Khokhlova O.I.

Novokuznetsk Scientific and Practical Centre for Medical and Social Expertise and Rehabilitation of Disabled Persons, Novokuznetsk, Russia

Traumatic spinal cord injury is associated with high rate of mortality and disability, with high social and economic influence on patients, their families, society and healthcare system [36, 39].
Owing to advances in medicine, rehabilitation and care, persons with spinal cord injury can live within decades after a traumatic event [57]. However, most persons face to serious problems including limitation of mobility, loss of sensitivity, disordered functions of internal organs, high rate of secondary complications and psychoemotional disorders which influence on all aspects of life.

Currently, there is not any efficient treatment, which promotes regeneration of axons, and recovery of lost neurological functions after spinal cord injury [20]. It determines the necessity for deep understanding of pathophysiology of spinal cord injury for determination of new therapeutic strategies [10]. As result, the objective of the study was analysis of literature data on mechanisms of traumatic spinal cord injury, and possibilities of pathogenetically substantiated therapy.

Mechanisms of traumatic spinal cord injury

Mechanisms of traumatic spinal cord injury include factors of primary and secondary injury [3, 58, 72]. Primary injury is presented by mechanic injury to nervous tissue and vascular network with fast death of cells and with bleeding [19]. Primary  injury appears as result of influence of physical forces on the spine and the spinal cord (flexion, extension, rotation, displacement, compression and their combination). The most common form of primary spinal cord injury is contusion with continuous compression, which usually appears after vertebral fractures with formation of bone fragments.

Acute phase of secondary spinal cord injury

The process of secondary injury can be divided into several stages in dependence on time interval from injury, and on a pathomechanism: acute, subacute (or intermediate) and chronic phases. It is considered that the acute phase lasts for 48 hours after primary physical injury [52]. Neurogenic shock, bleeding and subsequent hypovolemia and hemodynamic shock in patients with spinal cord injury causes disorders in spinal cord perfusion and ischemia [19]. Bigger vessels, such as the anterior spinal cord artery, usually stay intact, whereas rupture of smaller intramedullary vessels and capillaries, which are exposed to traumatic injury, leads to extravasation of leukocytes and erythrocytes. High tissue pressure in edematous injured spinal cord, and hemorrhage-induced spasm of intact vessels cause even higher disorders of spinal cord perfusion. Finally, bleeding and ischemia cause cell death and destruction of tissues through multiple mechanisms, including oxygen deprivation, loss of adenosine triphosphate (ATP), excitotoxicity, ion disbalance, and formation of free radicals [1]. Cellular necrosis and release of cytoplasmic substances increase the extracellular level of glutamate, resulting in glutamate excitotoxicity [19]. Recovery of blood flow in ischemic tissue (reperfusion) causes further injury by means of generation of free radicals, and activation of inflammatory response [8, 19]. Moreover, activated microglia and astrocytes, as well as peripheral infiltrating leukocytes, release cytokines and chemokines, which create proinflammatory microenviroment [8, 33, 58]. Cumulatively, it leads to progressing destruction of CNS tissue, known as "tissue injury of observer", resulting in significant worsening of functional recovery [77].
The literature data shows the efficiency of early surgical treatment of spinal cord injuries. Although optimal terms remain disputable, spinal cord decompression, vertebral stabilization and maintenance of blood perfusion are critical factors for achievement of optimal results for this abnormality. Although there are a lot of reports on improvement in neurological outcomes by means of early surgical decompression, there is not any uniform opinion in relation to the term early decompression: it varied from 4 hours to 4 days, but with a
  current trend (since 2010) to decompression within 24 hours after injury [28]. Particularly, it has been shown that surgical management of cauda equina syndrome within 24 hours promotes preservation of pelvic organs functioning. The worst results were observed in decompression after 48 hours from trauma [45]. A study by
D.-Y. Lee et al. (2018) showed that surgical decompression of the spinal cord within 8 hours after spinal injury between C1-L2, as compared to time interval of 8-24 hours, significantly improves neurological recovery. It allowed recommending early decompression (within 8 hours) as efficient treatment of spinal cord injuries [53]. Some similar results were reported by O. Tsuji еt al. (2019): patients with full motor paralysis after cervical spine fracture can recover to partial paralysis if surgical management was conducted within 8 hours after trauma [70]. Considering the complex synergetic effect of mechanisms of secondary injury to the spinal cord, such approach is pathogenetically substantiated.

