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].

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 [50–52]. 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, 52–55].

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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

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

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

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

transforming growth factor β (TGF-β) [64] and INF-γ, among others [62].

and endocrine tissue that aggravate the degeneration process of major functions [57].

2.2. Chronic phase

modulation of the immune response [61].

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 [50–52]. 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, 52–55].

## 2.2. Chronic phase

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 for-

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

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,

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 regulat-

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),

mation of a glial scar that acts as a barrier against possible regeneration [37, 38].

possibility of reparation and tissue regeneration [40, 41].

28 Essentials of Spinal Cord Injury Medicine

destroying the necessary anatomic substrate for neurological recovery [40].

ing the immunological response and subsequent phases [43].

neurotrophin-3 (NT-3) and brain neuronal derived factor (BNDF) [43, 47].

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].

are limited to surgical decompression, blood pressure control, and the possible use of methyl-

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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

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 objec-

Treatment outcome References

[78, 79]

[80, 81]

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

Increases the survival and reinnervating capacity of injured motor neurons; conferred significant neuroprotection and behavioral recovery, sparing

preservation.

both gray and white matter.

prednisolone (MP), which is not recommended due to its secondary effects [76].

recovery [77].

3.1. Pharmacological therapies

tives are mentioned in Table 1.

Therapy Mechanism of

Preclinical therapies Ionic channel blockers

Sodium a) Tetrodotoxin

b) Riluzole

neuroprotection ↑ Increase ↓ Decrease () Blocked (+) Activated

SCI

() Sodium entry channels after

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].
