, an opportunity exists for the development of a safeNMDA receptor antagonist. Riluzole (a sodium channelblocker/glutamate receptor modulator), a drug approved forthe treatment of amyotrophic lateral sclerosis, has been shownin a preclinical rodent study to act as a neuroprotectantthrough modulation of excitotoxicity (Wu et al. 2013;Schwartz and Fehlings 2001; Springer et al. 1997) . A phaseI safety trial of Riluzole in acute cervical spinal cord injurypatients reported a rate of complication with drug use similarto that of matched patients, as well as an enhanced improve-ment in motor score with drug- treated patients compared tomatched patients (Grossman et al. 2013). Follow-up placebocontrolled trials evaluating Riluzole in SCI patients areanticipated.

Downstream effectors of excitotoxicity, such as the activa-tion of intracellular proteases, provide additional targets fortherapeutic intervention. Calpain, a Ca+ activated cysteineprotease, has emerged as a potential target in SCI. The roleof calpain in spinal cord tissue degeneration has beendiscussed in the scientific literature for over 30 years (Baniket al. 1980, 1982). Mechanistally, the role of calpain in spinalcord tissue degeneration has been further elucidated over thepast 10 years. Studies have shown that apoptosis followingSCI requires de novo protein synthesis and can be blockedwith a pharmacological inhibitor of calpain (Ray et al. 2001,2003). Rodent studies have shown an improvement in both

Metab Brain Dis

tissue and motor function recovery after treatment with vari-ous synthetic calpain inhibitors (Akdemir et al. 2008; Yu et al.2008; Sribnick et al. 2007; Arataki et al. 2005). Calpaininhibition by the endogenous inhibitor, calpastatin, has alsobeen shown to be involved in Wallerian degeneration in anoptic nerve transection model (Ma et al. 2013). These findingssuggest that both early and prolonged inhibiton of calpain mayprovide protection against both apoptosis and Wallerian de-generation. Over the years, a number of calpain inhibitorshave been reported (leupeptin, calpeptin, E64D) (Momeniand Kanje 2006; Ray et al. 1999; Tsubokawa et al. 2006);however, difficulties with drug safety and solubility haveprecluded advancement of these compounds into the clinic.Currently, researchers have an intense interest in the develop-ment of a targeted safe therapeutic to inhibit pathologicalcalpain activation.

Melatonin, a naturally occurring hormone, has also beenreported to show beneficial effects in SCI potentially throughmechanisms modulating calpain activation (Samantaray et al.2008). Numerous rodent models of SCI have shown increasedneuroprotection with melatonin treatment (Schiaveto-de-Souza et al. 2013; Park et al. 2010, 2012; Esposito et al.2009; Fujimoto et al. 2000). Melatonin is a pleitropic agent,and thus may exert neuroprotective effects through its anti-oxidant, anti-nitrosative, and immunomodulatory mecha-nisms (Samantaray et al. 2009). The abundance of preclinicalstudies reporting neuroprotection with melatonin treatment aswell as melatonin’s high safety profile make melatonin apotential candidate for clinical trial investigation as either astand-alone agent or as an adjunctive therapeutic in acute SCItreatment.

Intermediate mechanisms

Inflammation The acute mechanisms of hypoxia, ischemiaand excitotoxicity give rise to an inflammatory response thatcontributes to the expansion of the secondary injury. In rodentmodels, activation of resident astrocytes and microglia can beseen as early as 2 h following injury and persist up to 6months(Gwak et al. 2012). Human studies have shown that the firstperipheral immune cell to enter the spinal cord lesion site isthe neutrophil, which arrives as early as 4 h post injury;activated microglia were found at 1 day post injury, andmacrophages were seen by day 5 (Fleming et al. 2006). Inanimal models, blockade of neutrophils has been found todecrease markers of inflammation following SCI (Gris et al.2004; Chatzipanteli et al. 2000). These findings suggest that,mechanistically, neutrophils may contribute to the inflamma-tion seen post SCI.

Significant advances in the understanding of the complexrole of macrophages in SCI have revealed macrophages play

dual roles as both pro- and anti-inflammatory mediators.Results of rodent studies indicate that altering the ratio ofM1/M2 macrophages in favor of the anti-inflammatory M2may promote regenerative growth (Kigerl et al. 2009; Buschet al. 2011) The complexity of macrophage signaling andtherapeutic potential are beyond the scope of the currentreview; however, signaling is detailed in two recent reviewarticles (David and Kroner 2011; Ren and Young 2013).While modulating the types of cells present in the setting ofacute neurotrauma may represent an avenue for therapeuticintervention, another important approach is regulation of cellsignaling.

Inflammation in the central nervous system is thought to beregulated by the nuclear transcription factor, nuclear factorkappaβ (NF-Kβ). Blockade of NF-Kβ, thereby, may be atherapeutic approach for decreasing inflammation. A trans-genic mouse model of SCI, where NF-Kβ is selectivelyinhibited in astrocytes, has been reported to show decreasedinflammation as well as increased axonal sprouting(Brambilla et al. 2005, 2009). Regulation of inflammationvia modulation of gene transcription has also been tested withThiazolidinediones (TZDs), synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ). One such TZD, pioglit-azone, has been tested in a rat model of SCI as a potentialneuroprotectant. Authors reported a significant decrease ininflammatory gene expression with enhanced motor functionrecovery in a rat SCI model were only seen when drugtreatment began within 2 h of injury induction (Park et al.2007). These findings highlight the critical role early inflam-mation may play in SCI.