Systemic inflammatory response syndrome

The studies with rodent models showed the dependence of CNS secondary injury on acute phase response, and systemic inflammatory response, mainly in the liver [7]. In response to CNS injury, liver expression of proinflammatory mediators significantly elevates already in two hours after an event. In its turn, these mediators initiate mobilization and priming of leukocytes from bone marrow which then translocate to the injury site and, probably, to non-involved peripheral organs. The spleen releases proinflammatory monocytes and increases expression of interferon-γ (IFN-γ), tumor necrosis factor (TNF) and IL-6 [12, 63]. SIRS, which can cause multiple organ dysfunction syndrome (MODS), is a common event in patients with CNS injury [17, 69]. Simultaneous immune suppression of adaptive immune components [15] is often observed. Therefore, patients are very sensitive to infections, and peripheral immune responses significantly increase the mortality and morbidity.
It has been shown that suppression of peripheral immune response decreases the activity of inflammatory process in CNS [18, 23].

Modulation of acute phase of inflammation (by means of targeting to release of acute phase proteins or depletion of Kupffer cells) decreases neutrophil recruitment in CNS in models of traumatic injury to the brain and the spinal cord. As result, suppression of acute phase of inflammation can offer the alternative strategy for minimization of tissue losses and functional deficiency after CNS traumatic injuries. However, one should accept that modulation of systemic inflammation is difficult. Despite some disputable moments, some data shows that exacerbation of peripheral inflammation can promote a decrease in size of lesion, and infiltration of leukocytes to CNS after trauma [22]. It was suggested that systemic response could be immune distraction, with redistribution of leukocyte populations from injured CNS to other regions, although mechanisms of this redistribution is unclear [7]. Also the signal, which initiates activation of peripheral response, is unclear.   
Yates A.G. et al. believe that mediators of communication between remote organs can be extracellular vesicles [78]. Extracellular vesicles (EVs) present the general term, which defines all cell-derived particles incapsulated in lipid bilayer. These particles are enriched with proteins, lipids and nucleatic acids. EVs are usually classified in concordance with their biogenesis: apoptotic cells (1,000-5,000 nm) release from plasmatic membrane as a part of programmed cell death; microvesicles (150-1,000 nm) release from cellular membrane; exosomes (40-150 nm) are generated by endolysosome pathway, and are kept in multivesicular organs up to release by means of exocytosis. The authors understand the acute phase mechanism in the following manner. Acute traumatic injury to the brain or the spinal cord causes release of extracellular vesicles into blood flow. These vesicles are located in peripheral organs. As result, they induce the release of proinflammatory molecules (chemokines, cytokines, acute phase proteins), stimulating the mobilization of leukocytes, which enter CNS and peripheral organs.
Therefore, besides local changes in the spinal cord, more attention is given to influence of peripheral organs on pathophysiology of spinal cord injury [7]. Great attention is given to the spleen. A study by Badner A. et al. shows that the spleen participates in secondary pathophysiology of spinal cord injury by means of increasing inflammatory transfer of signals [9]. Moreover, the spleen plays
  the important role in stromal cell-mediated immunomodulation, i.e. peripheral immune tissues can be therapeutic target in spinal cord injury. As the authors believe, this discovery can help in adaptation of cellular therapy and all systemic interventions to maximize the efficiency [9]. Previously, Badner A.,Vawda R. et al. supposed participation of IL-10 in cell-mediated immune modulation. They think that IL-10 makes the neuroprotective action in CNS injuries [10].

