Open access peer-reviewed chapter

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute and Chronic Spinal Cord Injury

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Elisa Garcia, Roxana Rodríguez-Barrera, Jose Mondragón-Caso, Horacio Carvajal and Antonio Ibarra

Submitted: 15 March 2017 Reviewed: 28 November 2017 Published: 13 June 2018

DOI: 10.5772/intechopen.72781

From the Edited Volume

Essentials of Spinal Cord Injury Medicine

Edited by Yannis Dionyssiotis

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Spinal cord injury (SCI) induces a series of anatomic and physiological disorders which have severe repercussions on neural function. SCI is classified chronologically into an acute (primary and secondary phase) and a chronic phase. The primary phase results directly from the initial trauma and is comprised of disturbances in neural tissue (mainly axons), blood vessels, and spinal shock. Secondary injury results from a series of time-dependent pathophysiological changes, beginning in the first minutes after SCI and lasting days and weeks. This phase is characterized by biochemical and immunological alterations in the injury site and periphery, leading to neuronal over-excitation, apoptosis, and axonal demyelination. In chronic stages, the pathophysiology consists of disturbances in fiber organization, oligodendrocyte apoptosis, fibroglial scar formation, and cyst formation, leading to parenchymal alterations such as syringomyelia and hydromyelia hindering the possibility for functional basal axonal regeneration. This chapter will review a wide range of pharmacological and nonpharmacological therapeutic strategies in preclinical and clinical phases, each targeting different pathological mechanisms of SCI in acute and chronic stages of SCI; taking into account limitations, advances, scope, and new trends. The chapter focuses on the general aspects of SCI pathophysiology, pharmacological and nonpharmacological treatments acute and chronic stages of SCI.


  • spinal cord injury
  • pharmacological strategies
  • nonpharmacological strategies
  • therapeutic
  • acute and chronic

1. Introduction

The spinal cord (SC) has three major functions in human beings: sensibility, autonomous control, and motor control. Destructive mechanisms following SCI can have grave consequences on these functions [1, 2].

Traumatic SCI can originate devastating consequences on patients and those close to them, requiring a great number of lifestyle adjustments. This injury results most commonly from vehicular accidents, falls, and sports injuries, among other traumatic accidents. According to the World Health Organization (WHO), there are approximately between 250,000 and 500,000 cases of SCI per year. Among these, 90% are traumatic in nature with an increased mortality risk within the first year [3].

The pathophysiology of SCI can be divided into primary and secondary damage based on the self-destructive mechanisms following initial injury. These mechanisms can be further divided into three phases according to their temporality: acute, subacute, and chronic phase. The acute phase is characterized by ionic changes, which interrupt nerve impulses and lead to edema; the subacute phase involves a series of events including ischemia, vasospasm, thrombosis, inflammatory response, free radicals (FR) production, lipid peroxidation (LP), and the activation of autoimmune responses resulting in apoptosis. In the chronic phase, all the auto destructive mechanisms generated during the acute and subacute phase increase and demyelination processes are triggered, alongside the formation of a glial scar, which hinders axonal regeneration [4, 5, 6].

The objective of this chapter is to review a wide range of pharmacological and nonpharmacological therapeutic options, each targeting different pathological mechanisms in the different time phases of SCI.


2. SCI pathophysiology

2.1. Acute and subacute phases

Primary damage occurs mechanically at the moment of injury, leading to irreversible sequelae. There are three main mechanisms of injury:

  1. Contusion in the SC without visible loss of its morphology producing a necrotic zone at the impact site, which mainly affects the dorsal region of the SC.

  2. Laceration or transection, which results from the penetration of the SC or extreme trauma, and affects SC conduction depending on whether the tissue is partly or completely transacted.

  3. Compression caused by fractures in the vertebral column, which limit irrigation and can occur without injuring the surrounding ligaments, resulting in ischemic damage in the area where the blood flow was interrupted [3, 5, 6].

Mechanical trauma initially tends to damage primarily gray central matter with a relative preservation of peripheral white matter. Irreversible damage to the gray matter occurs during the first hour after injury, with the same happening to white matter within the first 72 hours [5]. As a result of the mechanical injury, superficial vessels undergo vasospasm, originating an intraparenchymal hemorrhage, which damages the microvasculature of the gray matter [7]. This in turn leads to the decreased perfusion and local infarcts due to hypoxia and ischemia, depending on the severity of the lesion. Furthermore, these can be aggravated by neurogenic or hemorrhagic shock, arterial hypotension, bradycardia, arrhythmias, and intraparenchymal hemorrhage. Therefore, the damage initiated by mechanical trauma has a maximum extension from the third to fifth day after injury, extending from the rostral and caudal segments to the epicenter of the lesion, and affecting both gray and white matter. The main consequence of hemorrhage is neuronal death by necrosis, which is observed primarily in the gray matter [7, 8, 9].

The primary lesion causes the rupture of the blood brain barrier (BBB) at the injury site, leading to a focal destruction of neural tissue, which destabilizes neural and endothelial membranes [10]. This phenomenon results in the death of neurons in the hours following SCI, and is associated with edema, negatively impacting blood flow to the SC, thus extending the inflammatory response [11]. Therefore, primary injury gives rise to the cellular and molecular processes characteristic of the secondary injury stage, which promotes neuronal death and alter genetic expression patterns [12].

Autodestructive mechanisms triggered after SCI can persist with time, and thus be found in acute, subacute, or chronic phases. The acute and subacute phases are characterized by the following mechanisms:

2.1.1. Ionic deregulation

The first secondary mechanism appearing after SCI, ionic deregulation results from an increase intracellular Na+ and Ca2+ concentration and a decrease of K+ and Mg2+ ions. This results in the depolarization of neuronal membranes, decreased number of ionic channels, and increased transportation of water molecules associated with Na+ and Ca2+ ions, leading to edema [13].

2.1.2. Edema

Vasogenic edema initially appears as a consequence of the BBB rupture, and is further propagated by the loss of ionic regulation, giving way to water accumulation in extracellular spaces. Water accumulation is strongly related to the intensity of the initial trauma [14]. The presence of edema in any part of the CNS results in the compression of adjacent tissue, which leads to ischemia and promotes the development of other self-destructive mechanisms, such as the release of FR, LP, and inflammation [1, 14].

2.1.3. Excessive release of intracellular calcium

Once the lesion occurs, partial or total loss of the cellular membrane in neurons and axons is triggered, resulting in the depolarization due to the entrance of high concentrations of Ca2+ [13]. The resulting ionic unbalance and edema contribute to the massive entry of Ca2+, which is intrinsically related to neurotoxicity by the exaggerated release of glutamate and the activation of proteases and phospholipases. This activation triggers the destruction of neurofilaments and the destabilization of key proteins for cellular support, favoring axonal collapse, and fragmentation in the first hours or days post-trauma [15]. In addition to phospholipase activation, the increase in Ca2+ contributes to the production of pro-inflammatory molecules, such as arachidonic acid, leukotriene, and thromboxane due to the release of fatty acids from membrane phospholipids [4]. Likewise, intracellular mobilization of cytosolic Ca2+ generates reactive oxygen species (ROS), energetic failure, cytoskeletal damage, and errors in protein folding [16].

The sudden entry of intracellular Ca2+ likewise leads to the aforementioned glutamate excitotoxicity. These mechanisms conjointly contribute to immediate cell death or the activation of calcium-dependent signaling pathways, which result in cellular death [15, 17].

2.1.4. Glutamate excitotoxicity

SCI affects the regular equilibrium of glutamate and aspartate in the CNS, leading to significant alterations. Fifteen minutes after SCI, glutamate concentration increases to concentrations six times higher than physiological levels [18]. This increase is due to the overstimulation of ionotropic glutamate receptors (GluRs), provoked by the massive entry of Ca2+ and Na+. This ion flow can induce a secondary increase of intracellular Ca2+, leading to an overstimulation of viable neurons and neuronal death. This toxic effect, known as excitotoxicity [19], leads to neuronal and oligodendrocytic death [18, 20].

This phenomenon is mainly evidenced in glial cells, with axonal-myelinating oligodendrocytes showing greater susceptibility. Excitotoxicity signals are regulated by 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate type GluRs; their overactivation facilitates oligodendrocyte death and consequent demyelination after SCI [21].

2.1.5. FR production

Microvascular disruption, ionic deregulation, glutamate increase, mitochondrial dysfunction, and the activation of inflammatory mechanisms stimulate the formation of FR [4, 6, 22]. The cascade of FR production begins with intracellular Ca2+ elevation and the production of uncoupled electrons, which bind to O2 molecules, transforming them into superoxide radicals (O2) capable of increasing oxidative damage by promoting further FR formation [23].

Damage induced by FR, denominated oxidative stress or nitrosative stress, occurs when excessive amounts of ROS and reactive nitrogen species (RNS) are produced, along with low levels of antioxidant defenses. FR production following SCI can damage cellular lipids, proteins, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA), causing mutations or irreversible damage, which leads to cellular death [24]. Moreover, peroxidase (Prx) 1/6 and manganese superoxide dismutase (MnSOD) are modified by phosphorylation, oxidation, or nitration during oxidative stress after injury, inhibiting their antioxidant functions [25].

2.1.6. Lipid peroxidation

One of the most important pathophysiological mechanisms derived from FR production is LP. ROS such as hydroxyl radicals (OH) and O2, combine with nitric oxide (NO) to form the superoxidant agent peroxynitrite (ONOO). These reactants, in turn, can protonate at a physiological pH level, forming peroxynitrous acid (ONOOH) [23, 26].