Apoptosis Loss of cells in the spinal cord following injurymay be attributable to both apoptosis and necrosis. Necrosis,caused by mechanical tissue damage, is considered irrevers-ible. In contrast, apoptosis is regulated through cell signalingand may be triggered by a variety of external or internalstimuli, thereby becoming an attractive candidate for pharma-cological modulation. Cellular stressors triggering release ofpro-apoptotic signaling molecules from the mitochondria andactivation of death receptors are the two broad independentpathways through which apoptosis is triggered (Green 1998).The last 10 years of research into mechanisms of apoptosisspecific to SCI have yielded many promising therapeutictargets. One potential modulator of apoptosis in SCI is cellcycle activation. The cell cycle inhibitor, flavopiridol, wasshown to reduce both neuronal and oligodendrocyte apoptosisin a rat model of severe SCI (Byrnes et al. 2007). Anotherpotential modulator is Phospholipase A2 (PLA2); a lipolyticenzyme thought to contribute to neurodegeneration in second-ary injury, which has recently been implicated in the

Metab Brain Dis

pathogenesis of SCI through its ability to induce neuronaldeath when injected into normal spinal cord tissue (Liu et al.2006). An animal study has shown that PLA2 is upregulatedfollowing injury in vivo and blockade of PLA2 in vitro pro-tects against oligodendrocyte cell death (Titsworth et al.2009).

An additional promising anti-apoptotic therapeutic is theantibiotic Minocycline, which has been shown in numerousanimal models to decrease apoptosis (Sonmez et al. 2013;Watanabe et al. 2012; Takeda et al. 2011; Stirling et al.2004). Treatment withMinocycline has also shown functionalimprovement in a number of preclinical models (Wells et al.2003; Teng et al. 2004). Based on these preclinical studies,Minocycline was evaluated for safety in a placebo controlledphase II clinical trial in acute SCI patients. Authors report thatthe drug regimen was safe and well tolerated and suggestedimproved motor function in patients with cervical injuries(Casha et al. 2012). The positive results of the Minocyclinephase II clinical trial warrant further investigation of drugefficacy in a phase III multi-center placebo controlled trial.

Fast-tracking a drug (with prior FDA approval for analternate indication) is a potentially promising strategy forrapid translation into the treatment of acute SCI. This ap-proach is currently being applied to the development of estro-gen as a potential therapeutic in SCI. The naturally occurringsteroid hormone estrogen has emerged as a potential thera-peutic in the treatment of SCI. Clinically estrogen is deliveredvia the drug Premarin (cocktail of equine conjugated estro-gens) and has been used in hormone replacement therapysince 1942. Estrogen is highly pleitropic, and may serve as aneuroprotectant in part due to its action as an anti-apoptoticalong with its actions as an anti-inflammatory, antioxidant,and as a promoter of angiogenesis. Numerous studies con-ducted in a rat SCI model have shown a reduction in apoptosisand/or improved locomotor function recovery with estrogen(or Premarin) treatment (Siriphorn et al. 2012; Samantarayet al. 2011; Sribnick et al. 2010; Chen et al. 2010). A recentstudy reported that estrogen treatment protected against oligo-dendrocyte cell death mediated via the RhoA-JNK3 pathwayin a rat model of SCI (Lee et al. 2012). Preservation ofoligodendrocytes is key to preventing the Wallerian degener-ation seen in the secondary injury phase of SCI. Estrogen mayalso be exerting neuroprotective effects by modulatingexcitotoxicity. More specifically, estrogen was reported toupregulate expression of the glutamate transporter 1 (glialspecific glutamate transporter) along with the Kir4.1 channel(inwardly rectifying potassium channel) expression in a ratSCI model (Olsen et al. 2010). Since estrogen binds to itscognate receptor and, thus, can regulate expression of 137genes, estrogen may be simultaneously driving neuroprotec-tion through numerous mechanisms (Lin et al. 2004). Given

the highly pleitropic nature of estrogen and the robust preclin-ical findings, estrogen is a promising candidate for continueddevelopment as a therapeutic in SCI. Estrogen therapy, in theform of Premarin, has been clinically evaluated in a smallsafety trial of 5 patients with ASIA A or B grade injuries(Varma, et al. Medical University of South Carolina, resultspending publication). However, estrogen treatment poses sig-nificant safety concerns, as it is known to be a prothromboticagent. Recently, a study using a low dose of estrogen, 1 μg/kg,reported neuroprotective effects (Samantaray et al. 2011),suggesting potential for clinical translation at a safer dose.Another potential answer to this problem is the use of estrogenreceptor modulators such as Genistein. Genistein, an estrogenreceptor beta agonist, has been shown in in vitro models ofneurotoxicity to elicit protective effects (McDowell et al.2011). In vivo studies with estrogen receptor agonists areneeded, as this approach may alleviate safety concerns whilemaintaining the multiple neuroprotective effects seen withestrogen treatment. Pharmacological approaches, such asMinocycline and estrogen treatment, are not the only area ofresearch into preservation of spinal cord tissue. Additionalwork is being conducted to evaluate a centuries old approachto injury recovery, ice.

Hypothermia (both epidural and systemic) has been foundto decrease apoptosis in a rat model of SCI (Ok et al. 2012).Two clinical trials investigating the safety and potential ben-efit of modest hypothermia in acute cervical spinal cord injuryreported promising results for both safety and potential neu-roprotection (Levi et al. 2010; Dididze et al. 2013). As hypo-thermia treatment is posited to potentially provide an earlyadjunctive therapeutic in the treatment of SCI, additionalclinical studies investigating hypothermia are warranted.