An agent with strong anti-inflammatory action and neuroprotective potential for traumatic spinal cord injury is methylprednisolonum sodium succinate (MPSS), a synthetic corticosteroid. Its use is limited by high risk of secondary infections [71]. However, there is a manual (2017) from AO Spine North America, AO Spine International, and AANS/CNS (AANS – American Association of Neurological Surgeons; CNS – Congress of Neurological Surgeons). According to these guidelines, 24-hour high dose infusion of MPSS is recommended as a variant of treatment for adult patients with spinal cord injury. If treatment is initiated within the first 8 hours after trauma (quality of evidence − moderate; strength of recommendation -weak) [32].

Lipid peroxidation

One of the key mechanisms of secondary injury after spinal cord trauma is lipid and protein peroxidation [19]. The final products of the stage of "completion" of lipid peroxidation is 4-hydroxynonenal (HNE) and 2-propenal, which are very toxic for cells [40, 41].
Subsequences of lipid and protein peroxidation at cellular level include respiratory and metabolic insufficiency of mitochondria, and changes in DNA, which finally result in cell death [3].

Lipid peroxidation is the main cause of cellular membrane destabilization such as cytoplasmic membrane and endoplasmic reticulum, resulting in dysfunction of Na +/K + ATPase, disorders of permeability for ions and intracellular overload with Na + ions [19]. Combination of events
  after intake of Na ions into the cell causes regional cell death and present the main pathogenesis of secondary injury to nervous system. This mechanism of secondary injury is the basis for use of measures, which block natrium channels, for decrease in injury degree [31]. According to
Fehlings M.G. et al., a perspective agent is riluzole (anti-seizure medication) [31]. Neuroprotective effects of riluzole are probably associated with blocking of natrium channels, and prevention of excessive intake of Ca2+ cell. Moreover, riluzole plays the role of antiglutamatergic agent by means of inhibition of release of glutamate. prevention of hypofunction of glutamate receptor, and increasing uptake of glutamate through activation of glutamate transporters. Multi-sided influence of riluzole on excitotoxicity and neuromodulation makes it the perspective variant of neuroprotective treatment after spinal cord injury. The group of  researchers headed by Fehlings M.G. confirmed the effect of riluzole for spinal cord injuries in rats. Currently, a clinical randomized double blinded multi-center placebo-controlled study is being conducted, which includes two groups of patients with spinal cord injury. It will be completed in 2021 as expected [31].

Subacute phase of secondary injury to the spinal cord

The subacute phase of traumatic spinal cord injury lasts up to 2 weeks after trauma. The feature of this phase is phagocytal response. In 24 hours after spinal cord injury, peripheral blood monocytes enter the lesion focus, with manifestation of macrophagal activity. Resident microglia becomes morphologically undistinguishable from infiltrated macrophages, which originate from monocytes [14]. There is a phenotypic spectrum of macrophages originating from monocytes or microglia, from proinflammatory (M1, which releases TNFα, IL-1β, IL-6, IL-12) to proreparative (M2, which releases IL-10, IL13). After confirmation of spinal cord injury, a mixed response of M1/M2 is initially observed [48]. Release of proinflammatory cytokines in the injury site additionally mobilizes resident cells and blood cells to phagocytosis  debris [37, 38], and influences on phenotype of other resident cells. Monocytes or microglia-released  macrophages remain in the injured spinal cord forever [24].
Another feature of subacute phase of traumatic spinal cord injury is reactive proliferation of astrocytes - astrogliosis [59]. Astrogliosis supposes deep molecular and functional rebuilding of astrocytes [46], and consists of two phases: early hypertrophic neuroprotective phase, and hyperplastic phase with formation of glial scar, which hinders tissue regeneration [68]. The first phase promotes recovery of injured hematoencephalic barrier, the second phase - process of gliolisis. Up to the present time, glial scar was considered as the main cause of limited regeneration after central nervous system injury; it presents physical and molecular barrier in the injury site. It was shown that glial scar provides protection through inhibition of formation of aberrant synapse in the injured site [66], with limitation of inflammatory response and cellular degeneration [29]. Some other researchers present the data that astrocytic scars are the main factors, which maintain regeneration of axons, their positive roles in subacute phase of traumatic injury to CNS in such processes as local immunity, neuroprotection and tissue regeneration [6, 54, 64].