At a physiological pH, ONOO reacts with polyunsaturated fatty acids (PUFAs), taking one electron to form a lipid radical (L•) that interacts with molecular oxygen to form peroxyl lipid radicals (LOO•). Without regulatory mechanisms, LP will result in membrane depolarization and ensuing demyelination in the SC [26, 27]. Substantial damage induced by FR involves an oxidative attack to the cellular membrane, which is made of PUFAs (arachidonic acid, linoleic acid, eicosapentaenoic acid, or docosahexaenoic acid) [28, 29]. Two aldehydic products arise from LP: 4-hidroxynonenal (4-HNE) y 2-propenal (acrolein). These molecules have been characterized in SCI models, forming covalent bonds with basic amino acids found in cellular proteins, and thus altering their structure and functional properties [28].

Likewise, the inflammatory response is partially responsible for FR production after SCI due to its stimulation of NO production. This molecule is produced by different cellular types after SCI and is capable of damaging medullar parenchyma when produced by inducible nitric oxide synthase (iNOS) [29]. High concentrations of NO, which are mainly produced by iNOS, require an immunological/inflammatory stimulus, such as inflammatory cytokines (IL-6, IL-1, and IFN-γ), resulting in nanomolar quantities produced for prolonged time periods [30, 31].

After SCI, high concentrations of NO (produced by iNOS) and peroxynitrite increase up to three or five times, reaching their peak 12 hours after injury [32]. Some studies have detected iNOS activity 3, 4, 24, and 72 hours following SCI, vinculating its presence to LP, and neural destruction [31, 32, 33]. High concentrations of NO simultaneously participate in cellular damage and increase vascular permeability. Consequently, NO contributes to the formation of edema, as well as excitotoxicity through the release of high concentrations of Ca2+ and glutamate. Furthermore, NO alters the electron transport chain in the mitochondria, generating further FR by affecting enzymes with a sulfuric catalytic center, such as ubiquinone succinate [34]. In addition, iNOS expression and production of NO have a retroactive effect on the development of the inflammatory response, due to their role in the production of cyclooxygenase 2 (COX)-2, which increases the levels of inflammatory products such as prostaglandins and thromboxane [34, 35].

2.1.7. Inflammatory response

Immediately after the traumatic rupture of the BBB, an inflammatory reaction takes place. This reaction involves the actions of chemical mediators and the participation of inflammatory cells, derived from the activation of resident immunological cells (astrocytes and microglia) and recruitment of peripheral cells (macrophages, lymphocytes, etc.) [8, 36].

The production and release of pro-inflammatory cytokines and chemokines are some of the first inflammatory events triggered after SCI. Cytokines such as IL1, IL6, and tumor necrosis factor-alpha (TNFα) are known as mediators of the peripheral inflammatory response, and are synthesized and released by various cells in the CNS. TNFα promotes the immediate recruitment of neutrophils to the damaged site by inducing the expression of molecules, such as endothelial cell intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). It also stimulates the release of IL8, an important neutrophil chemotactic factor, which modifies endothelial cells permeability and consequently affects the BBB. Furthermore, TNFα also stimulates astrocyte proliferation and hypertrophy, promoting the formation of a glial scar that acts as a barrier against possible regeneration [37, 38].

During the inflammatory response, the infiltration of immunological cells is the principal contributor to neuronal degeneration. These cells are guided from the periphery to the injury site by chemokines and cytokines released by microglia cells and astrocytes, which conjointly with peripheral macrophages constitute the main components of the injury [10, 39]. These events begin with the acute inflammatory response and persist in the chronic phase, characterized by a constant migration of cells (neutrophils, macrophages, lymphocytes, basophils, and eosinophils) from the periphery. This leads to the increased levels of inflammatory cytokines and extended damage, as well as the increase in neural destruction, which hinder the possibility of reparation and tissue regeneration [40, 41].

After injury, two infiltration waves have been described. The first wave, constituted by polymorphonuclear cells (PMN), predominates during the first few hours following injury. Neutrophils appear in the vein and venule walls surrounding the injury within the first 4 hours and have been observed from 8 to 24 hours post-trauma. The inflammatory response is reflected by increased number of leukocytes in the cerebrospinal fluid (CSF), infiltration by PMN, an increase in leukotriene levels (mainly LTB4), and myeloperoxidase activity [41]. The second infiltration is characterized by the presence of macrophages, which are observed in the first 2 days, reaching peak levels at day 5–7. After 2 days, proliferation and recruitment of macrophages and microglia occurs, alongside leukocyte infiltration from the third to seventh day. All of these alterations and phenomena that occur in a molecular environment promote gradual tissue degeneration, destroying the necessary anatomic substrate for neurological recovery [40].

Macrophage and monocyte infiltration after SCI aims to remove cellular debris and stimulate the infiltration of new blood vessels and parenchymal cells. The infiltration of these cells helps T-cell interaction, regulating their activation and proliferation through their role as antigen-presenting cells (APC) [42]. The microglia are pluripotent resident cells capable of expressing different phenotypes. The intensity of inflammatory response varies according to lesion severity, affecting cell recruitment and the magnitude of the immune response at the site of injury. Regulation of the inflammatory response occurs due to the interaction of the microglia with T cells, leading to their activation against specific antigens, and thus regulating the immunological response and subsequent phases [43].

Microglia cells are distributed across the CNS, serving as pathological sensors, which react to harmful stimuli [44]. The activated microglia migrate to the pathogen-invaded injury site and transform from the resting phenotype (ramified cells) into amoeboid cells (phagocytic) [45]. Activated microglia can release a series of cytokines, chemokines, and enzymes, depending on the activation stimulus, including: IL1-β, IL-6, TNFα, transformation growth factor-β1 (TGF-β1), macrophage-colony stimulating factors (M-CSF) [46]; iNOS, neural growth factor (NGF), neurotrophin-3 (NT-3) and brain neuronal derived factor (BNDF) [43, 47].

Lymphocytes are cells that modulate the intensity of the inflammatory response. Their participation following SCI has also been related to neural tissue damage due to their production of pro-inflammatory cytokines, such as IFNγ and IL1β [43, 48]. IFNγ is directly related to neuronal destruction, inducing the expression of further pro-inflammatory cytokines (TNFα, IL6, IL12, and IL1β) and pro-inflammatory molecules (ROS and iNOs) through induction of nuclear factor kappa B (NFkB) and activator protein-1 (AP-1) signaling pathways [11, 43, 49].

After SCI, a self-reactive/autoreactive response, defined as an immune response against autologous constituents, is triggered within the CNS [50, 51, 52]. This response targets neural constituents, such as myelin basic protein (MBP), promoting an increase in the expansion of neurological damage at the injury site. This response is capable of increasing the damage to the nerve tissue, but is also able to promote protection and even restoration of damaged tissue [48, 52, 53, 54, 55].

2.2. Chronic phase

In chronic stages of SCI, the formation of a barrier occurs, precluding axonal regeneration in the area surrounding the lesion. This barrier consists of two main components: glial (astrocytes) and fibrotic elements that synthesize inhibitory molecules, hindering interconnection and axonal regeneration [56]. It has been observed that the cicatrization process restores the vital function of the blood–brain-barrier and limits the resulting damage at the injury site. However, in addition to having beneficial effects, this process also prevents restoration [57].

During this phase, some disturbances regarding the organization of fibers are observed, such as demyelination, Wallerian degeneration, oligodendrocyte apoptosis, and the formation of a scar of collagen fibers [56, 58, 59]. In this phase, a strong, nonregulated interaction between the CNS and the immune system takes place, which includes the vegetative innervations to the lymphatic and endocrine tissue that aggravate the degeneration process of major functions [57].

The glial scar around the injury is formed by a wide net of fibrous astrocytes and collagen fibers, which release proteoglycans and neurofilaments, such as vimentin and nestin, which act as inhibitory molecules of neural growth [59, 60]. Therefore, the fibrous scar developed after an injury in the CNS is considered a hindrance for axonal regeneration [59]. Although traditionally astrocytes have been considered to be detrimental to regeneration, they possess beneficial effects when presented in their reactive form at the glial scar, including BBB repair and modulation of the immune response [61].

Astrocytes present a gradual response to the lesion, including changes in gene expression, hypertrophy, extension of the process, and in some cases cellular division [62, 63]. The currently known factors responsible for increasing the formation of glial scars in SCI are transforming growth factor β (TGF-β) [64] and INF-γ, among others [62].

Reactive astrogliosis, defined as an atypical increase of astrocytes, is characteristic of astrocytes surrounding the lesion. This phenomenon presents with a rapid synthesis of intermediate filaments, such as glial fibrillary acidic protein (GFAP), vimentin and nestin. Moreover, there is an excessive secretion of extracellular matrix (ECM) components, such as tenascins, type IV collagen, and chondroitin sulphate proteoglycans (CSPGs), which form a glial scar at the injury site. This scar develops into a fibrous barrier, preventing regeneration of nervous connections adjacent to the lesion. Furthermore, the reactive astrocytes contribute to the release of pro-inflammatory cytokines, such as TNF-α, INF-γ, IL-1β, and IL-6, which inhibit differentiation processes of neural stem cells (NSC) [65], and contribute to the chronic inflammatory response [62].

In addition, the formation of a glial scar favors cavitation, a process detrimental to regeneration at the injury site. This phenomenon can lead to the extension of the injury size days or even weeks after the lesion, resulting in the formation of an encapsulated scar, which prevents neuronal connection [66, 67].

At the chronic stage, the central canal is frequently involved in fluid-filled cyst development, which gives rise to malformations in the SC parenchyma; this condition is known as syringomyelia [68]. This term, first introduced by Ollivier D’Angers in 1827, derives from the Greek word for tube (syrinx) and is used to describe dilation of the central canal extending over many segments. Before trauma, CSF normally flows into the inner parts of the brain and SC. However, SCI evokes morphological changes, which disrupt correct circulation enhancing the volumetric growth of cavities. Syringomyelia appears to be related to irregular pressure conditions and hydrodynamic mechanisms related to the CSF [68, 69].

