2.1.2. Edema

1. Introduction

24 Essentials of Spinal Cord Injury Medicine

quences on these functions [1, 2].

risk within the first year [3].

regeneration [4–6].

time phases of SCI.

transacted.

2. SCI pathophysiology

2.1. Acute and subacute phases

There are three main mechanisms of injury:

The spinal cord (SC) has three major functions in human beings: sensibility, autonomous control, and motor control. Destructive mechanisms following SCI can have grave conse-

Traumatic SCI can originate devastating consequences on patients and those close to them, requiring a great number of lifestyle adjustments. This injury results most commonly from vehicular accidents, falls, and sports injuries, among other traumatic accidents. According to the World Health Organization (WHO), there are approximately between 250,000 and 500,000 cases of SCI per year. Among these, 90% are traumatic in nature with an increased mortality

The pathophysiology of SCI can be divided into primary and secondary damage based on the self-destructive mechanisms following initial injury. These mechanisms can be further divided into three phases according to their temporality: acute, subacute, and chronic phase. The acute phase is characterized by ionic changes, which interrupt nerve impulses and lead to edema; the subacute phase involves a series of events including ischemia, vasospasm, thrombosis, inflammatory response, free radicals (FR) production, lipid peroxidation (LP), and the activation of autoimmune responses resulting in apoptosis. In the chronic phase, all the auto destructive mechanisms generated during the acute and subacute phase increase and demyelination processes are triggered, alongside the formation of a glial scar, which hinders axonal

The objective of this chapter is to review a wide range of pharmacological and nonpharmacological therapeutic options, each targeting different pathological mechanisms in the different

Primary damage occurs mechanically at the moment of injury, leading to irreversible sequelae.

a. Contusion in the SC without visible loss of its morphology producing a necrotic zone at

b. Laceration or transection, which results from the penetration of the SC or extreme trauma, and affects SC conduction depending on whether the tissue is partly or completely

c. Compression caused by fractures in the vertebral column, which limit irrigation and can occur without injuring the surrounding ligaments, resulting in ischemic damage in the

the impact site, which mainly affects the dorsal region of the SC.

area where the blood flow was interrupted [3, 5, 6].

Vasogenic edema initially appears as a consequence of the BBB rupture, and is further propagated by the loss of ionic regulation, giving way to water accumulation in extracellular spaces. Water accumulation is strongly related to the intensity of the initial trauma [14]. The presence of edema in any part of the CNS results in the compression of adjacent tissue, which leads to ischemia and promotes the development of other self-destructive mechanisms, such as the release of FR, LP, and inflammation [1, 14].

#### 2.1.3. Excessive release of intracellular calcium

Once the lesion occurs, partial or total loss of the cellular membrane in neurons and axons is triggered, resulting in the depolarization due to the entrance of high concentrations of Ca2+ [13]. The resulting ionic unbalance and edema contribute to the massive entry of Ca2+, which is intrinsically related to neurotoxicity by the exaggerated release of glutamate and the activation of proteases and phospholipases. This activation triggers the destruction of neurofilaments and the destabilization of key proteins for cellular support, favoring axonal collapse, and fragmentation in the first hours or days post-trauma [15]. In addition to phospholipase activation, the increase in Ca2+ contributes to the production of pro-inflammatory molecules, such as arachidonic acid, leukotriene, and thromboxane due to the release of fatty acids from membrane phospholipids [4]. Likewise, intracellular mobilization of cytosolic Ca2+ generates reactive oxygen species (ROS), energetic failure, cytoskeletal damage, and errors in protein folding [16].

2.1.6. Lipid peroxidation

2.1.7. Inflammatory response

ROS such as hydroxyl radicals (OH) and O2

ological pH level, forming peroxynitrous acid (ONOOH) [23, 26].

proteins, and thus altering their structure and functional properties [28].

resulting in nanomolar quantities produced for prolonged time periods [30, 31].

the levels of inflammatory products such as prostaglandins and thromboxane [34, 35].

recruitment of peripheral cells (macrophages, lymphocytes, etc.) [8, 36].

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

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

One of the most important pathophysiological mechanisms derived from FR production is LP.

Pharmacological and Nonpharmacological Therapeutic Strategies Based on the Pathophysiology of Acute…

superoxidant agent peroxynitrite (ONOO). These reactants, in turn, can protonate at a physi-

At a physiological pH, ONOO reacts with polyunsaturated fatty acids (PUFAs), taking one electron to form a lipid radical (L•) that interacts with molecular oxygen to form peroxyl lipid radicals (LOO•). Without regulatory mechanisms, LP will result in membrane depolarization and ensuing demyelination in the SC [26, 27]. Substantial damage induced by FR involves an oxidative attack to the cellular membrane, which is made of PUFAs (arachidonic acid, linoleic acid, eicosapentaenoic acid, or docosahexaenoic acid) [28, 29]. Two aldehydic products arise from LP: 4-hidroxynonenal (4-HNE) y 2-propenal (acrolein). These molecules have been characterized in SCI models, forming covalent bonds with basic amino acids found in cellular

Likewise, the inflammatory response is partially responsible for FR production after SCI due to its stimulation of NO production. This molecule is produced by different cellular types after SCI and is capable of damaging medullar parenchyma when produced by inducible nitric oxide synthase (iNOS) [29]. High concentrations of NO, which are mainly produced by iNOS, require an immunological/inflammatory stimulus, such as inflammatory cytokines (IL-6, IL-1, and IFN-γ),

After SCI, high concentrations of NO (produced by iNOS) and peroxynitrite increase up to three or five times, reaching their peak 12 hours after injury [32]. Some studies have detected iNOS activity 3, 4, 24, and 72 hours following SCI, vinculating its presence to LP, and neural destruction [31–33]. High concentrations of NO simultaneously participate in cellular damage and increase vascular permeability. Consequently, NO contributes to the formation of edema, as well as excitotoxicity through the release of high concentrations of Ca2+ and glutamate. Furthermore, NO alters the electron transport chain in the mitochondria, generating further FR by affecting enzymes with a sulfuric catalytic center, such as ubiquinone succinate [34]. In addition, iNOS expression and production of NO have a retroactive effect on the development of the inflammatory response, due to their role in the production of cyclooxygenase 2 (COX)-2, which increases

, combine with nitric oxide (NO) to form the

http://dx.doi.org/10.5772/intechopen.72781

27

The sudden entry of intracellular Ca2+ likewise leads to the aforementioned glutamate excitotoxicity. These mechanisms conjointly contribute to immediate cell death or the activation of calcium-dependent signaling pathways, which result in cellular death [15, 17].