Schachtrup C. et al. found that reactive astrocytosis and deposition of extracellular matrix molecules of chondroitin sulfate proteoglycan (CSPG), produced by astrocytes, cause fibrinogen in the brain after hemorrhage which regulates TGF-β-mediated transfer of signal in CNS tissues after vascular injury [61]. The authors present the data that fibrinogen inhibits distention of neurons and activates microglia/macrophages. Therefore, fibrinogen can contribute to inhibiting medium after traumatic injury to CNS, resulting in accumulation of proteoglycans and direct suppression of axon regeneration, with activation of inflammatory response. Considering multi-sided functions of fibrinogen as proinflammatory and profibrinolytic blood protein in sites of vascular injuries, anticoagulant therapy, which prevents fibrin formation or fibrin binding with integrin receptors or growth factors, can be efficient for tissue regeneration [61].
Moreover, it was shown that high amounts of critical chondroitin sulfate proteoglycans were produced by non-astrocytic cells, mainly by macrophages and fibroblasts [6], which are the main units of fibrous scars.

Chronic phase of traumatic injury to the spinal cord

The chronic phase (or recovery stage) of spinal cord injury, as supposed, lasts for more than six months [49]. Formation of cysts and fibrous scars appears at this time.
Spinal cord injury causes significant response of fibroblasts [14], which originate from meningeal cells, if dura matter is injured [30], or from perivascular cells [67]. Fibroblasts produce components of intercellular matrix, including fibronectin, collagen of types 1 and 4, and laminin with formation of fibrous scar [50]. This scar presents the physical barrier for recovery of axon growth, but also produces some various inhibiting molecules, particularly, tenascin-C, ephirinB2 [47, 67].

Matrix components of fibrous scar can directly inhibit regeneration of nervous tissue, and promote long term remodeling of tissue by means of interaction with inflammatory cells [84]. It was shown that therapy for inhibition of fibrous scarring promotes regeneration of axons in various paradigms of CNS injury in mammals [50].

It is considered that fibrous scars are unidirectional and irreversible in spinal cord injury. It is supposed that their formation is regulated by complex and combined inter- and intracellular signal mechanisms. Transforming growth factor beta-1 (TGF-β1) is the key cytokine for fibrosis. It shows high expression after spinal cord injury, promotes activation of spinal fibroblasts in vitro [74]. However, cellular and molecular mechanisms of scar formation in fibrosis are not clear to the full degree [44]. A study by Wang W. et al. showed a relationship between expression of miR-21-5p and an increase in TGF-β1 after spinal cord injury (miR-21-5p – microRNA – small non-coding molecule of ribonucleic acid, length of 21 nucleotides, participating in transcription and posttranscription regulation of gene expression by means of RNA-interference, and playing the main role in realization of cellular response to induction of DNA injuries) [74]. The authors showed the role of miR-21-5p in formation of fibrous scar and regeneration of axons after spinal cord injury in studies in vitro and in vivo. It allowed making the conclusion on significance of results for therapeutic strategies for decreasing intensity of fibrous scar formation, and for improvement in functional results after spinal cord injury.
Molecular mechanisms of limitation of axon growth by CSPG are not clear completely. There is an assumption, which found its confirmation in some experimental studies: CSPG mediate suppression of neuronal growth mainly by means of binding and activation of functional receptors on cellular membranes [34]. The authors report that transmembrane leukocyte common antigen-related phosphatase receptor (LAR), a member of subfamily of receptor protein tyrosine phosphatase σ (RPTPσ), plays the important role in regulation of inhibition of axon lengthening, acting as receptor for CSPG receptors. Treatment with LAR-targeted
  peptides induces significant descendant growth of axons in caudal part of the spinal cord, and promotes recovery of motion function in rodents with traumatic spinal cord injury. The received results allowed making a conclusion that LAR-phosphatase is the new molecular target for acceleration of axon regeneration and recovery of injured CNS function [34].  Dyck S. et al. used specific functionally blocking peptides in a clinically significant model of contusion and compression injury to the spinal cord. They showed that inhibition of RPTPσ and LAR receptors promoted oligodendrogenesis performed by endogenous progenitor cells, weakened the caspase 3 mediated cell death in mature oligodendrocytes, and preserved myeline [27].
One of the common strategies for degradation of the main component of scars of CSPG is the use of enzyme, which is called chondroitinase ABC (ChABC), which breaks down glucosaminoglycan chains of CSPG. An animal study showed that introduction of this enzyme immediately after trauma significantly improved locomotor functions and promoted regeneration of axons below the injury site [43].