Hydromyelia, a closely related term that is often used interchangeably, also refers to a dilatation of the central canal by CSF. Some have defined hydromyelia as a congenital dilatation [70] of the central canal, which is partially lined with ependymal cells, strongly associated with hydrocephalus, an obstruction of the foramina of Luschka and Magendie [71]. The term syringomyelia has been affixed to every kind of intramedullary cyst, with some authors defining it as a cavity distinct from the central canal and lined by ependymal cells or primarily glial cells [71, 72]. However, others restrict its use to certain subtypes of cystic lesions and distinguish syringomyelia, hydromyelia, or myelomalacia as separate entities. In spite of this, some authors combine these terms into syringohydromyelia or hydrosyringomyelia [71]. Lee et al. stated that a clear communication between intramedullary cavities and the ventricular system is rarely demonstrated, making it difficult to differentiate syringomyelia from hydromyelia, although a truly eccentric location within the spinal cord may be more characteristic of syringomyelia than of hydromyelia [73]. Batzdorf states that the distinction between syringomyelia and hydromyelia is no longer considered absolute or critical [72].


3. Therapy after acute SCI

In recent years, neuroprotective or neuroregenerative strategies regarding the injury site have been chosen to mitigate autodestructive events following a SCI. These strategies include: preservation or regeneration of damaged neural tissue, neutralization of toxic mediators, and increasing tissue resistance to toxicity [74].

Although there is a substantial evidence showing new preclinical strategies that aim to promote neuroprotection, achieved with certain efficiency in murine SCI models [75], there are few clinically approved treatments available to patients with SCI. Currently, clinical treatments are limited to surgical decompression, blood pressure control, and the possible use of methylprednisolone (MP), which is not recommended due to its secondary effects [76].

However, for each treatment strategy, it is important to consider the time elapsed between the injury and the initial treatments, in order to promote a beneficial effect by inhibiting or diminishing secondary damage as rapidly as possible. Despite the promising results shown by several treatments, there is currently no therapy that satisfies all the requirements necessary for an optimal recovery [77].

3.1. Pharmacological therapies

During the last 25 years, different preclinical and clinical studies evaluating neuroprotection in SCI have been conducted. As previously mentioned, careful consideration of the time frame for treatment after SCI is essential when selecting a therapeutic option. At the clinical level, conventional norms have recommended initiating treatment within the first 3 hours following injury. However, some preclinical studies have begun treatment administration within the first hour after lesion, which complicates the clinical application of these therapies [75]. Diverse drugs have been used in preclinical and clinical studies, with each having different effects depending of the therapeutic objective. However, the majority of drugs studied as possible neuroprotective agents focus solely on one type of damage, with some being tailored to specific mechanisms of the primary injury. The vast majority of these have consisted of pharmacological treatments, although many preclinical studies have included additional therapeutic strategies for acute and chronic SCI. Current pharmacological agents used in the treatment of acute SCI can be grouped into: ionic channel blockers, inhibitors of N-Methyl-D-asparate acid (NMDA), and AMPA-kainate receptors, inhibitors of FR and LP, antiapoptotics, and immunosupressors or immunomodulators [77]. All the therapies and their therapeutic objectives are mentioned in Table 1.

Therapy Mechanism of neuroprotection
↑ Increase
↓ Decrease
(−) Blocked
(+) Activated
Treatment outcome References
Preclinical therapies
Ionic channel blockers
a) Tetrodotoxin

b) Riluzole

(−) Sodium entry channels after SCI

Binds to voltage-dependent sodium channels in nervous system cell membranes, facilitating motor function recovery by reducing long-term white matter loss, thus improving neural tissue preservation.

Increases the survival and reinnervating capacity of injured motor neurons; conferred significant neuroprotection and behavioral recovery, sparing both gray and white matter.

[78, 79]

[80, 81]
a) Nimodipine

↓Oxidative damage caused by FR

Decreases LP end products, such as MDA and 4-Hydroxy Acrolein, resulting in a better motor recovery. However, it should be noted that nimodipine does not allow membrane repair.

[82, 83]
Inhibitors of NMDA and AMPA-kainate receptors
a) Memantine

b) Gacyclidine

↓ Neurological damage by glutamate and NMDA.

(−)noncompetitive NMDA receptor

AMPA-kainate receptor antagonist.
Noncompetitive NMDA antagonist that prevents neurotoxicity. In combination with antiapoptotic agents, provides better histological and clinical results, diminished necrosis and apoptosis.

Improved motor recovery, neural tissue preservation in a dose–dependent manner. In rats, gacyclidine exerts dose- and time-dependent neuroprotection.

Improves mitochondrial function and reduces levels of ROS and lipid peroxidation products.
[84, 85]

[86, 87]

Inhibitors of FR and LP
a) PUFAs

b) Glutathione (GSH)
↓FR formation, scavenging of ROS and RNS.

(−) FR by the free thiol group.
Prevents white matter damage, increases synaptic connections, neuronal survival, and improves motor recovery. Possesses antioxidant and anti-inflammatory effects.

Anti-excitotoxic peptide through the inhibition of the union between specific ligands and inotropic GluRs by the modulation of redox reactions. Improves motor recovery, rubrospinal tract neuronal survival, blood flow stabilization.
[89, 90, 91, 92, 93, 94, 95, 96]

[97, 98, 99, 100]
a) zDEVD-fmk

b) LEHD-fmk
(−) Caspase 3 and 9 respectively The application of z-DEVD-fmk reduces secondary tissue injury and helps preserve motor function.

Electron microscopy showed that z-LEHD-fmk treatment protects neurons, glia, myelin, axons, and intracellular organelles.
[101, 102]
Immunosuppressive or immunomodulatory drugs
  1. Inhibitors of cyclooxygenase

a) Indomethacin

b) Celecoxib

c) Meloxicam
(−) COX 1 and COX 2

(−) COX 2

(−) COX 2
Mixed results: some report improved neurological function and blood flow to injury site, as well as decreased neuronal damage, while others report delayed recovery.

Reduction of prostanoids and FR synthesis, inhibition of arachidonic acid pathways. Increased motor recovery and diminished damaged spinal tissue.

Improved neurological function, amelioration of LP.
[103, 104]


2. Immunophilin ligands
a) Cyclosporine A

b) Tacrolimus
(−) Calcineurin activity Inhibits the proliferation of T-helper lymphocytes and interferes with cytokine production (IL-1, IL-2 e IL-6), cytoskeleton motility of neutrophils, and activation of iNOS or ROS production.
Reduces LP levels, glutamate excitotoxicity, and demyelination processes, increasing neuronal survival and motor recovery.

NF-kB and caspase 3 inhibition, leading to improved recovery and reduced neuronal loss.
In mesenchymal stem cells (MSCs) transplantation, improves MSCs survival and neurological recovery after SCI.
Tacrolimus may induce neuroregeneration by binding to heat shock protein 90.
[104, 106, 107, 108, 109]

[110, 111, 112, 113, 114]
3. Immunomodulatory peptides
a) Monocyte locomotion inhibitory factor (MLIF)

b) Nogo-A

c) A91
↓ VCAM-1, pro-inflammatory cytokines (IL-1β, IL-6, IL-12, and IFN-γ)

(+) T-cell-mediated protective autoimmunity

(+)T-cell-mediated protective autoimmunity
Motor recovery and survival of ventral and corticospinal tract neurons associated with a reduction in iNOS gene expression and up regulation of IL-10 and TGF-β expression. MLIF also reduces the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation.

Nogo-A-derived peptide p472 and the transfer of anti-Nogo-A T-cells showed a significant reduction in neuronal loss.
Promotes motor recovery and the long-term production of BDNF and NT-3.

Reduces LP levels, iNOS expression, NO levels, caspase 3 activity, and TNF-α concentration.
A91 combined with GME induced a better motor recovery, a higher number of myelinated axons, and better rubrospinal neuron survival than A91 alone.
[115, 116]

[117, 118]

[100, 119, 120, 121, 122, 123, 124, 125]
Clinical therapies
Methylprednisolone (−) Immune response Contradicting data, with some showing improved motor recovery and others showing no recovery and increased side effects. [126, 127, 128]
Minocycline Multiple anti-inflammatory pathways Improved motor recovery and decreased cell death through inhibition of caspase 3, matrix metalloproteinases, NO levels, and TNF-α. [129, 130, 131]
GM-1 Ganglioside ↓ Excitatory neurotoxicity Improved motor recovery evaluated by American Spinal Injury Association (ASIA) motor, light touch, and pinprick scores. [132, 133, 134]

Table 1.

Pharmacological treatments used in acute SCI.

3.2. Nonpharmacological therapies

Nonpharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established. This may be due in part because of methodological weaknesses in available studies. However, preclinical studies have demonstrated neuroprotective effect, although results from clinical studies remain controversial and require further studies. These treatments are summarized in Table 2.

Therapy Mechanism of neuroprotection
↑ Increase
↓ Decrease
(−) Blocked
(+) Activated
Treatment outcome References
Preclinical therapies
a) Vitamin B3 (niacin)

b) Vitamin C (ascorbic acid)

c) Vitamin E (alpha-tocopherol)
Phenotypic shift in macrophages from M1 to M2

(−) FR formation

(−) FR formation
Reduced p65 NF-κB phosphorylation, reducing M1 markers such as iCD86, IL-12, and IL-6 and increasing anti-inflammatory M2 markers, such as CD206, IL-10, and IL-13.

Reduces tissue damage and improves functional recovery in rats.

Improves cell survival and motor function significantly following SCI.