Chronic mechanisms

Epigenetic alterations Over the last 10 years, the field ofepigenetics has expanded to include research into the mecha-nisms that may limit the central nervous system’s ability toregenerate. More specifically, researchers have speculated thatthe mature chromatin status of the cells comprising the spinalcord may be blocking these cells from reactivating the devel-opmental programs necessary to successfully rebuild the dam-aged tissue (York et al. 2013). DNA methylation, chromatinstructure, and histone acetylation status are the broad catego-ries of epigenetic modifications that drive changes in geneexpression. Histones, the spool like proteins that DNAwindsaround to achieve the highly condensed state in chromatin,can be modified through acetylation. The acetylation status ofa histone will then drive gene silencing or transcription.Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor,has been found to reduce gliosis and increase production of

Metab Brain Dis

both brain and glial-derived neurotrophic factors in a rodentmodel of SCI (Abdanipour et al. 2012). Another study inrodent SCI has reported that treatment with VPA can decreasegliosis and improve functional outcomes in open-field behav-ioral assays (Lu et al. 2013). The field of epigenetic regulationin both spinal cord injury and, more broadly, inneuroregeneration is arguably still in its infancy. A tremen-dous promise exists in the approach of selectively regulatinggene expression to simultaneously decrease degenerative pro-cesses and increase regenerative processes that will ultimatelydrive restoration of damaged nervous tissue. Hopefully, as thisfield matures an emergence of new therapeutics will providethe tools necessary to achieve these goals.

Blockade of myelin inhibitors Regeneration of axons follow-ing injury is inhibited by a number of molecules, such as NoGo,myelin associated glycoprotein (MAG), and oligodendrocytemyelin glycoprotein (OMgP) (Hunt et al. 2002). The existenceof these inhibitors and their ability to block regeneration havebeen known since the late 1980s (Schwab et al. 1993). Earlypublications in the field of axon regeneration have shown thatblockade of NoGo with the IN-1 antibody promoted regrowthafter injury in animal models (Brosamle et al. 2000; Schnell andSchwab 1990). The exact contribution of these molecules tosuccessful axon regeneration in vivo, however, is not yet clearlydefined, as a recent publication investigating the role of thesethree inhibitors demonstrates. The authors of this publicationdemonstrate using mutant transgenic mouse models that block-ade of all three myelin inhibitors (NoGo, MAG and OMgP)compared to blockade of any single inhibitor failed to showadditive effects (Lee et al. 2010). These authors state that while“MAG, Nogo, and OMgp may modulate axon sprouting, theydo not play a central role in CNS axon regeneration failure”(Lee et al. 2010). Regardless of the exact role each of theseinhibitors may play in spinal cord regeneration, the wealth ofpositive preclinical findings with pharmacological blockadehas resulted in two agents moving into clinical evaluation.The two agents, ATI-355 (humanized anti- Nogo antibody,Novartis) and Cethrin (recombinant protein RHO GTPase an-tagonist, BioAxone BioSciences) are being clinically evaluatedfor their potential to modulate axon regeneration in SCI.Results from the ATI-355 trials have not yet been released,although the trial was registered as complete in November,2013. Results from the phase I/IIa clinical trial reportedCethrin to be safe and tolerable in acute SCI patients, andalso suggested that Cethrin enhanced motor function recovery(Fehlings et al. 2011). Cethrin works by inhibiting the RHOpathway, the final common signaling pathway of the myelininhibitors. To date, Cethrin is the only drug to attain orphandrug status from the FDA 2005 in the treatment of acutecervical and thoracic spinal injuries. The next step in thedevelopment path of Cethrin will be a placebo-controlledefficacy trial.

Myelin regeneration & scar remodeling Progesterone, a nat-urally occurring steroid hormone, has emerged as a potentialtherapeutic in SCI through findings that suggest it may serveas both a neuroprotectant and promyelinating agent. Results ofa study conducted in a rat SCI model indicated that treatmentwith progesterone resulted in sparing of white matter tissuewith concomitant improvement in motor function (Thomaset al. 1999). A mechanistic study examining the effects ofprogesterone in a rat model of SCI reported that progesteronetreatment restored myelin levels and increased the density ofoligodendrocyte progenitor cells, potentially responsible forremyelination (De Nicola et al. 2006). An additional studyreported that progesterone may be working by suppressinggliosis at the early stage of SCI while promoting oligodendro-cyte differentiation and remyelination at the later stages(Labombarda et al. 2011).

Glial scarring and wound cavitation are thought to bemajor inhibitors of spinal cord regeneration. Recently, apan Tgfβ 1/2 antagonist, Decorin, was shown to de-crease wound cavitation and scar tissue mass throughsuppression of inflammatory fibrosis (Ahmed et al.2013). The authors of this study also reported thatDecorin treatment has potential for dissolution of maturescars through induction of matrix metalloproteinaseswith subsequent axonal regeneration. The concept thatexisting scar tissue may be remodeled to drive regener-ation is an exciting one, as it would potentially offer atreatment option to patients chronically living with pa-ralysis due to SCI.

Conclusions

The complex pathophysiological mechanisms driving second-ary injury and regenerative capacity of the spinal cord arebeginning to be unraveled. For a field that has suffered from adearth of clinical trials, SCI research has greatly expandedover the last 10 years, evaluating a number of potential treat-ments: hypothermia, Riluzole, Cethrin, Premarin, ATI-355,and Minocycline to name some. As this review highlights,SCI involves a sequence of pathophysiological changes thatcan bemanipulated tominimize secondary injury and promoteregeneration. In addition to the review presented here there aremany other earlier reviews that pay particular attention to bothtranslation and clinical studies advancing the field of SCI (Tsaiand Tator 2005; Kwon et al. 2010; Hawryluk et al. 2008). Asthe field advances, combination therapeutic strategies utilizingagents aimed at multiple pathological processes occur-ring in acute, intermediate and chronic stages of SCImay be developed. A rational, timed, combination drugtreatment approach may thus prove successful intreating SCI patients and, with that hope, SCI will nolonger be an “ailment not to be treated.”