Main mechanisms of cell death in traumatic spinal cord injury

Cellular death is the main event in pathogenesis of damages after spinal cord injury [4, 27]. It can originate through various mechanisms in response to various mediators caused by trauma. Necrosis and apoptosis were initially determined as two main mechanisms of cell death after spinal cord injury [13, 75]. However some recent studies showed additional forms of cell death [3]. In 2012, Nomenclature Committee on Cell Death (NCCD) determined 12 various forms of cell death [35]. Currently, necrosis, necroptosis, apoptosis and autophagy are the most studied factors among all identified ways of cell death [3].


After trauma, neurons and glial cells die as result of necrosis after mechanic impact during primary injury and during acute and subacute phases of secondary injury [55]. Necrosis appears because of multiple factors, including accumulation of toxic blood components, glutamate excitotoxicity, ion disbalance, ATP depletion, release of proinflammatory cytokines by neutrophils and lymphocytes, and formation of free radicals. Necrosis was usually considered as sudden and non-programmed cell death without dependence on energy. Some recent studies showed another form of necrosis, which is called as necroptosis, stimulated by regulated mechanisms [55].


Programmed necrosis or necroptosis was described as strictly regulated, caspase-independent cell death with morphological characteristics similar with necrosis [26].
An experimental study by Liu M. et al. shows that inhibition of necroptosis by necrostatin-1 improves functional results after spinal cord injury [55]. These primary results show that modulation of necroptosis pathways is probably a promising strategy for neuroprotective strategies after spinal cord injury.


Spinal cord injury also causes disregulation of autophagy [56]. Usually, autophagy plays the important role in maintenance of cell homeostasis, promoting the metabolism of proteins and organelles. During autophagy, cells break down harmful, defective or useless cytoplasmic proteins and organelles by means of lysosome-dependent mechanisms [83]. The modern findings show the neuroprotective role of autophagy after spinal cord injury [42, 83]. Pharmacological induction of autophagy by Tat-Bec specific peptide in a mice model was associated with improved growth of neurons, and regeneration of axons after spinal cord injury, with evident therapeutic effect [42]. Autophagy is considered as a useful mechanism in spinal cord injury. Autophagy-enhancing agents can positively influence on cells of various types, promoting survival of neurons and oligodendrocytes, differentiation of oligodendrocytes, and decreasing neuroinflammation [76]. The role of autophagy in axonal homeostasis is still unclear, and further studies are required [42].


