Methylprednisolone (MP) is one of the most commonly used pharmacological agents. The basic background is based on the anti-inflammatory effects of steroids. In an animal study, the antioxidant effect, and reduction of expression of inflammatory cytokines such as TNF-α, IL-1, and IL-6 have been demonstrated.30313233) Based on these experimental results, three major clinical trials have been performed since 1984.343536) Recently, the Congress of Neurological Surgeons released its opinion on the usage of high-dose steroids for treating SCI through a systematic review.37) In this review, it concluded that the beneficial effects of MP administration in the setting of acute SCI are inconsistent with the absence of convincing and significant neurological improvement. Moreover, as harmful side effects of MP in the setting of acute SCI have been reported with high clinical evidence, it denied recommending the use of MP for the treatment of acute SCI.

Gangliosides, sialic acid-containing glycophospholipids, are major components of cell membranes of the mammalian central nervous system. Among them, GM-1 ganglioside has been reported to have neuroprotective and neuroregenerative functions. Induction of neurotrophic factors, anti-excitotoxic effects and promotion of neurite growth in pathologic conditions were also reported.38) Based on these findings, clinical trials of GM-1 in SCI have been performed from the 1990s to the early 2000s.394041) Accelerated recovery of motor function and bowel/bladder function was noted in the first 3 months post-injury in a randomized double-blinded study.41) However, subsequent studies have not been performed to confirm or refute these results in the last decade.

Excitotoxicity, as one of the secondary mechanisms, has been investigated as the target of neuroprotective trials for SCI. Antagonists of ionotropic receptors (N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]-kainate receptor) have been experimentally investigated for treatment of SCI, and they showed neuroprotective effects on histological and biochemical analyses.12134243) Anti-apoptotic and anti-inflammatory effects and decreased proliferation of astrocytes were reported.12) A phase II clinical trial was also performed using a noncompetitive NMDA receptor antagonist, gacyclidine.44) At the l-month follow-up, clinical results, which were assessed by the American Spinal Injury Association (ASIA) scale, showed an improvement in the studied patients; however, results at 12 months posttreatment failed to show a long-term benefit in this trial. After that, there is a lack of clinical trials and evidence, and experimental trials for preventing excitatory neurotoxicity by using various other agents are still underway.

The receptor for erythropoietin (EPO) is widely observed in the developing and adult brain, and it is upregulated in the condition of trauma. Beneficial effects of peripherally administered EPO on neurogenesis and neuronal differentiation were noted in an animal study.4546) For neuroprotective anti-inflammatory, anti-oxidant effects and induction of neurotrophic factors, there are other proposed mechanisms of neuroprotective effects following SCI.4748) As concerns such as excessive stimulation of hematopoietic activity and the possibility of thrombosis in clinical trials of EPO are suggested, a clinical trial for SCI has not yet been performed.

Intracellular ionic over-influx is related to the excitability of the affected neuron and death of neurons and glial cells. Especially, calcium influx into the cell following SCI is known to result in cell death due to excitotoxicity. Nimodipine, one of the Ca²⁺ channel blockers, has shown neuroprotective effects in SCI in animal studies.49) But, another report did not demonstrate any superiority compared to the control group at the 1-year follow-up.50)

The physiology of voltage-gated Na⁺ channels and K⁺ channels associated with the node of Ranvier in normal myelinated axons is well known. When demyelination occurs due to pathologic conditions, the constraining effect of myelin on K⁺ channels is lost. Consequently, the action potential progressively declines, resulting in conduction failure and marked slowing of the conduction velocity.

Demyelination of intact and injured axons is a prominent feature of SCI. A double-blind, randomized, placebo-controlled, parallel group phase II clinical trial performed to assess the safety and efficacy of fampridine-sustained-release, a blocker of rapidly inactivating voltage-gated K⁺ channels, showed a significant improvement in subject global impression scores and spasticity in chronic SCI patients with use of a low dose.51) However, in the patients who received a high dose of fampridine, a higher discontinuation rate was noted due to more frequent adverse side effects such as generalized spasm, hypertonia, insomnia and dizziness compared to the low dose and control groups.

Minocycline is most lipid-soluble of the tetracycline-class antibiotics, showing the greatest penetration into the central nervous system through the BBB. Neuroprotective effects of minocycline have been demonstrated in animal studies of SCI. Its proposed mechanism of neuroprotection includes anti-inflammatory and anti-apoptotic effects and a decrease in the activation of microglia.1352) A recent double-blind, randomized, controlled study performed to assess the safety and dose optimization showed a significant ASIA score improvement in cervical SCI patients at 1 year after injury.53)