Metab Brain Dis

Acknowledgments The work cited here was supported in part by theNIH-NINDS, RO1 NS-31622; NS-45967. Additional support by the VAIOBX001262-01, Spinal Cord Injury Research Fund of the State of SouthCarolina, and from the Medical University of South Carolina Departmentof Neurosciences (Neurosurgery).

References

Abdanipour A, Schluesener HJ, Tiraihi T (2012) Effects of valproic acid,a histone deacetylase inhibitor, on improvement of locomotor func-tion in rat spinal cord injury based on epigenetic science. IranBiomed J 16(2):90–100

Ahmed Z, Bansal D, Tizzard K, Surey S, Esmaeili M, Douglas MR,Gonzalez AM, Berry M, Logan A (2013) Decorin blocks scarringand cystic cavitation in acute and induces scar dissolution in chronicspinal cord wounds. Neurobiol Dis. doi:10.1016/j.nbd.2013.12.008

Akdemir O, UcankaleM, Karaoglan A, Barut S, Sagmanligil A, BilguvarK, Cirakoglu B, Sahan E, Colak A (2008) Therapeutic efficacy ofSJA6017, a calpain inhibitor, in rat spinal cord injury. J ClinNeurosci: Off J Neurosurg Soc Australa 15(10):1130–1136. doi:10.1016/j.jocn.2007.08.011

Anthes DL, Theriault E, Tator CH (1995) Characterization of axonalultrastructural pathology following experimental spinal cord com-pression injury. Brain Res 702(1–2):1–16

Arataki S, Tomizawa K,Moriwaki A, Nishida K, Matsushita M, Ozaki T,Kunisada T, Yoshida A, Inoue H, Matsui H (2005) Calpain inhibi-tors prevent neuronal cell death and ameliorate motor disturbancesafter compression-induced spinal cord injury in rats. J Neurotrauma22(3):398–406. doi:10.1089/neu.2005.22.398

Banik NL, Powers JM, Hogan EL (1980) The effects of spinal cordtrauma on myelin. J Neuropathol Exp Neurol 39(3):232–244

Banik NL, Hogan EL, Powers JM, Whetstine LJ (1982) Degradation ofcytoskeletal proteins in experimental spinal cord injury. NeurochemRes 7(12):1465–1475

BellMT, Puskas F, Agoston VA, Cleveland JC Jr, Freeman KA, GamboniF, Herson PS, Meng X, Smith PD,WeyantMJ, Fullerton DA, ReeceTB (2013) Toll-like receptor 4-dependent microglial activation me-diates spinal cord ischemia-reperfusion injury. Circulation 128(11Suppl 1):S152–S156. doi:10.1161/CIRCULATIONAHA.112.000024

Bracken MB (1992) Pharmacological treatment of acute spinal cordinjury: current status and future prospects. Paraplegia 30(2):102–107. doi:10.1038/sc.1992.34

Bracken MB, Collins WF, Freeman DF, Shepard MJ, Wagner FW, SiltenRM, Hellenbrand KG, Ransohoff J, Hunt WE, Perot PL Jr et al(1984) Efficacy of methylprednisolone in acute spinal cord injury.JAMA: J Am Med Assoc 251(1):45–52

Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, BaskinDS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J et al(1990) A randomized, controlled trial of methylprednisolone ornaloxone in the treatment of acute spinal-cord injury. Results ofthe Second National Acute Spinal Cord Injury Study. N Engl J Med322(20):1405–1411. doi:10.1056/NEJM199005173222001

Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF,Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, NockelsRP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F,Wilberger JE, Winn HR, Young W (1997) Administration of meth-ylprednisolone for 24 or 48 h or tirilazad mesylate for 48 h in thetreatment of acute spinal cord injury. Results of the Third NationalAcute Spinal Cord Injury Randomized Controlled Trial. NationalAcute Spinal Cord Injury Study. JAMA: J AmMed Assoc 277(20):1597–1604

Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A,Karmally S, Green EJ, Bethea JR (2005) Inhibition of astroglialnuclear factor kappaB reduces inflammation and improves function-al recovery after spinal cord injury. J ExpMed 202(1):145–156. doi:10.1084/jem.20041918

Brambilla R, Hurtado A, Persaud T, Esham K, Pearse DD, Oudega M,Bethea JR (2009) Transgenic inhibition of astroglial NF-kappa Bleads to increased axonal sparing and sprouting following spinalcord injury. J Neurochem 110(2):765–778. doi:10.1111/j.1471-4159.2009.06190.x

Brosamle C, Huber AB, Fiedler M, Skerra A, Schwab ME (2000)Regeneration of lesioned corticospinal tract fibers in the adult ratinduced by a recombinant, humanized IN-1 antibody fragment. JNeurosci: Off J Soc Neurosci 20(21):8061–8068

Busch SA, Hamilton JA, Horn KP, Cuascut FX, Cutrone R, Lehman N,Deans RJ, Ting AE, Mays RW, Silver J (2011) Multipotent adultprogenitor cells prevent macrophage-mediated axonal dieback andpromote regrowth after spinal cord injury. J Neurosci: Off J SocNeurosci 31(3):944–953. doi:10.1523/JNEUROSCI.3566-10.2011