[136, 137]

[137, 138]
Resveratrol ↑ Transcription factor Nrf-2 and sirtuin (SIRT) 1 Reduces neutrophil infiltration, production of inflammatory cytokines (IL-1β, IL-10, TNF-α), and myeloperoxidase (MPO) by inhibition of NF-κB; diminishes iNOS expression, apoptosis, and caspase-3, as well as inducing important locomotor recovery. [139, 140, 141, 142]
Gene therapy
Chondroitinase gene therapy via lentiviral vector (LV-ChABC)
(−) Chondroitin sulfate proteoglycans (CSPGs) Reduced cavitation and enhanced preservation of spinal neurons and axons.
Improved sensorimotor function and increased neuronal survival correlated with reduced apoptosis.
Hypothermia Vasoconstriction,
(−) Inflammatory response
Decreases the degree of the hemorrhage at the injured site and neurotoxicity by reducing the levels of glutamate and glutamanergic receptors.
Prevents changes in the BBB, thus hindering extravasation of leukocytes into the CNS.
Inactivation of production of pro-inflammatory cytokines, such as IL-1β, IL-18, and TNF-α. Also reduces O2, NO, and OH FR. Reduces cell death and apoptotic mechanisms through caspase-3 and cytochrome C inhibition.
[144, 145]
Cell therapy
a) Schwann cells

b) Embryonic stem cells.

c) Olfactory ensheathing cells (OECs)

d) MSCs
(+) Myelination

Pluripotent cells capable of differentiating into every type of cell

Found in the center and periphery of the olfactory nerve; capable of differentiating into neuronal or glial lineage cells

Obtained from bone marrow; capable of differentiating into every type of cell
Treatment with these cells improves sensitive and motor functions due to the remyelinating potential of Schwann cells, permitting the transmission of action potentials through regenerated axons wrapped in Schwann cells.

Induce motor recovery through the ability to transform into astrocytes, oligodendrocytes, and/or neurons in vitro prior to transplantation, in order to avoid their tumorigenicity.

Enhanced locomotor recovery, axon myelination, and neuroprotection.

MSCs may facilitate recovery from SCI by remyelinating spared white matter tracts and/or enhancing axonal growth with low immunogenicity. Modulate the inflammatory microenvironment to reduce pro-inflammatory cytokine levels.
[146, 147]



[150, 151]
Low-energy extracorporeal shockwave therapy (ESWT) ↑ Electric stimulus Improved motor and sensory recovery, decreased neural cell death. Stimulates angiogenesis and neurogenesis. [152]
Physical therapy ↓ Spasticity
↑Neurological outcome
Upregulates the expression of NT3, NT4, BDNF, and GDNF, while reducing levels of apoptosis-related proteins such as caspase 3 and 9.
Induces axonal regeneration, broadening the scope of physical therapy from neuroprotection to neuroregeneration.
[152, 153, 154, 155, 156]
Clinical therapies
Cell therapy
Autologous transplant of MSC Obtained from bone marrow; capable of differentiating into every type of cell Improved motor, sensory recovery, and neurological outcome.
Improved sexual function and bladder and bowel control
Increased levels of BDNF, NGF, NT3, and NT4.
[157, 158, 159, 160, 161]
Physical therapy ↓ Spasticity
↑Neurological outcome
Further translational studies are required in order to provide favorable results in patients similar to those seen in animal models of SCI. However, patients with incomplete SCI saw an improvement on their ASIA score after receiving physical therapy. [162, 163, 164]

Table 2.

Nonpharmacological therapies used in acute SCI.


4. Therapies for chronic SCI

Many patients with chronic SCI experience little partial recovery with the use of acute phase treatments. When compared to acute SCI treatments, the efficacy of therapies that promote axonal regeneration in chronic models is reduced due to the generalized stability, induced by protective means or restoration promoters not present during the acute phase [165]. Studies indicate that this period of stability is reached in up to 3 months [166], followed by a progressive decline of neurologic functions in rodents that underwent SCI [167, 168].

Treatments for chronic SCI focus on avoiding or improving characteristic pathophysiological mechanisms, such as glial scar formation, demyelination, and astrogliosis. Moreover, it must be emphasized that while strategies for acute SCI are limited to preventing further damage, therapeutic strategies for chronic SCI instead focus on promoting neuronal regeneration and treating accompanying symptoms of chronic complications. Pharmacological and nonpharmacological therapies utilized in the treatment of chronic SCI are summarized in Tables 3 and 4.

Therapy Mechanism of neuroprotection
↑ Increase
↓ Decrease
(−) Blocked
(+) Activated
Treatment outcome References
Preclinical therapies
Antagonists of Rho signaling pathway
a) C3 transferase

b) Y27632

c) Fasudil

d) P21

e) Ibuprofen
(−)Rho protein

(−)Rho protein, nonselective inhibitor

(−)Rho protein

(−)Rho protein
Stimulates axonal growth and improves motor function.

Promotes axonal regeneration and motor function recovery.

Conjoint administration with MP promotes recovery of motor activity and reflex movements, as well as tissue preservation.

Capable of stimulating axonal regeneration and improving motor function of extremities.

Enhances recovery by limiting tissue loss and stimulating axonal growth.




Glial scar inhibitors
a) 2,2′-bipiridine (BPY).

b) Decorine

c) Olomoucine

d) α,α’-dipyridyl

e) ChABC
(−) prolyl 4-hydroxylase

(−) TGF-β

(−) CDK1/Cycline B and related kinases

(−) prolyl-4 hydroxylase

(−) ECM molecules
Growth of corticospinal tract neurons through the injury site and improved motor function recovery.

Suppresses glial scar formation, favors axonal growth.

Limits astroglial proliferation and increases GAP-43 expression, improving motor function.

Decreases collagen synthesis.

Promotes spinal cord plasticity along injured corticospinal tract and uninjured serotonergic projections, facilitates growth of new fibers, and stimulates rubrospinal projection neuron growth.




[174, 175]
Anti-Nogo therapies
a) Nogo receptor (NgR) Myelin-associated inhibitors NgR immunization markedly reduced the total lesion volume, improved locomotor recovery and grid walking performance. [176]
Clinical therapies
Rho-ROCK inhibitor
(−)Rho protein Significant improvement in long-term motor scores (18.5 ASIA points) for cervical patients. Currently under study in a phase III trial in patients with acute cervical SCI which commenced in 2016. [177, 178]
Anti-Nogo antibodies Myelin-associated inhibitors Promotes axonal sprouting and functional recovery. [117, 179]

Table 3.

Pharmacological therapies in chronic SCI.

Preclinical therapies
Glial scar removal ↓ or (−) glial scar (Surgical) Promotes axonal development, although surgical removal may lead to a second injury. [180]
Biocompatible matrices
a) Fibrin glue (Tissucol)

b) Alginate

c) Hyaluronic acid

d) Polyethylene glycol

e) Matrigel
Fibrinogen and thrombin compound, potentially adequate biological vehicle for cell transplant.

Vehicle for drug release, cellular encapsulation and cellular transplant

Porous structures that gradually release growth factors, cellular encapsulation, or drugs

Seals injured membranes and allows them to reassemble

Matrix conformed by multiple growth factors and extracellular proteins
Promotes growth and incorporation of primary myelinated and unmyelinated afferent axons, and intervenes in the support and directionality of axons with Schwann cells.
Fibrin-stabilizing factor (Factor XII), also contained in Tissucol, favors migration of MSCs on the highly reticulated structure of the glue and increases their proliferation.

Facilitates axonal guidance and cell adherence by delivering ECM components, such as fibronectin, laminin, collagen, and polyornithine, alongside progenitor neuronal cells.

Minimizes the formation of glial scar and promotes astrocyte and microglia migration.

Repairs cell membranes in the CNS, although it does not provide three-dimensional support.

Compounds facilitate cellular adherence, differentiation, Schwann cell growth, and axonal regeneration.
[181, 182]




Cell therapies
a)Neural stem cells

b) Mesenchymal stem cells

c) Schwann cells

d) OECs
Integrates with host circuits to enhance behavioral recovery

Modulate inflammatory response, promote angiogenesis

Stimulation of remyelination

Phagocytosis of debris and microbes, growth factor signaling
Improves phrenic motor output after high cervical SCI, improving spontaneous respiratory motor recovery.

Promotes repair by anti-inflammatory molecule secretion and stimulation of macrophage polarization, secretion of trophic and neurotrophic factors.

Promotes angiogenesis, prevents apoptosis, and stabilizes the BSB through astrocyte regulation, forming axonal guidance filaments through the injury site.
Increased preservation of white matter and host Schwann cells and astrocyte ingress, as well as axon ingrowth and myelination.

Improves neurite outgrowth and endogenous remyelination, as well as white matter preservation, sensory, and motor recovery.
[187, 188]

[189, 190, 191, 192, 193, 194, 195]

[196, 197, 201]

[198, 199, 200, 202, 203, 204]
Combination therapy
a) Cocktail with 10 growth factors.

b) Anti-Nogo-A antibody followed by ChABC and physical rehabilitation.

c) ChABC and NSCs

d) A91 and surgical glial scar removal.

e) Degenerated peripheral nerves with MSCs and fibrin glue
↑ NT-3, BDNF, EGF, βfgf, GDNF, PDGF, αfgf, HGF, IGF-1, and calpain inhibitor in a fibrin gel conjointly with NSC transplantation

Myelin-associated inhibitors
(−) ECM molecules
↓ spasticity

(−) ECM molecules
Integrate with host circuits to enhance behavioral recovery

↑ Growth factor
(−) glial scar

↑ Growth factor
(+) neural regeneration
Induces significant motor recovery.