Despite promising experimental and clinical results in the 1970s, its efficacy in clinical use has been limited. Studies on hypothermia for treating traumatic SCI became less popular by the 1980s because of potential complications related to systemic hypothermia. Since successful application of hypothermia in an American football player who sustained a cervical SCI is already known, resurgence in the interest in systemic hypothermia has arisen. Neuroprotective effects of systemic and regional hypothermia have been demonstrated.5455) Lately, a technique for rapid and safe induction of hypothermia using an intravascular catheter to reduce systemic complications, such as coagulopathy, sepsis, and cardiac dysrhythmia, was developed and approved by the Food and Drug Administration (FDA). Recent reports on clinical application of modest (33℃) hypothermia showed that 15 of the total 35 patients with cervical SCI improved at least one neurological grade (ISNCSCI) at the last follow-up at 10 months. The overall risk of thromboembolic complications was 14.2%.56) However, because of a lack of sufficient randomized clinical trial data, the Congress of Neurological Surgeons Joint Section on Disorders of the Spine and Peripheral Nerves recently decided that not enough evidence is available to recommend for or against the practice of therapeutic hypothermia as a treatment for SCI.37)

Spontaneous remyelination is known to occur after SCI. Increased remyelination following neural precursor cell transplantation was correlated with improved functional recovery in an animal model of SCI.5758) However, it is possible to achieve axonal conduction ability without remyelination, even if denuded axons persist over a long region of demyelination. For this adaptation, it is known that increased expression of Na⁺ channels along the length of the demyelinated internodes is required. This upregulation of Na⁺ channels causes more energy consumption as the influx of sodium is a procedure that requires energy.59) However, as myelination plays essential roles in effective propagation of the action potential and survival of axons and corresponding neurons, remyelination is an attractive therapeutic target in regenerative trials following SCI.

Historically, the following two approaches for improving remyelination have been attempted: cellular transplantation and enhancement of the endogenous repair process. Among various cell sources including Schwann cells, olfactory ensheathing cells, neural progenitor cells and oligodendrocyte progenitor cells (OPCs), OPCs have been widely studied.5960616263) The transplantation of human embryonic stem cell-derived OPCs (hESC-derived OPCs) into rat spinal cord injuries has been found to enhance remyelination and promote improvement in motor function.6465)

Enhancing endogenous repair is another crucial aspect of remyelination. In the pathologic condition caused by SCI, differentiation of OPCs from ependymal stem cells or other neuronal stem cells was also noted besides recruitment of OPCs from surrounding parenchyma.6667) On this background, basic fibroblast growth factor, insulin growth factor 1, and ciliary neurotrophic factor have successfully demonstrated positive effects on proliferation of OPCs.6869)

To date, it is understood that there are two distinct limitations in regeneration after CNS injury: the limited intrinsic regenerative potential and the inhibitory environment of the injured CNS. A comparison of myelin from the CNS and the peripheral nervous system has revealed that CNS white matter is selectively inhibitory for axonal outgrowth. In the late 1980s, Caroni and Schwab7071) demonstrated that oligodendrocyte myelin was a major inhibitor of axonal growth in the CNS. Two inhibitory fractions (35 and 250 kDa) were recognized in these myelin preparations (NI 35 and NI 250, subsequently identified as Nogo), and a monoclonal antibody (termed IN-1) was developed to block these inhibitory factors. The IN-1 antibody also caused a moderate degree of axonal regeneration and functional recovery after SCI.

Chondroitin sulfate proteoglycan (CSPGs) in the injured CNS plays a role in inhibiting axonal regeneration. The degrading enzyme chondroitinase ABC (ChABC) cleaves the inhibitory glycosaminoglycans from the protein core of CSPGs, thereby removing the axonal growth inhibitory properties of intact CSPGs. Local and systemic administration of ChABC caused axonal regeneration and functional recovery in an animal model.7273)

Besides the trials described above, alteration of the microenvironment of the injured spinal cord has been considered as one of the promising targets. Enhancement of survival of the transplanted cells and induction of intrinsic potent stem cells are the goals.

Timing of cell transplantation is one of the most important points that needs to be considered because transplantation in the acute phase of SCI results in a low rate of engraftment by severe inflammatory environment, and transplantation in the chronic phase results in a low rate of engraftment and functional restoration due to a glial scar.74) Therefore, co-transplantation of mesenchymal stem cells with manipulated neural stem cells in the acute phase of SCI has been attempted in order to modulate the acute inflammatory condition and to enhance survival of the transplanted cells.75) To overcome the glial scar, use of chondroitinase ABC (ChABC) for CSPG degradation has also been attempted.

Enhancing the production of endogenous neural/progenitor cells is one of the attractive ways which avoids ethical issues and possible concerns related to cell manipulation. Subventricular zone of the brain and ependymal cells are the sources of cellular recruitment for neural regeneration. Ependymal cells of the spinal cord are descended developmentally from neuroepithelial stem cells located in the ventral neural tube. In lower vertebrates, ependymal cells play an important role in the regeneration observed following spinal cord transection. However, in mammals, who are known to have a lack of regenerative ability, ependymal cells are thought to perform primary functions such as endocrinologic or protective functions instead of regenerative functions. Recent studies show that ependymal cells undergo reactive proliferation, and express neural stem cell properties following SCI.767778) Further work is still needed to determine the exact mechanism and its therapeutic possibility.