**2.1. Neuroinflammation**

**1. Introduction**

2 Essentials of Spinal Cord Injury Medicine

injuries.

quality of life.

**2. Pathology**

Intensive lifestyle brought about by the modern age of the twenty-first century often brings risks of trauma to the CNS. Both trauma of brain and spinal cord are considered not only as lifethreatening conditions, but also as substantial, social, and economic problems that affect mainly the young population. The increased incidence of trauma may be related to popular sports such as ice hockey, American football, rugby, horse riding, and diving, but the most common causes include traffic accidents [1]. Spinal cord trauma accounts for 70% of the total number of CNS

Many spinal cord (SCI) patients remain permanently paralyzed with complete or partial loss of neurological functions below the site of injury [2]. The most common is paralysis of the body, usually affecting both lower limbs. At the same time, complications may arise when loss of sensitivity, urinary tract control, or the development of spasticity occur in the affected area [3]. Statistics shows that victims are twice as often men as women, with the highest occurrence of cases between the 19 and 40 years of age [4]. Care for patients with injured spinal cord is

The neurological outcomes depend on the range of damaged neuronal populations at the injury site, the level of disconnection of ascending and descending neuronal pathways, the secondary damage (edema, inflammation, and ischemia), and the age-dependent activation of regenerative processes (endogenous production of trophic factors and revascularization). Thus, patients with incomplete injury who retain some sensory or motor function below the lesion, undergo an extensive rehabilitation program to have a better chance of recovering some function. On the contrary, severe spinal cord injury causes a life-lasting disability for which currently no effective therapy is available. Another important factor is age; statistics

Therefore, the main objective of biomedical research is the development of new therapeutic procedures that would contribute to a more effective functional outcome and improvement of the

In this chapter, we would like to highlight pathological consequences that could be evaluated by temporal and spatial proteomic analyses, leading to discrimination of the proteome within the entire spinal cord after acute injury. These data will be correlated with delivery of individual neuroprotective and combinatory neuroregenerative strategies for SCI treatment.

Spinal cord trauma triggers a pathophysiological complex of cellular and molecular reactions leading to edema, hemorrhage, free radical formation, glutamate excitotoxicity, ischemia, macrophage phagocytic activation, glial scar formation, and apoptotic changes in the injured tissue [5]. These processes take place within a few minutes to weeks and years after the injury.

demanding and often requires lifelong financial costs [4].

shows that younger patients have better prognosis of recovery.

In the CNS, immune cells acquire diverse phenotypes depending on the pathophysiology of the microenvironment.

The inflammatory environment of injured spinal cord contains pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukins IL-1 and IL -6. Anti-inflammatory molecules, like transforming growth factor β1 (TGFβ) and IL-10, are released as well. Immune response in the CNS is mediated by resident microglia and astrocytes, which are innate immune cells without direct counterparts in the periphery.

Among glial cells, microglia are firstly activated and are able to play a bifunctional role. They secrete toxic factors and contribute to tissue damage, but at the same time also release neuroprotective and neurotrophic molecules to allow tissue repair [11]. Interestingly, microglia and astrocytes are able to cross-talk with CNS-infiltrating immune cells, such as neutrophils, T cells, and other components of the innate immune system, as well as with neurons.

**Neutrophils** are considered as the first inflammatory cells to arrive at the site of injury with a peak at 24 h after injury [12]. They are rapidly mobilized from the bone marrow in response to signals from pro-inflammatory CXC (CXCL8) family chemokines, IL- and cytokine-induced neutrophil chemoattractant 1 (CINC-1) to mediate pleiotropic functions in the immuneinflammatory response [13]. Neutrophils adhere to post-capillary venules 6–12 h post SCI and afterwards they migrate into the lesion site to phagocytose debris [14]. Neutrophils generate their own cytokines after stimulation by pro-inflammatory mediators and produce proteases via the NF-kB translocation pathway. Phagocytic activity can induce NF-kB activation [15, 16], and other mediators such as matrix metalloproteases (MMPs), and cytokines TNFα, IL-1, IL-8, and TGF-β [17].