Spontaneous recovery of forelimb functions reflected the extent of the lesion on the ipsilateral side and improved motor recovery when compared to the groups receiving individual treatments.
Histological results showed increased neuronal regeneration.

Allows the transplanted cells to differentiate into neuroglial cells and permits proper axonal regeneration and growth across the injury site, leading to significant motor recovery.

Increases motor function.
Facilitates the axonal regeneration in the region caudal to the injury site.

Induces axonal regeneration and myelination with molecules associated to GAP-43 and neuritin, which are present in axonal growth cones and axonal remyelinization.

[206, 207]



Clinical therapies
Physical therapy ↓ Spasticity Upregulation of BDNF, IGF-1, other growth factors.
Improves axonal plasticity and regeneration, motor function.
[210, 211, 212, 213, 214, 215]
Muscle electrical stimulation ↑ Muscle electric stimulus Improvement in their motor and sensory function, as well as an increase in muscle size and strength [216]
Spinal cord stimulation ↑ Spinal cord electric stimulus Treated patients were able to initiating limb movement and improve posture control, bladder emptying (urinary retention), and sexual function. This therapy also provoked escalated extension-flexion movements.
Additional trials (NCT02592668, NCT02313194) are now ongoing to assess safety/feasibility and validate this exciting finding, with results expected by 2018.
Glial scar removal with NeuroRegen scaffold. ↑ Spinal cord regeneration Better recovery of autonomous nervous functions, as well as the recovery of somatosensory-evoked potentials of lower limbs. [218]
Cell therapies
a) NSC transplant

b) Oligodendrocyte precursor cells

c) MSCs transplant

d) Schwann cells transplant

e) OECs transplant
Cervical transplant (n = 31; NCT02163876) and thoracic transplant (n = 12; NCT01321333). Preliminary results from these trials do not show increased complication rates, although results on motor and sensitive recovery remain pending.

Asterias Biotherapeutics Inc. phase I/II dose-escalation trial (n = 35; NCT02302157).
This study is expected to be completed in 2018.

Phase II/III clinical trial in South Korea (NCT01676441) by Pharmicell Co. with intraparenchymal and intrathecal administration of MSC. Results are still pending, with an estimated completion date of 2020.

An open-label phase I trial (n = 10) by the Miami Project to Cure Paralysis is now investigating Schwann cells in the treatment of patients with chronic ASIA A, B, and C cervical or thoracic injuries, with results expected by 2018.

Phase I clinical trial, with results showing an improvement in sensory and motor function, along with improved preservation of white matter at the site of injury.
[219, 220]


[220, 221, 222]


[223, 224]

Table 4.

Nonpharmacological therapies in chronic SCI.


5. Conclusion

In conclusion, despite promising innovative advances in preclinical treatments, there is currently no consolidated therapeutic strategy at clinical settings. Further research is needed to establish novel therapeutic strategies, including immunomodulatory strategies and combinatorial therapy, in order to improve recovery and therefore the quality of life for patients.