Byrnes KR, Stoica BA, Fricke S, Di Giovanni S, Faden AI (2007) Cellcycle activation contributes to post-mitotic cell death and secondarydamage after spinal cord injury. Brain: J Neurol 130(Pt 11):2977–2992. doi:10.1093/brain/awm179

Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ(2012) Results of a phase II placebo-controlled randomized trial ofminocycline in acute spinal cord injury. Brain: J Neurol 135(Pt 4):1224–1236. doi:10.1093/brain/aws072

Chatzipanteli K, Yanagawa Y, Marcillo AE, Kraydieh S, Yezierski RP,Dietrich WD (2000) Posttraumatic hypothermia reduces polymor-phonuclear leukocyte accumulation following spinal cord injury inrats. J Neurotrauma 17(4):321–332

Chen SH, Yeh CH, LinMY, Kang CY, Chu CC, Chang FM,Wang JJ (2010)Premarin improves outcomes of spinal cord injury in male rats throughstimulating both angiogenesis and neurogenesis. Crit Care Med 38(10):2043–2051. doi:10.1097/CCM.0b013e3181ef44dc

ChoDC, Cheong JH, YangMS, Hwang SJ, Kim JM,KimCH (2011) Theeffect of minocycline on motor neuron recovery and neuropathicpain in a rat model of spinal cord injury. J Korean Neurosurg Soc49(2):83–91. doi:10.3340/jkns.2011.49.2.83

David S, Kroner A (2011) Repertoire of microglial and macrophageresponses after spinal cord injury. Nat Rev Neurosci 12(7):388–399. doi:10.1038/nrn3053

De Nicola AF, Gonzalez SL, Labombarda F, Deniselle MC, Garay L,Guennoun R, Schumacher M (2006) Progesterone treatment ofspinal cord injury: effects on receptors, neurotrophins, andmyelination. J Molec Neurosci MN 28(1):3–15. doi:10.1385/JMN:30:3:341

Dididze M, Green BA, Dalton Dietrich W, Vanni S, Wang MY, Levi AD(2013) Systemic hypothermia in acute cervical spinal cord injury: acase-controlled study. Spinal Cord 51(5):395–400. doi:10.1038/sc.2012.161

Doble A (1999) The role of excitotoxicity in neurodegenerative disease:implications for therapy. Pharmacol Ther 81(3):163–221

Donovan WH (2007) Donald Munro Lecture. Spinal cord injury–past,present, and future. J Spinal Cord Med 30(2):85–100

Ducker TB, Hamit HF (1969) Experimental treatments of acute spinalcord injury. J Neurosurg 30(6):693–697. doi:10.3171/jns.1969.30.6.0693

Esposito E, Genovese T, Caminiti R, Bramanti P, Meli R, Cuzzocrea S(2009)Melatonin reduces stress-activated/mitogen-activated proteinkinases in spinal cord injury. J Pineal Res 46(1):79–86. doi:10.1111/j.1600-079X.2008.00633.x

Esposito E, Paterniti I, Mazzon E, Genovese T, Galuppo M, Meli R,Bramanti P, Cuzzocrea S (2011)MK801 attenuates secondary injuryin a mouse experimental compression model of spinal cord trauma.BMC Neurosci 12:31. doi:10.1186/1471-2202-12-31

Metab Brain Dis

Fehlings MG, Theodore N, Harrop J, Maurais G, Kuntz C, Shaffrey CI,Kwon BK, Chapman J, Yee A, Tighe A, McKerracher L (2011) Aphase I/IIa clinical trial of a recombinant Rho protein antagonist inacute spinal cord injury. J Neurotrauma 28(5):787–796. doi:10.1089/neu.2011.1765

Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE,Saenz AD, Pasquale-Styles M, Dietrich WD, Weaver LC (2006)The cellular inflammatory response in human spinal cords afterinjury. Brain: J Neurol 129(Pt 12):3249–3269. doi:10.1093/brain/awl296

Fujimoto T, Nakamura T, Ikeda T, Takagi K (2000) Potent protectiveeffects of melatonin on experimental spinal cord injury. Spine 25(7):769–775

Geisler FH, Dorsey FC, ColemanWP (1991) Recovery of motor functionafter spinal-cord injury—a randomized, placebo-controlled trialwith GM-1 ganglioside. N Engl J Med 324(26):1829–1838. doi:10.1056/NEJM199106273242601

Geisler FH, Coleman WP, Grieco G, Poonian D (2001) The Sygenmulticenter acute spinal cord injury study. Spine 26(24 Suppl):S87–S98

Green DR (1998) Apoptotic pathways: the roads to ruin. Cell 94(6):695–698

Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA,Weaver LC (2004) Transient blockade of the CD11d/CD18 integrinreduces secondary damage after spinal cord injury, improving sen-sory, autonomic, and motor function. J Neurosci: Off J Soc Neurosci24(16):4043–4051. doi:10.1523/JNEUROSCI.5343-03.2004

Grossman RG, Fehlings MG, Frankowski RF, Burau KD, Chow DS,Tator C, Teng A, Toups EG, Harrop JS, Aarabi B, Shaffrey CI,JohnsonMM, Harkema SJ, BoakyeM, Guest JD, Wilson JR (2013)A prospective, multicenter, phase i matched-comparison group trialof safety, pharmacokinetics, and preliminary efficacy of riluzole inpatients with traumatic spinal cord injury. J Neurotrauma. doi:10.1089/neu.2013.2969