The most studied mechanisms of cell death after spinal cord injury is apoptosis. Apoptosis presents a well-programmed, energy-dependent way of cell death which is initiated within several hours after primary injury [3]. Apoptosis usually happens with delay in regions, which are remote from the injury site, and it has the strongest effect on oligodendrocytes. In rats with spinal cord injury, apoptosis appears already in 4 hours after trauma, and reaches the peak values on the 7th day [11].
Apoptosis is induced through external and internal pathways. The external pathway is initiated by activation of apoptosis receptors such as FAS and TNFR1, which activate caspase-8 [81]. The internal pathway is regulated by means of balance between intracellular pro- and antiapoptotic proteins, and is initiated by release of cytochrome C from mitochondria, and by activation of caspase-9 [81]. In spinal cord injury, apoptosis is mainly caused by trauma-induced uptake of
Ca 2+, which activates caspases and calpain. It is considered that death of neurons and oligodendrocytes in remote sites from lesion center can be mediated by cytokines (such as TNF-α), and free radicals since calcium hardly achieves these remote sites from injured cells in lesion site [5, 25]. FAS-mediated cell death was offered as a key mechanism of apoptosis after spinal cord injury [21, 60].
Postmortem studies of the spinal cord in the human and in animals showed the key role of FAS-mediated apoptosis in apoptosis of oligodendrocytes and in inflammatory response in acute and subacute stages of spinal cord injury [80]. Mice with deficiency of FAS demonstrate a high decrease in apoptosis and inflammatory response testified by reduction of macrophage infiltration and decreasing expression of inflammatory cytokines in the spinal cord. Moreover, mice with FAS deficiency demonstrate significant improvement in functional recovery after traumatic spinal cord injury [80]. These findings suppose efficiency of antiapoptotic strategies for decreasing intensity of secondary injury, and for prevention of extension of zone of spinal cord injury. Lanthionine and metformin, compound ester of ketimine, are considered as potential antiapoptotic agents in experimental research of animals with spinal cord injury [51, 73, 79]. It was shown that nimodipine, methylprednisolone and ganglioside were efficient clinical agents with antiapoptotic action in spinal cord injury [16]. Zhang Z. et al. showed antiapoptotic and neuroprotective effect of tauroursodeoxycholic acid (TUDCA) in a mice model of spinal cord injury at the early stage [82].

Dyck S. et al. performed a study in vitro, and found that apoptosis in populations of progenitor cells of nervous cells, and in progenitor cells of oligodendrocytes induce CSPG by means of LAR and RPTPσ. Therefore, the authors determined the role of these receptors in inhibition of oligodendrocytes differentiation, and in indirect initiators of apoptosis in the human injured spinal cord [27]. The use of specific blocking peptides is presented as a new real therapeutic strategy for spinal cord injury.

Therefore, there are a lot of approaches to limitation of cell death in spinal cord injury. However, variety of pathways of cell death, which are associated with crossing and various molecular mechanisms, such as narrow therapeutic windows for some types of neuronal cell death, are the obstacles for efficient therapy of neurotrauma caused by neuronal death [76]. Therefore, efficient neuroprotective strategies should simultaneously modulate multiple signal pathways to reflect spatial and time changes, which consist the basis of variety of neuronal cell death [76].


Therefore, traumatic spinal cord injury presents heterogenous and complex pathophysiology, including primary and secondary mechanisms of injury. Although both mechanisms are involved in neurological dysfunction, most studies are focused on understanding of pathophysiology of secondary injury. Presence of therapeutic targets in mechanisms of secondary injury has been shown. These mechanisms can be manipulated with corresponding exogenous interventions, which allow optimistic consideration of possible therapeutic perspectives.
Clinical therapy of spinal cord injuries includes three approaches: limitation of death of living cells, stimulation of growth of living cells, and replacement of injured cells [62]. Considering the variety of pathogenesis of the reviewed pathology, one should consider several complex tasks, including regulation of intensity of inflammation and lipid peroxidation, limitation of nerve cell death, limitation of scarry process, recovery of healthy nerve cells, stimulation of functional regeneration of axons. Despite of evident progress in these fields, multiple forces are still required for use of experimental data in clinical practice.

Information on financing and conflict of interest

The study was conducted without sponsorship.
The author declare the absence of any clear or potential conflicts of interests relating to publication of this article.


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