  1. 1. Sharma H. Pathophysiology of blood-spinal cord barrier in traumatic injury and repair. Current Pharmaceutical Design. 2005;11(11):1353-1389
  2. 2. Rowland JW et al. Current status of acute spinal cord injury pathophysiology and emerging therapies: Promise on the horizon. Neurosurgical Focus. 2008;25(5):E2
  3. 3. Dalbayrak S, Yaman O, Yılmaz T. Current and future surgery strategies for spinal cord injuries. World Journal of Orthopedics. 2015 Jan;6(1):34-41
  4. 4. Oyinbo CA. Secondary injury mechanisms in traumatic spinal cord injury: A nugget of this multiply cascade. Acta Neurobiologiae Experimentalis (Wars). 2011;71(2):281-299
  5. 5. Dumont RJ et al. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clinical Neuropharmacology. 2001;24(5):254-264
  6. 6. Lee J, Thumbikat P. Pathophysiology, presentation and management of spinal cord injury. Surgery. 2015;33(6):238-247
  7. 7. Mautes AE et al. Vascular events after spinal cord injury: Contribution to secondary pathogenesis. Physical Therapy. 2000;80(7):673-687
  8. 8. Fleming JC et al. The cellular inflammatory response in human spinal cords after injury. Brain. 2006;129(12):3249-3269
  9. 9. Sinescu C et al. Molecular basis of vascular events following spinal cord injury. Journal of Medicine and Life. 2010;3(3):254-261
  10. 10. Profyris C et al. Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiology of Disease. 2004;15:415-436
  11. 11. Esposito E, Cuzzocrea S. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Current Medicinal Chemistry. 2009;16(24):3152-3167
  12. 12. Nesic O et al. DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition. Journal of Neuroscience Research. 2002;68(4):406-423
  13. 13. Agrawal SK, Nashmi R, Fehlings MG. Role of L- and N-type calcium channels in the pathophysiology of traumatic spinal cord white matter injury. Neuroscience. 2000;99(1):179-188
  14. 14. Wagner I et al. Radiopacity of intracerebral hemorrhage correlates with perihemorrhagic edema. European Journal of Neurology. 2011;19(3):525-528
  15. 15. Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. Journal of Molecular Medicine. 2000;78(1):3-13
  16. 16. D’Autréaux B, Toledano MB. ROS as signaling molecules: Mechanisms that generate specificity in ROS homeostasis. Nature Reviews. Molecular Cell Biology. 2007;8(10):813-824
  17. 17. Sapolsky RM. Cellular defenses against excitotoxic insults. Journal of Neurochemistry. 2001;76(6):1601-1611
  18. 18. Liu D, Xu GY, Pan E, McAdoo DJ. Neurotoxicity of glutamate at the concentration released upon spinal cord injury. Neuroscience. 1999;93(4):1383-1389
  19. 19. Faden AI, Simon RP. A potential role for excitotoxins in the pathophysiology of spinal cord injury. Annals of Neurology. 1988 Jun;23(6):623-626
  20. 20. Xu G-Y et al. Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord. Experimental Neurology. 2004 Jun;187(2):329-336
  21. 21. Matute C et al. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends in Neurosciences. 2001;24:224-230
  22. 22. Bains M, Hall ED. Antioxidant therapies in traumatic brain and spinal cord injury. Biochimica et Biophysica Acta (BBA)–Molecular Basis of Disease. 2012 May [cited 2017 Jun 10];1822(5):675-684
  23. 23. Hall ED et al. Lipid peroxidation in brain or spinal cord mitochondria after injury. Journal of Bioenergetics and Biomembranes. 2016 Apr 18;48(2):169-174
  24. 24. de Zwart LL, Meerman JH, Commandeur JN, Vermeulen NP. Biomarkers of free radical damage. Free Radical Biology & Medicine. 1999;26(1–2):202-226
  25. 25. Banes AJ, Tsuzaki M, Yamamoto J, Brigman B, Fischer T, Brown T, et al. Mechanoreception at the cellular level: The detection, interpretation, and diversity of responses to mechanical signals. Biochemistry and Cell Biology. 1995;73(7–8):349-365
  26. 26. Hall ED. Antioxidant therapies for acute spinal cord injury. Neurotherapeutics. 2011;8(2):152-167
  27. 27. Xu W et al. Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury. Spinal Cord. 2005 Apr 2;43(4):204-213
  28. 28. Vaishnav RA et al. Lipid peroxidation-derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function. Journal of Neurotrauma. 2010;27(7):1311-1320
  29. 29. Hamada Y et al. Roles of nitric oxide in compression injury of rat spinal cord. Free Radical Biology & Medicine. 1996;20(1):1-9
  30. 30. Xu J et al. iNOS and nitrotyrosine expression after spinal cord injury. Journal of Neurotrauma. 2001;18(5):523-532
  31. 31. Xu M, Ng YK, Leong SK. Neuroprotective and neurodestructive functions of nitric oxide after spinal cord hemisection. Experimental Neurology. 2000;161(2):472-480
  32. 32. Liu C, Jin A, Zhou C, Chen B. Gene expression of inducible nitric oxide synthase in injured spinal cord tissue. Chinese Journal of Traumatology = Zhonghua chuang shang za zhi. 2001 Nov;4(4):231-233
  33. 33. Liu CL, Jin AM, Tong BH. Detection of gene expression pattern in the early stage after spinal cord injury by gene chip. Chinese Journal of Traumatology. 2003 Feb;6(1):18-22
  34. 34. Kwak EK et al. The role of inducible nitric oxide synthase following spinal cord injury in rat. Journal of Korean Medical Science. 2005;20(4):663-669
  35. 35. Boje KM, Arora PK. Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Research. 1992;587(2):250-256
  36. 36. Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Research 2015 Jan;1619:1-11
  37. 37. Camand E et al. Long-term changes in the molecular composition of the glial scar and progressive increase of serotoninergic fibre sprouting after hemisection of the mouse spinal cord. The European Journal of Neuroscience. 2004;20(5):1161-1176
  38. 38. Wang J, Asensio VC, Campbell IL. Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice. Current Topics in Microbiology and Immunology. Springer Science + Business Media; 2002. 265 pp. 23-48
  39. 39. Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Experimental Neurology. 2008;209(2):378-388
  40. 40. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord. 2003;41(7):369-378
  41. 41. Trivedi A, Olivas AD, Noble-Haeusslein LJ. Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes. Clinical Neuroscience Research. 2006;6(5):283-292
  42. 42. Popovich PG et al. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. Journal of Neuropathology and Experimental Neurology. 2002;61(7):623-633
  43. 43. Shaked I et al. Protective autoimmunity: Interferon-γ enables microglia to remove glutamate without evoking inflammatory mediators. Journal of Neurochemistry. 2005;92(5):997-1009
  44. 44. Kreutzberg GW. Microglia: A sensor for pathological events in the CNS. Trends in Neurosciences. 1996;19(8):312
  45. 45. Kim SU, de Vellis J. Microglia in health and disease. Journal of Neuroscience Research. 2005;81(3):302-313
  46. 46. Hao AJ, Dheen ST, Ling EA. Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage. Neuroscience. 2002;112(4):889-900
  47. 47. Nakajima K et al. Neurotrophin secretion from cultured microglia. Journal of Neuroscience Research. 2001;65(4):322-331
  48. 48. Popovich PG, Stokes BT, Whitacre CC. Concept of autoimmunity following spinal cord injury: Possible roles for T lymphocytes in the traumatized central nervous system. Journal of Neuroscience Research. 1996;45(4):349-363
  49. 49. Mir M et al. Complementary roles of tumor necrosis factor alpha and interferon gamma in inducible microglial nitric oxide generation. Journal of Neuroimmunology. 2008;204(1–2):101-109
  50. 50. Hauben E et al. Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet. 2000;355:286-287
  51. 51. Ibarra A et al. Effects of cyclosporin–A on immune response, tissue protection and motor function of rats subjected to spinal cord injury. Brain Research. 2003;979(1–2):165-178
  52. 52. Ibarra A et al. The therapeutic window after spinal cord injury can accommodate T cell-based vaccination and methylprednisolone in rats. The European Journal of Neuroscience. 2004;19(11):2984-2990
  53. 53. Schwartz M, Kipnis J. Autoimmunity on alert: Naturally occurring regulatory CD4+CD25+ T cells as part of the evolutionary compromise between a “need” and a “risk”. Trends in Immunology. 2002;23(11):530-534
  54. 54. Kipnis J et al. Myelin specific Th1 cells are necessary for post-traumatic protective autoimmunity. Journal of Neuroimmunology. 2002;130(1–2):78-85
  55. 55. Schwartz M, Kipnis J. Protective autoimmunity: Regulation and prospects for vaccination after brain and spinal cord injuries. Trends in Molecular Medicine. 2001;7:252-258
  56. 56. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Experimental Neurology. 2008;209:294-301
  57. 57. Kawano H et al. Role of the lesion scar in the response to damage and repair of the central nervous system. Cell and Tissue Research. 2012 Jul;349(1):169-180
  58. 58. Göritz C et al. A pericyte origin of spinal cord scar tissue. Science. 2011;333(6039):238-242
  59. 59. Klapka N, Müller HW. Collagen matrix in spinal cord injury. Journal of Neurotrauma. 2006 Apr;23(3–4):422-436
  60. 60. Haan N et al. Crosstalk between macrophages and astrocytes affects proliferation, reactive phenotype and inflammatory response, suggesting a role during reactive gliosis following spinal cord injury. Journal of Neuroinflammation. 2015;12(1):109
  61. 61. Faulkner JR et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience. 2004;24(9):2143-2155
  62. 62. Di Prospero NA, Meiners S, Geller HM. Inflammatory cytokines interact to modulate extracellular matrix and astrocytic support of neurite outgrowth. Experimental Neurology. 1997 Dec;148(2):628-639
  63. 63. Faulkner JR. Reactive Astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience. 2004;24(9):243-255
  64. 64. Kohta M, Kohmura E, Yamashita T. Inhibition of TGF-beta1 promotes functional recovery after spinal cord injury. Neuroscience Research. 2009 Dec;65(4):393-401
  65. 65. Gallo V, Deneen B. Glial development: The crossroads of regeneration and repair in the CNS. Neuron. 2014;83:283-308
  66. 66. Burda JE, Bernstein AM, Sofroniew MV. Astrocyte roles in traumatic brain injury. Experimental Neurology. 2015 Mar;3:305-315
  67. 67. Holley JE et al. Astrocyte characterization in the multiple sclerosis glial scar. Neuropathology and Applied Neurobiology. 2003;29(5):434-444
  68. 68. Cramer GD. Clinical anatomy of the spine, spinal cord, and ANS. Elsevier Health Sciences. 2014:135-209
  69. 69. Mohrman AE, et al. Spinal cord transcriptomic and metabolomic analysis after excitotoxic injection injury model of syringomyelia. Journal of Neurotrauma. 2016 Feb;34(3)
  70. 70. Hinsdale G. Syringomyelia: A Disorder of CSF. Circulation. 1897
  71. 71. Article C. Diagnosis and treatment. In: Syringomyelia. 2011. pp. 655-657
  72. 72. Flint G, Rusbridge C. Syryngomyelia: A disorder of CFS circulation. In: Syringomyelia: Current Concepts in Diagnosis and Treatment. 1991. pp. 1-26
  73. 73. Lee BCP et al. MR imaging of syringomyelia and hydromyelia. American Journal of Roentgenology. 1985 Jun;144(6):1149-1156
  74. 74. Faden AI, Stoica B. Neuroprotection: Challenges and opportunities. Archives of Neurology. 2007 Jun;64(6):794-800
  75. 75. Kwon BK et al. A systematic review of directly applied biologic therapies for acute spinal cord injury. Journal of Neurotrauma. 2011 Aug;28(8):1589-1610
  76. 76. Hurlbert RJ et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2015 Mar;76:S71-S83
  77. 77. Hilton BJ, Moulson AJ, Tetzlaff W. Neuroprotection and secondary damage following spinal cord injury: Concepts and methods. Neuroscience Letters. 2016 Dec;652:3-10
  78. 78. Rosenberg LJ, Teng YD, Wrathall JR. Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury. The Journal of Neuroscience. 1999 Jul;19(14):6122-6133
  79. 79. Rosenberg PA et al. Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocytes in culture. Journal of Neurochemistry. 1999 Aug;73(2):476-484