Gwak YS, Kang J, Unabia GC, Hulsebosch CE (2012) Spatial andtemporal activation of spinal glial cells: role of gliopathy in centralneuropathic pain following spinal cord injury in rats. Exp Neurol234(2):362–372. doi:10.1016/j.expneurol.2011.10.010

Hawryluk GW, Rowland J, Kwon BK, Fehlings MG (2008) Protectionand repair of the injured spinal cord: a review of completed, ongo-ing, and planned clinical trials for acute spinal cord injury.Neurosurg Focus 25(5):E14. doi:10.3171/foc.2008.25.11.e14

Hunt D, Coffin RS, Anderson PN (2002) The Nogo receptor, its ligandsand axonal regeneration in the spinal cord; a review. J Neurocytol31(2):93–120

Joint Section on Disorders of the Spine and Peripheral Nerves of theAmerican Association of Neurological Surgeons and the Congressof Neurological Surgeons (2013) Guideline for the management ofacute cervical and spinal cord injuries. Neurosurgery 72 (supple-ment 2):1–259. http://neurosurgerycns.wordpress.com/2013/02/20/guidelines-for-the-management-of-acute-cervical-spine-and-spinal-cord-injury/. 2013

Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, PopovichPG (2009) Identification of two distinct macrophage subsets withdivergent effects causing either neurotoxicity or regeneration in theinjured mouse spinal cord. J Neurosci: Off J Soc Neurosci 29(43):13435–13444. doi:10.1523/JNEUROSCI.3257-09.2009

Kwon BK, Sekhon LH, Fehlings MG (2010) Emerging repair, regener-ation, and translational research advances for spinal cord injury.Sp ine 35(21 Supp l ) :S263–S270 . do i :10 .1097 /BRS.0b013e3181f3286d

Labombarda F, Gonzalez S, Lima A, Roig P, Guennoun R, SchumacherM, De Nicola AF (2011) Progesterone attenuates astro- andmicrogliosis and enhances oligodendrocyte differentiation followingspinal cord injury. Exp Neurol 231(1):135–146. doi:10.1016/j.expneurol.2011.06.001

Lee JK, Geoffroy CG, Chan AF, Tolentino KE, Crawford MJ, Leal MA,Kang B, Zheng B (2010) Assessing spinal axon regeneration andsprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron66(5):663–670. doi:10.1016/j.neuron.2010.05.002

Lee JY, Choi SY, Oh TH, Yune TY (2012) 17beta-Estradiol inhibitsapoptotic cell death of oligodendrocytes by inhibiting RhoA-JNK3activation after spinal cord injury. Endocrinology 153(8):3815–3827. doi:10.1210/en.2012-1068

Levi AD, Casella G, Green BA, Dietrich WD, Vanni S, Jagid J, WangMY (2010) Clinical outcomes using modest intravascular hypother-mia after acute cervical spinal cord injury. Neurosurgery 66(4):670–677. doi:10.1227/01.NEU.0000367557.77973.5F

Lin CY, Strom A, Vega VB, Kong SL, Yeo AL, Thomsen JS, Chan WC,Doray B, Bangarusamy DK, Ramasamy A, Vergara LA, Tang S,Chong A, Bajic VB, Miller LD, Gustafsson JA, Liu ET (2004)Discovery of estrogen receptor alpha target genes and responseelements in breast tumor cells. Genome Biol 5(9):R66. doi:10.1186/gb-2004-5-9-r66

Liu D, ThangniponW, McAdoo DJ (1991) Excitatory amino acids rise totoxic levels upon impact injury to the rat spinal cord. Brain Res547(2):344–348

Liu NK, Zhang YP, Titsworth WL, Jiang X, Han S, Lu PH, Shields CB,Xu XM (2006) A novel role of phospholipase A2 in mediatingspinal cord secondary injury. Ann Neurol 59(4):606–619. doi:10.1002/ana.20798

LuWH,WangCY, Chen PS,Wang JW, Chuang DM,Yang CS, Tzeng SF(2013) Valproic acid attenuates microgliosis in injured spinal cordand purinergic P2X4 receptor expression in activated microglia. JNeurosci Res 91(5):694–705. doi:10.1002/jnr.23200

MaM, Ferguson TA, Schoch KM, Li J, Qian Y, Shofer FS, Saatman KE,Neumar RW (2013) Calpains mediate axonal cytoskeleton disinte-gration during Wallerian degeneration. Neurobiol Dis 56:34–46.doi:10.1016/j.nbd.2013.03.009

Mahon RT, Auker CR, Bradley SG, Mendelson A, Hall AA (2013) Theemulsified perfluorocarbon Oxycyte improves spinal cord injury ina swine model of decompression sickness. Spinal Cord 51(3):188–192. doi:10.1038/sc.2012.135

McDowell ML, Das A, Smith JA, Varma AK, Ray SK, Banik NL (2011)Neuroprotective effects of genistein in VSC4.1 motoneurons ex-posed to activated microglial cytokines. Neurochem Int 59(2):175–184. doi:10.1016/j.neuint.2011.04.011

Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma PL (2013)Excitotoxicity: bridge to various triggers in neurodegenerative disorders.Eur J Pharmacol 698(1–3):6–18. doi:10.1016/j.ejphar.2012.10.032

Momeni HR, Kanje M (2006) Calpain inhibitors delay injury-inducedapoptosis in adult mouse spinal cord motor neurons. Neuroreport17(8):761–765. doi:10.1097/01.wnr.0000220127.01597.04

