PATHOGENETIC ASPECTS OF TRAUMATIC SPINAL CORD INJURY AND THERAPEUTIC PERSPECTIVES (LITERATURE REVIEW)
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].
Necrosis
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].
Necroptosis
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.
Autophagy
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].
Apoptosis
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].
CONCLUSION
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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