  80. 80. Schwartz G, Fehlings MG. Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: Improved behavioral and neuroanatomical recovery with riluzole. Journal of Neurosurgery. 2001 Apr;94(2 suppl.):245-256
  81. 81. Wang S-J, Wang K-Y, Wang W-C. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience. 2004 Jan;125(1):191-201
  82. 82. Liu W-M et al. Ion channel blockers and spinal cord injury. Journal of Neuroscience Research. 2011 Jun;89(6):791-801
  83. 83. Steroids BMB. For acute spinal cord injury. Cochrane Database of Systematic Reviews. 2012;1(10):CD001046
  84. 84. Gentile NT, McIntosh TK. Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. Annals of Emergency Medicine. 1993 Jun;22(6):1028-1034
  85. 85. Aydoseli A et al. Memantine and Q-VD-OPh treatments in experimental spinal cord injury: Combined inhibition of necrosis and apoptosis. Turkish Neurosurgery. 2016;26(5):783-789
  86. 86. Feldblum S et al. Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. Journal of Neurotrauma. 2000 Nov;17(11):1079-1093
  87. 87. Gaviria M et al. Neuroprotective effects of a novel NMDA antagonist, gacyclidine, after experimental contusive spinal cord injury in adult rats. Brain Research. 2000 Aug;874(2):200-209
  88. 88. Mu X, Azbill RD, Springer JE. NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury. Journal of Neurotrauma. 2002 Aug;19(8):917-927
  89. 89. Wall R et al. Fatty acids from fish: The anti-inflammatory potential of long-chain omega-3 fatty acids. Nutrition Reviews. 2010;68:280-289
  90. 90. Dyall SC, Michael T. Neurological benefits of omega-3 fatty acids. NeuroMolecular Medicine. 2008:219-235
  91. 91. Lang-Lazdunski L et al. Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats. Journal of Vascular Surgery. 2003;38(3):564-575
  92. 92. Michael-Titus AT, Priestley JV. Omega-3 fatty acids and traumatic neurological injury: From neuroprotection to neuroplasticity? Trends in Neurosciences. Elsevier Ltd. 2014; 37:30-38
  93. 93. Zendedel A et al. Omega-3 polyunsaturated fatty acids ameliorate neuroinflammation and mitigate ischemic stroke damage through interactions with astrocytes and microglia. Journal of Neuroimmunology. 2015;278:200-211
  94. 94. Trépanier MO et al. N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update. European Journal of Pharmacology. 2016 Aug;785:187-206
  95. 95. Figueroa JD, De Leon M. Neurorestorative targets of dietary long-chain Omega-3 fatty acids in neurological injury. Molecular Neurobiology. 2014;50(1):197-213
  96. 96. Ward RE et al. Docosahexaenoic acid prevents white matter damage after spinal cord injury. Journal of Neurotrauma. 2010;27(10):1769-1780
  97. 97. Dringen R et al. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. European Journal of Biochemistry. 2000 Aug;267(16):4912-4916
  98. 98. Lucas S-M et al. The role of inflammation in CNS injury and disease. British Journal of Pharmacology. 2006;147:S232-S240
  99. 99. Guízar-Sahagún G et al. Glutathione monoethyl ester improves functional recovery, enhances neuron survival, and stabilizes spinal cord blood flow after spinal cord injury in rats. Neuroscience. 2005 Jan;130(3):639-649
  100. 100. Martiñon S et al. Vaccination with a neural-derived peptide plus administration of glutathione improves the performance of paraplegic rats. The European Journal of Neuroscience. 2007;26(2):403-412
  101. 101. Seref Barut MD et al. The neuroprotective effects of zDEVD-fmk, a caspase-3 inhibitor on traumatic spinal cord injury in rats. Surgical Neurology. 2005;64:213-220
  102. 102. Colak A et al. Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury. Journal of Neurosurgery. Spine. 2005. Mar;2(3):327-334
  103. 103. Hou X-l et al. Combination of fasudil and celecoxib promotes the recovery of injuried spinal cord in rats better than celecoxib or fasudil alone. Neural Regeneration Research. 2015 Nov;10(11):1836-1840
  104. 104. Attur MG et al. Differential anti-inflammatory effects of immunosuppressive drugs: Cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production. Inflammation Research. 2000;49(1):20-26
  105. 105. Hakan T et al. Meloxicam exerts neuroprotection on spinal cord trauma in rats. The International Journal of Neuroscience. 2011
  106. 106. Gold BG et al. Neuroregenerative and neuroprotective actions of neuroimmunophilin compounds in traumatic and inflammatory neuropathies. Neurological Research. 2004;26(4):371-380
  107. 107. Gold BG. Neuroimmunophilin ligands: Evaluation of their therapeutic potential for the treatment of neurological disorders. Expert Opinion on Investigational Drugs. 2000;9(10):2331-2342
  108. 108. Ruiz F et al. Cyclosporin–A targets involved in protection against glutamate excitotoxicity. European Journal of Pharmacology. 2000;404(2):29-39
  109. 109. Diaz-Ruiz A et al. Lipid peroxidation inhibition in spinal cord injury: Cyclosporin-a vs methylprednisolone. Neuroreport. 2000;11(8):1765-1767
  110. 110. Nottingham S. FK506 treatment inhibits caspase-3 activation and promotes oligodendroglial survival following traumatic spinal cord injury. Experimental Neurology. 2002 Sep;177(1):242-251
  111. 111. Liu G et al. FK506 attenuates the inflammation in rat spinal cord injury by inhibiting the activation of NF-kB in microglia cells. Cellular and Molecular Neurobiology. 2016 Aug:1-13
  112. 112. Voda J, Yamaji T, Gold BG. Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats. Journal of Neurotrauma. 2005 Oct;22(10):1150-1161
  113. 113. Quintá HR, Galigniana MD. The neuroregenerative mechanism mediated by the Hsp90-binding immunophilin FKBP52 resembles the early steps of neuronal differentiation. British Journal of Pharmacology. 2012;166(2):637-649
  114. 114. Torres-Espín A et al. Immunosuppression of allogenic mesenchymal stem cells transplantation after spinal cord injury improves graft survival and beneficial outcomes. Journal of Neurotrauma. 2015;32(6):367-380
  115. 115. Kretschmer RR, Rico G. A novel anti-inflammatory oligopeptide produced by Entamoeba histolytica. Molecular and Biochemical Parasitology. 2001 Feb;112(2):201-209
  116. 116. Bermeo G et al. Monocyte locomotion inhibitory factor produced by E. histolytica improves motor recovery and develops neuroprotection after traumatic injury to the spinal cord. BioMed Research International. 2013;2013:340727
  117. 117. Yu P et al. Immunization with recombinant Nogo-66 receptor (NgR) promotes axonal regeneration and recovery of function after spinal cord injury in rats. Neurobiology of Disease. 2008 Dec;32(3):535-542
  118. 118. Freund P et al. Anti-Nogo-a antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey. The Journal of Comparative Neurology. 2007 Jun 1;502(4):644-659
  119. 119. Ibarra A et al. Prophylactic neuroprotection with A91 improves the outcome of spinal cord injured rats. Neuroscience Letters. 2013;554:59-63
  120. 120. Hauben E et al. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. The Journal of Clinical Investigation. 2001;108(4):591-599
  121. 121. Ibarra A et al. Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury. Neuroscience Letters. 2010;476(2):62-65
  122. 122. Rodríguez-Barrera R et al. Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury. BMC Neuroscience. 2017
  123. 123. García E et al. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury. Journal of Neuroscience Research. 2012;90(3):656-663
  124. 124. Martiñón S et al. Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury. BMC Neuroscience. 2016;17(1):42
  125. 125. del Rayo Garrido M, et al. Therapeutic window for combination therapy of A91 peptide and glutathione allows delayed treatment after spinal cord injury. Basic & Clinical Pharmacology & Toxicology 2013;112(5):314-318
  126. 126. Bracken MB. Treatment of acute spinal cord injury with methylprednisolone: Results of a multicenter, randomized clinical trial. Journal of Neurotrauma. 1991;8:S-50
  127. 127. Evaniew N et al. Methylprednisolone for the treatment of patients with acute spinal cord injuries: A systematic review and meta-analysis. Journal of Neurotrauma. 2016;33(5):468-481
  128. 128. Evaniew N et al. Methylprednisolone for the treatment of patients with acute spinal cord injuries: A propensity score-matched cohort study from a Canadian multi-center spinal cord injury registry. Journal of Neurotrauma. 2015;32(21):1674-1683
  129. 129. Lee SM et al. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. Journal of Neurotrauma. 2003;20(10):1017-1027
  130. 130. Festoff BW et al. Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. Journal of Neurochemistry. 2006;97(5):1314-1326
  131. 131. Casha S et al. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012;135(4):1224-1236
  132. 132. Filho EGF,et al. Cross-linking mast cell specific gangliosides stimulates the release of newly formed lipid mediators and newly synthesized cytokines. Mediators of Inflammation 2016:9160540
  133. 133. Fehlings MG, Bracken MB. Summary statement: The Sygen(GM-1 ganglioside) clinical trial in acute spinal cord injury. Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S99-100
  134. 134. Geisler FH et al. Recruitment and early treatment in a multicenter study of acute spinal cord injury. Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S58-S67
  135. 135. Cristante AF et al. Antioxidative therapy in contusion spinal cord injury. Spinal Cord–Official Journal of the International Medical Society of Paraplegia: International Medical Society of Paraplegia. 2009;47(6):458-463
  136. 136. Yan M et al. High-dose ascorbic acid administration improves functional recovery in rats with spinal cord contusion injury. Spinal Cord. 2014;52(11):803-808
  137. 137. Robert AA et al. The efficacy of antioxidants in functional recovery of spinal cord injured rats: An experimental study. Neurological Sciences. 2012;33(4):785-791
  138. 138. Anderson DK, Waters TR, Means ED. Pretreatment with alpha tocopherol enhances neurologic recovery after experimental spinal cord compression injury. Journal of Neurotrauma. 1988;5(1):61-67
  139. 139. Kesherwani V et al. Resveratrol protects spinal cord dorsal column from hypoxic injury by activating Nrf-2. Neuroscience. 2013;241:80-88
  140. 140. Fu Y et al. Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating Sirt1 and limiting NLRP-3 inflammasome activation. International Journal of Molecular Sciences. 2013;14(7):14105-14118
  141. 141. Zhu X et al. Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in fibroblasts. PLoS One. 2011;6(10)
  142. 142. Liu C et al. Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Research. 2011;1374:100-109
  143. 143. Bartus K et al. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury. The Journal of Neuroscience. 2014;34(14):4822-4836
  144. 144. Wang J, Pearse DD. Therapeutic hypothermia in spinal cord injury: The status of its use and open questions. International Journal of Molecular Sciences. 2015;16(8):16848-16879
  145. 145. Dietrich WD, et al. Hypothermic treatment for acute spinal cord injury. Neurotherapeutics.2011Apr 18;8(2):229-39
  146. 146. Kan EM, Ling EA, Lu J. Stem cell therapy for spinal cord injury. Current Medicinal Chemistry 2010;17(36):4492-4510
  147. 147. Xu XM et al. Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. Journal of Neurocytology. 1997 Jan;26(1):1-16
  148. 148. Tscherter A et al. Embryonic cell grafts in a culture model of spinal cord lesion: Neuronal relay formation is essential for functional regeneration. Frontiers in Cellular Neuroscience. 2016 Sep 21;10:220
  149. 149. Wang C et al. Improved neural regeneration with olfactory ensheathing cell inoculated PLGA scaffolds in spinal cord injury adult rats. Neuro-Signals. 2017 Mar 30;25(1):1-14
  150. 150. Jiang Y et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002 Jul 4;418(6893):41-49