Muradov JM, Hagg T (2013) Intravenous infusion of magnesium chlo-ride improves epicenter blood flow during the acute stage ofcontusive spinal cord injury in rats. J Neurotrauma 30(10):840–852. doi:10.1089/neu.2012.2670

Muradov JM, Ewan EE, Hagg T (2013) Dorsal column sensory axonsdegenerate due to impairedmicrovascular perfusion after spinal cordinjury in rats. Exp Neurol 249:59–73. doi:10.1016/j.expneurol.2013.08.009

Ok JH, Kim YH, Ha KY (2012) Neuroprotective effects of hypothermiaafter spinal cord injury in rats: comparative study between epiduralhypothermia and systemic hypothermia. Spine 37(25):E1551–E1559. doi:10.1097/BRS.0b013e31826ff7f1

OlsenML, Campbell SC, McFerrinMB, Floyd CL, Sontheimer H (2010)Spinal cord injury causes a wide-spread, persistent loss of Kir4.1 andglutamate transporter 1: benefit of 17 beta-oestradiol treatment.Brain: J Neurol 133(Pt 4):1013–1025. doi:10.1093/brain/awq049

Park SW, Yi JH, Miranpuri G, Satriotomo I, Bowen K, Resnick DK,Vemuganti R (2007) Thiazolidinedione class of peroxisomeproliferator-activated receptor gamma agonists prevents neuronal

Metab Brain Dis

damage, motor dysfunction, myelin loss, neuropathic pain, andinflammation after spinal cord injury in adult rats. J PharmacolExp Ther 320(3):1002–1012. doi:10.1124/jpet.106.113472

Park K, Lee Y, Park S, Lee S, Hong Y, Kil Lee S (2010) Synergistic effectof melatonin on exercise-induced neuronal reconstruction and func-tional recovery in a spinal cord injury animal model. J Pineal Res48(3):270–281. doi:10.1111/j.1600-079X.2010.00751.x

Park S, Lee SK, Park K, Lee Y, HongY, Lee S, Jeon JC, Kim JH, Lee SR,Chang KT (2012) Beneficial effects of endogenous and exogenousmelatonin on neural reconstruction and functional recovery in ananimal model of spinal cord injury. J Pineal Res 52(1):107–119. doi:10.1111/j.1600-079X.2011.00925.x

Ray SK, Wilford GG, Matzelle DC, Hogan EL, Banik NL (1999)Calpeptin and methylprednisolone inhibit apoptosis in rat spinalcord injury. Ann N YAcad Sci 890:261–269

Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (2001) Celldeath in spinal cord injury (SCI) requires de novo protein synthesis.Calpain inhibitor E-64-d provides neuroprotection in SCI lesion andpenumbra. Ann N YAcad Sci 939:436–449

Ray SK, Hogan EL, Banik NL (2003) Calpain in the pathophysiology ofspinal cord injury: neuroprotection with calpain inhibitors. BrainRes Brain Res Rev 42(2):169–185

Ren Y, Young W (2013) Managing Inflammation after spinal cord injurythrough manipulation of macrophage function. Neural Plast 2013:945034. doi:10.1155/2013/945034

Samantaray S, Sribnick EA, Das A, Knaryan VH, Matzelle DD,Yallapragada AV, Reiter RJ, Ray SK, Banik NL (2008) Melatoninattenuates calpain upregulation, axonal damage and neuronal deathin spinal cord injury in rats. J Pineal Res 44(4):348–357. doi:10.1111/j.1600-079X.2007.00534.x

Samantaray S, Das A, Thakore NP, Matzelle DD, Reiter RJ, Ray SK,Banik NL (2009) Therapeutic potential of melatonin in traumaticcentral nervous system injury. J Pineal Res 47(2):134–142. doi:10.1111/j.1600-079X.2009.00703.x

Samantaray S, Smith JA, Das A, Matzelle DD, Varma AK, Ray SK,Banik NL (2011) Low dose estrogen prevents neuronal degenera-tion andmicroglial reactivity in an acute model of spinal cord injury:effect of dosing, route of administration, and therapy delay.Neurochem Res 36(10):1809–1816. doi:10.1007/s11064-011-0498-y

Schiaveto-de-Souza A, da Silva CA, Defino HL, Del Bel EA (2013)Effect of melatonin on the functional recovery from experimentaltraumatic compression of the spinal cord. Braz J Med Biol Res RevBras Pesquisas Med Biol/Soc Bras Biofis [et al] 46(4):348–358

Schnell L, Schwab ME (1990) Axonal regeneration in the rat spinal cordproduced by an antibody against myelin-associated neurite growthinhibitors. Nature 343(6255):269–272. doi:10.1038/343269a0

Schomberg D, Olson JK (2012) Immune responses of microglia in thespinal cord: contribution to pain states. Exp Neurol 234(2):262–270.doi:10.1016/j.expneurol.2011.12.021

Schroeder JL, Highsmith JM, Young HF, Mathern BE (2008) Reductionof hypoxia by perfluorocarbon emulsion in a traumatic spinal cordinjury model. J Neurosurg Spine 9(2):213–220. doi:10.3171/spi/2008/9/8/213

Schwab ME, Kapfhammer JP, Bandtlow CE (1993) Inhibitors of neuritegrowth. Annu Rev Neurosci 16:565–595. doi:10.1146/annurev.ne.16.030193.003025

Schwartz G, Fehlings MG (2001) Evaluation of the neuroprotectiveeffects of sodium channel blockers after spinal cord injury: im-proved behavioral and neuroanatomical recovery with riluzole. JNeurosurg 94(2 Suppl):245–256

