4.1. Stress and transcription response

3.3. Glial-associated damage

126 Essentials of Spinal Cord Injury Medicine

3.4. Necrosis and apoptosis

3.5. Lipid peroxidation

secondary injury mechanism.

molecules, which inhibit functional recovery [17].

major triggers for apoptosis and mitochondrial dysfunction [19].

4. Molecular alterations involved in injured spinal cord

In SCI, damage to the myelin sheet that is demyelination causes the exposure of axons to the harmful surroundings that lead to necrosis or apoptosis of overall neurons [9]. Moreover, the process of demyelination delays or blocks signal conduction via axons that leads to ineffective communication between neurons. This process of demyelination is a result of damages to the oligodendrocytes that were generated by glutamate excitotoxicity [16]. Later on, an inflammatory reaction regresses, which is followed by a formation of glial scars. In the initial stages of SCI, astrocytes proliferate at the damaged site to form glial scars, which separate neural tissue to decline neuroinflammation in early phases. Cells in this scar region secrete inhibitory

In the initial stages of SCI, neurons, microglia, oligodendrocytes and astrocytes undergo apoptosis and necrosis, while in later stages apoptosis is mostly limited to white matter [18]. In majority of cases, the SCI results in calcium influx and increased excitotoxicity, which are the

Lipids are abundantly found in tissues of CNS and PNS, which indicate that spinal cord is more vulnerable to lipid peroxidation that can lead to lysis of cell membrane [9]. Since free radicals are abundantly present in injury site, increases in their level will eventually lead to lysis of cell membranes via lipid peroxidation. Consequently, mitochondrial dysfunction occurs as a result of oxidative damage and induces calcium overload [20]. The calcium influx causes ion imbalance and excitotoxicity, which is triggered through acute SCI [9]. Additionally, high level of glutamate is released after SCI, which results in increased calcium influx and damage to the spinal cord by stimulating the AMPA and NMDA receptors that induce neuronal death by apoptosis or necrosis [21]. The oligodendrocytes and neurons are susceptible to glutamate excitotoxicity as they express glutamate receptors [3]. Consequently, excitotoxic injury induces axonal demyelination. Additionally, nitrous oxide is involved in glutamate excitotoxic injury [22]. The increased calcium ions level has a major role in the

An advanced physiopathology induced by SCI affects the cellular growth and overall integrity of nervous system by comprehensive and progressive molecular pathways [23]. The initial stages of SCI are recognized by higher expression of genes mostly involved in inflammation and lower expression of genes involved in tissue architecture and neuronal signal transduction. The later stages of SCI are characterized by upregulation of proteins involved in angiogenesis, cell growth, axon guidance and reformation of extracellular matrix. Other molecular At the initial stage of SCI, different cellular factors such as nuclear factor kappa B (NF-κB) and 70 kD heat shock protein (HSP-70) get activated that last for 24 hours. A stimulation of NF-κB facilitates more expression of genes to moderate regeneration or apoptosis [24]. Moreover, an increased level of HSP-70 with metallothioneins 1 & 2 protects the cells from oxidative stress. An activation of catalase, superoxide dismutases and glutathione peroxidase occurs in later stages [25].