  151. 151. Kim M et al. Transplantation of human bone marrow-derived clonal mesenchymal stem cells reduces fibrotic scar formation in a rat spinal cord injury model. Journal of Tissue Engineering and Regenerative Medicine. 2017;23
  152. 152. Yamaya S et al. Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury. Journal of Neurosurgery. 2014;121(6):1514-1525
  153. 153. Keeler BE et al. Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Research. 2012;1438(1438):8-21
  154. 154. Tashiro S et al. BDNF induced by treadmill training contributes to the suppression of spasticity and allodynia after spinal cord injury via upregulation of KCC2. Neurorehabilitation and Neural Repair. 2015 Aug;29(7):677-689
  155. 155. Cote M-P et al. Exercise modulates chloride homeostasis after spinal cord injury. The Journal of Neuroscience. 2014;34(27):876-887
  156. 156. Theisen CC et al. Exercise and peripheral nerve grafts as a strategy to promote regeneration after acute or chronic spinal cord injury. Journal of Neurotrauma. 2017 May;34(10):1909-1914
  157. 157. Satti HS et al. Autologous mesenchymal stromal cell transplantation for spinal cord injury: A phase I pilot study. Cytotherapy. 2016 Apr;18(4):518-522
  158. 158. Chhabra HS et al. Autologous bone marrow cell transplantation in acute spinal cord injury—An Indian pilot study. Spinal Cord. 2016 Jan 18;54(1):57-64
  159. 159. Vaquero J et al. Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy. 2017 mar;19(3):349-359
  160. 160. Vaquero J et al. An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy. 2016. Aug;18(8):1025-1036
  161. 161. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subject with chronic spinal cord injury. Stem Cell Research & Therapy. 2014. Nov.17; 5(6)
  162. 162. Scivoletto G, Morganti B, Molinari M. Early versus delayed inpatient spinal cord injury rehabilitation: An Italian study. Archives of Physical Medicine and Rehabilitation. 2005;86(3):512-516
  163. 163. Teeter L et al. Relationship of physical therapy inpatient rehabilitation interventions and patient characteristics to outcomes following spinal cord injury: The SCIRehab project. The Journal of Spinal Cord Medicine. 2012;35(6):503-526
  164. 164. Morawietz C, Moffat F. Effects of locomotor training after incomplete spinal cord injury: A systematic review. Archives of Physical Medicine and Rehabilitation. 2013 Nov;94(11):2297-2308
  165. 165. Houle JD, Tessler A. Repair of chronic spinal cord injury. Experimental Neurology. 2003;182:247-267
  166. 166. Beck KD et al. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: Evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain. 2010;133(2):433-447
  167. 167. Bravo G et al. Indorenate improves motor function in rats with chronic spinal cord injury. Basic & Clinical Pharmacology & Toxicology. 2007;100(1):67-70
  168. 168. Dietz V. Degradation of neuronal function following a spinal cord injury. Brain. 2004;127(10):2221-2231
  169. 169. Dergham P, et al. Rho signaling pathway targeted to promote spinal cord repair. The Journal of Neuroscience. 2002 1;22(15):6570-6577
  170. 170. Chan CCM et al. Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Experimental Neurology. 2005 Dec;196(2):352-364
  171. 171. Hara M et al. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. Journal of Neurosurgery. 2000 Jul;93(1 Suppl):94-101
  172. 172. Tanaka H et al. Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience. 2004 Jan;127(1):155-164
  173. 173. Wang X, et al. Ibuprofen enhances recovery from spinal cord injury by limiting tissue loss and stimulating axonal growth. Journal of Neurotrauma. 2009 Jan [cited 2017 Jun 12];26(1):81-95
  174. 174. Hermanns S, Reiprich P, Müller HW. A reliable method to reduce collagen scar formation in the lesioned rat spinal cord. Journal of Neuroscience Methods. 2001 Sep 30;110(1–2):141-146
  175. 175. Logan A et al. Decorin attenuates gliotic scar formation in the rat cerebral hemisphere. Experimental Neurology. 1999 Oct;159(2):504-510
  176. 176. Tian D et al. Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Research. 2007 Jun 18;1154:206-214
  177. 177. Veselý J et al. Inhibition of cyclin-dependent kinases by purine analogues. European Journal of Biochemistry. 1994;224(2):771-786
  178. 178. Klapka N et al. Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. The European Journal of Neuroscience. 2005;22(12):3047-3058
  179. 179. Kawano H et al. Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons. Journal of Neuroscience Research. 2005;80(2):191-202
  180. 180. Forgione N, Fehlings MG. Rho-ROCK inhibition in the treatment of spinal cord injury. World Neurosurgery. 2014 Sep;82(3–4):e535-e539
  181. 181. Fehlings MG et al. A phase I/IIa clinical trial of a recombinant rho protein antagonist in acute spinal cord injury. Journal of Neurotrauma. 2011 May;5:787-796
  182. 182. Bregman BS et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature. 1995 Nov 30;378(6556):498-501
  183. 183. Zörner B, Schwab ME. Anti-Nogo on the go: From animals models to a clinical trial. Annals of the New York Academy of Sciences. 2010 Jun; 1198(Suppl 1): E22-E34
  184. 184. Rasouli A et al. Resection of glial scar following spinal cord injury. Journal of Orthopaedic Research. 2009 Jul;27(7):931-936
  185. 185. Wang X. Overview on biocompatibilities of implantable biomaterials. Advances in Biomaterials Science and Applications in Biomedicine. 2013
  186. 186. Liu J et al. Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury. Cells, Tissues, Organs. 2013;198(1):35-46
  187. 187. Prang P et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials. 2006;27(19):3560-3569
  188. 188. Preston M, Sherman LS. Neural stem cell niches: Roles for the hyaluronan-based extracellular matrix. Frontiers in Bioscience (Scholar Edition). 2011;3:1165-1179
  189. 189. Estrada V et al. Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiology of Disease. 2014;67:165-179
  190. 190. Cassell OC et al. The influence of extracellular matrix on the generation of vascularized, engineered, transplantable tissue. Annals of the New York Academy of Sciences. 2001;944:429-442
  191. 191. Parra-Cid C, García-López J, García E, Ibarra C. An enteric nervous system progenitor cell implant promotes a behavioral and neurochemical improvement in rats with a 6-OHDA-induced lesion. Neurotoxicology and Teratology 2014;43:45-50
  192. 192. Salewski RP et al. Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through remyelination of axons. Stem Cells Translational Medicine. 2015 Jul;4(7):743-754
  193. 193. Teixeira FG et al. Mesenchymal stem cells secretome: A new paradigm for central nervous system regeneration? Cellular and Molecular Life Sciences. 2013;70:3871-3882
  194. 194. Oliveri RS, Bello S, Biering-Sørensen F. Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: Systematic review with meta-analyses of rat models. Neurobiology of Disease. 2014;62:338-353
  195. 195. Nakajima H et al. Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. Journal of Neurotrauma. 2012;29(8):1614-1625
  196. 196. Hawryluk GWJ et al. An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells and Development. 2012;21(12):2222-2238
  197. 197. Quertainmont R et al. Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions. PLoS One. 2012;7(6)
  198. 198. Park HJ et al. Mesenchymal stem cells stabilize the blood–brain barrier through regulation of astrocytes. Stem Cell Research & Therapy. 2015 Dec;6(1):187
  199. 199. Saberi H et al. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: An interim report on safety considerations and possible outcomes. Neuroscience Letters. 2008;443(1):46-50
  200. 200. Saberi H et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. Journal of Neurosurgery. Spine. 2011 Nov;15(5):515-525
  201. 201. Bastidas J et al. Human schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord. Glia. 2017 May;65(8):1278-1301
  202. 202. Zhang J et al. The effects of co-transplantation of olfactory ensheathing cells and Schwann cells on local inflammation environment in the contused spinal cord of rats. Molecular Neurobiology. 2017 Mar;54(2):943-953
  203. 203. Ekberg JK, St John J. Olfactory ensheathing cells for spinal cord repair: Crucial differences between subpopulations of the glia. Neural Regeneration Research. 2015 Sep;10(9):1395
  204. 204. Wang C et al. Improved neural regeneration with olfactory ensheathing cell inoculated PLGA scaffolds in spinal cord injury adult rats. Neuro-Signals. 2017 Mar;25(1):1-14
  205. 205. Olson L. Combinatory treatments needed for spinal cord injury. Experimental Neurology. 2013 Oct;248:309-315
  206. 206. Zhao R-R, et al. Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. European Journal of Neuroscience. 2013 Jun;38(6)
  207. 207. Shinozaki M et al. Combined treatment with chondroitinase ABC and treadmill rehabilitation for chronic severe spinal cord injury in adult rats. Neuroscience Research. 2016 Dec;113:37-47
  208. 208. Suzuki H et al. Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. PLoS One. 2017;12(8)
  209. 209. Buzoianu-Anguiano V et al. The morphofunctional effect of the transplantation of bone marrow stromal cells and predegenerated peripheral nerve in chronic paraplegic rat model via spinal cord transection. Neural Plasticity. 2015;2015:389520
  210. 210. Weishaupt N et al. Synergistic effects of BDNF and rehabilitative training on recovery after cervical spinal cord injury. Behavioural Brain Research. 2013;239(1):31-42
  211. 211. Leech KA, Hornby TG. High-intensity locomotor exercise increases brain-derived neurotrophic factor in individuals with incomplete spinal cord injury. Journal of Neurotrauma. 2017;34(6):1240-1248
  212. 212. Moghaddam A et al. Elevated serum insulin-like growth factor 1 levels in patients with neurological remission after traumatic spinal cord injury. PLoS One. 2016;11(7):1-17
  213. 213. Dietz V. Improving outcome of sensorimotor functions after traumatic spinal cord injury. Research. 2016;5(May):1018
  214. 214. Jones ML et al. Activity-based therapy for recovery of walking in individuals with chronic spinal cord injury: Results from a randomized clinical trial. Archives of Physical Medicine and Rehabilitation. 2014 Dec;95(12):2239-2246.e2
  215. 215. Lam T et al. Training with robot-applied resistance in people with motor-incomplete spinal cord injury: Pilot study. Journal of Rehabilitation Research and Development. 2015;52(1):113-130
  216. 216. Sadowsky CL et al. Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury. The Journal of Spinal Cord Medicine. 2013;36(6):623-631
  217. 217. Angeli CA et al. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014 May;137(Pt 5):1394-1409
  218. 218. Xiao Z et al. One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Science China. Life Sciences. 2016 Jul;59(7):647-655
  219. 219. Ahuja CS et al. Traumatic spinal cord injury—Repair and regeneration. Neurosurgery. 2017 Mar;80(3S):S9-22
  220. 220. Study of Human Central Nervous System Stem Cells (HuCNS-SC) in Patients with Thoracic Spinal Cord Injury. 2016. Available from:
  221. 221. Dasari VR. Mesenchymal stem cells in the treatment of spinal cord injuries. World Journal of Stem Cells. 2014;6(2):120
  222. 222. Ide C, Nakano N, Kanekiyo K. Cell transplantation for the treatment of spinal cord injury–Bone marrow stromal cells and choroid plexus epithelial cells. Neural Regeneration Research. 2016 Sep;11(9):1385-1388
  223. 223. Li L. A et al. effects of transplantation of olfactory ensheathing cells in chronic spinal cord injury: A systematic review and meta-analysis. Eur. The Spine Journal. 2015 May;24(5):919-930
  224. 224. Tabakow P et al. Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transplantation. 2013 Sep;22(9):1591-1612

Written By

Elisa Garcia, Roxana Rodríguez-Barrera, Jose Mondragón-Caso, Horacio Carvajal and Antonio Ibarra

Submitted: 15 March 2017 Reviewed: 28 November 2017 Published: 13 June 2018