Siriphorn A, DunhamKA, Chompoopong S, Floyd CL (2012) Postinjuryadministration of 17beta-estradiol induces protection in the gray andwhitematter with associated functional recovery after cervical spinalcord injury inmale rats. J CompNeurol 520(12):2630–2646. doi:10.1002/cne.23056

Sonmez E, Kabatas S, Ozen O, Karabay G, Turkoglu S, Ogus E, YilmazC, Caner H, Altinors N (2013) Minocycline treatment inhibits lipidperoxidation, preserves spinal cord ultrastructure, and improvesfunctional outcome after traumatic spinal cord injury in the rat.Spine 38(15):1253–1259. doi:10.1097/BRS.0b013e3182895587

Springer JE, Azbill RD, Kennedy SE, George J, Geddes JW (1997) Rapidcalpain I activation and cytoskeletal protein degradation followingtraumatic spinal cord injury: attenuation with riluzole pretreatment. JNeurochem 69(4):1592–1600

Sribnick EA,Matzelle DD, Banik NL, Ray SK (2007)Direct evidence forcalpain involvement in apoptotic death of neurons in spinal cordinjury in rats and neuroprotection with calpain inhibitor. NeurochemRes 32(12):2210–2216. doi:10.1007/s11064-007-9433-7

Sribnick EA, Samantaray S, Das A, Smith J, Matzelle DD, Ray SK,Banik NL (2010) Postinjury estrogen treatment of chronic spinalcord injury improves locomotor function in rats. J Neurosci Res88(8):1738–1750. doi:10.1002/jnr.22337

Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD,RamerMS, TetzlaffW (2004)Minocycline treatment reduces delayedoligodendrocyte death, attenuates axonal dieback, and improves func-tional outcome after spinal cord injury. J Neurosci: Off J Soc Neurosci24(9):2182–2190. doi:10.1523/jneurosci.5275-03.2004

TakedaM, Kawaguchi M, Kumatoriya T, Horiuchi T, Watanabe K, InoueS, Konishi N, Furuya H (2011) Effects of minocycline on hind-limbmotor function and gray and white matter injury after spinal cordischemia in rats. Spine 36(23):1919–1924. doi:10.1097/BRS.0b013e3181ffda29

Tator CH, Fehlings MG (1991) Review of the secondary injury theory ofacute spinal cord trauma with emphasis on vascular mechanisms. JNeurosurg 75(1):15–26. doi:10.3171/jns.1991.75.1.0015

Tator CH, Koyanagi I (1997) Vascular mechanisms in the pathophysiol-ogy of human spinal cord injury. J Neurosurg 86(3):483–492. doi:10.3171/jns.1997.86.3.0483

Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ,Snyder EY, Eichler ME, Friedlander RM (2004) Minocycline in-hibits contusion-triggered mitochondrial cytochrome c release andmitigates functional deficits after spinal cord injury. Proc Natl AcadSci U S A 101(9):3071–3076. doi:10.1073/pnas.0306239101

Thomas AJ, Nockels RP, Pan HQ, Shaffrey CI, Chopp M (1999)Progesterone is neuroprotective after acute experimental spinal cordtrauma in rats. Spine 24(20):2134–2138

TitsworthWL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, LiuNK, Shao H, Cao QL, Xu XM (2009) Differential expression ofsPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 57(14):1521–1537.doi:10.1002/glia.20867

Tsai EC, Tator CH (2005) Neuroprotection and regeneration strategies forspinal cord repair. Curr Pharm Des 11(10):1211–1222

Tsubokawa T, Solaroglu I, Yatsushige H, Cahill J, Yata K, Zhang JH(2006) Cathepsin and calpain inhibitor E64d attenuates matrixmetalloproteinase-9 activity after focal cerebral ischemia in rats.Stroke J Cereb Circ 37(7):1888–1894. doi:10.1161/01.STR.0000227259.15506.24

Watanabe K, Kawaguchi M, Kitagawa K, Inoue S, Konishi N, Furuya H(2012) Evaluation of the neuroprotective effect of minocycline in arabbit spinal cord ischemia model. J Cardiothorac Vasc Anesth26(6):1034–1038. doi:10.1053/j.jvca.2012.05.003

Wells JE, Hurlbert RJ, Fehlings MG, Yong VW (2003) Neuroprotectionby minocycline facilitates significant recovery from spinal cordinjury in mice. Brain: J Neurol 126(Pt 7):1628–1637. doi:10.1093/brain/awg178

Wu Y, Satkunendrarajah K, Teng Y, Chow DS, Buttigieg J,Fehlings MG (2013) Delayed post-injury administration ofriluzole is neuroprotective in a preclinical rodent model ofcervical spinal cord injury. J Neurotrauma 30(6):441–452.doi:10.1089/neu.2012.2622

Metab Brain Dis

Yacoub A, Hajec MC, Stanger R, Wan W, Young H, Mathern BE(2013) Neuroprotective effects of perflurocarbon (Oxycyte)after contusive spinal cord injury. J Neurotrauma. doi:10.1089/neu.2013.3037

York EM, Petit A, Roskams AJ (2013) Epigenetics of neuralrepair following spinal cord injury. Neurother: J Am Soc

Exp Neuro Ther 10(4):757–770. doi:10.1007/s13311-013-0228-z

Yu CG, Joshi A, Geddes JW (2008) Intraspinal MDL28170 microinjec-tion improves functional and pathological outcome following spinalcord injury. J Neurotrauma 25(7):833–840. doi:10.1089/neu.2007.0490

Metab Brain Dis