Activated astrocytes proliferate and, together with other glial cells, produce a glial scar that encloses the lesion site and prevents the diffusion of ions, neurotransmitters, and other metabolites from damaged tissue into surrounding healthy tissue [22]. This protects undamaged tissue from inflammation and demyelinization, while at the same time, it also prevents regeneration of nerve fibers, which is a serious problem for the treatment of spinal cord injuries. Activated astrocytes reveal thicker projections that intersect with each other and are connected by tight joints. Astrogliosis is accompanied by increased expression of glial fibrillary acidic protein (GFAP), vimentin, and markers for neural precursor cells (Nestin) [23]. In reactive astrocytes, increased synthesis of extracellular matrix protein CSPGs has been reported, which are inhibitory to axon growth itself [23]. Similarly, oligodendroglia, together with meningeal cells migrating into the lesion, form a significant barrier for axonal growth by producing inhibitory molecules (NOGO)

Understanding Molecular Pathology along Injured Spinal Cord Axis: Moving Frontiers…

http://dx.doi.org/10.5772/intechopen.72118

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NOGO inhibitory protein [25, 26], myelin glycoprotein oligodendrocyte (OMGP) [27], myelinassociated glycoprotein (MAG) [28] together with secondary inhibitors, including the large group of chondroitin sulfate proteoglycans (CSPGs), are among the major inhibitory molecules that block axonal regeneration [24, 29]. While blocking the penetration of axons, they contribute to the formation of so-called blind clusters, unable to form functional connections with terminal neurons. These pathological formations often cause painful irritable syndrome [30]. Inhibitory CSPGs are synthesized by neurons and glial cells. They play an important role in the physiological development of the CNS, such as cell migration, maturation, differentiation, survival, and tissue homeostasis, but in the case of disruption of tissue homeostasis, increase their expression and consequently inhibit regeneration [31]. These molecules interact extensively with extracellular matrix components [32], for example, with laminin, fibronectin, tenascin, and collagen [33]. Additionally, they bind to growth factors, midkine, pleiotrophin, fibroblast growth factor [34], or inhibitory growth factors such as semaphorins [19] and contribute to the formation of a glial scar that inhibits regeneration of axons [35]. NG2 glycoprotein, which belongs to the most important inhibitors of the CSPGs group, is produced by oligodendrocytes precursor, meningeal cells and macrophages [36]. Accumulation of NG2 was seen at the site of injury, where it blocks regeneration of the axons [31]. Co-expression of NG2 and PDGF-α receptors in the same population of CNS cells confirmed its specific expression in oligodendrocyte precursors [37]. NG2-positive oligodendrocyte precursor cells are often the first cells to respond to injury. Unlike microglia, reactive oligodendrocyte changes are local and occur only in the immediate vicinity of the injury. Previous experiments confirm the initiation of spontaneous regeneration in SCI, as reflected by the incidence of GAP-43-positive axons. They were found in the segments above the lesion at first week [38]. In the central lesion, which forms a mechanical and chemical barrier, the inhibitory proteoglycan NG2 was significantly enhanced [39]. Immunohistochemical analyses using specific NG2/GAP-43 antibody confirmed that increased accumulation of NG2-positive cells at the central injury creates a barrier for successful diffusion and further ingrowth of GAP-43-labeled axonal fibers at acute phase [38]. Sequential administration of ChABC enzyme caused degradation of NG2 glycoprotein, which modified the extracellular matrix and created a tolerant environment for longer term recovery (2–3 weeks).

and other proteoglycans [24].

**2.4. Inhibitory molecules**

**Microglia** are a unique myeloid cell population, derived from the yolk sac during a narrow time window during development (before vascularization or definitive hematopoiesis) in the embryo. Microglia cells, present in the CNS parenchyma, are sustained by the proliferation of resident progenitors, independently of blood cells.

Their response following pathological stimuli is characterized by an accumulation at the lesion site and the release of various bioactive molecules. Two categories of molecules are released, some are cytotoxic or pro-inflammatory, and others may aid survival and regeneration. Resident monocytes are the first cell types to respond after injury within 1–2 h, which starts the initial acute inflammatory response accompanied by an expression of TNFα and IL-1 (M1 phenotype). This leads to the recruitment of other immune cells. M1 macrophages promote phagocytosis. Eight hours after injury, the production of pro-inflammatory cytokines is terminated, thus promoting the differentiation of macrophages into an anti-inflammatory M2 phenotype with the expression of arginase 1 and a mannose receptor (CD206). M2 macrophages promote angiogenesis and matrix remodeling, while suppressing destructive immunity [18]. The ratio M1/M2 varies in terms of the microenvironment.

These findings correlate with accumulating evidence pointing to a chronological time line expression of different degeneration- and regeneration-associated genes that are involved in the pathogenesis and endogenous repair or plasticity during days to months following SCI.
