Page 29 - Read Online

Kaya et al. Neuroimmunol Neuroinflammation 2019;6:5 I http://dx.doi.org/10.20517/2347-8659.2018.70 Page 3 of 15

Figure 1. A diagram depicting the mechanism of glutamate excitotoxicity. SCI: spinal cord injury

neurotoxic because it causes the activation of certain enzymes such as calpain protease that degrade cellular
proteins and membranes [21,22] , leading to p53-mediated apoptosis [10,23] [Figure 1].

High level of intracellular calcium
2+
Ionic balance is essential to protecting the functional integrity of neural cells. Therefore, Ca imbalance
2+
provides a mechanism for a severe secondary injury. The influx of Ca is triggered by trauma through
2+
glutamate toxicity and continues for some time once it has been triggered. Ca influx has serious negative
2+
effects in neural cells, including mitochondrial damage that further destabilizes Ca balance, generation
of free radicals, and activation of many enzymes, including calpain. This ultimately triggers degradation
of cellular components, leading to p53 induction and subsequent caspase-dependent apoptosis [24,25] and
the spread of the axoplasmic damage into adjacent cells [26,27] . One therapeutic strategy to reduce the degree
of secondary damage in the neural pathways of SCI patients would be the inhibition of the apoptotic
2+
downstream effects of Ca influx.
Apoptosis after SCI
Programmed cell signaling pathways play an important role in the pathobiology of neurological diseases
such as SCI. After spinal cord trauma, a number of cells at the lesion site die via apoptosis or necrosis.
Apoptosis is a programmed cell suicide mechanism which can be triggered by cytokines, post traumatic
inflammation, free radicals and excitotoxicity. Recent studies confirm that cells of injured spinal cord tissue
[28]
primarily die due to apoptosis .

Apoptosis is commonly observed in both neurons and oligodendrocytes, increasing the possibility of
paralysis in patients with SCI. An experimental study in rats showed that apoptosis occurred 4 h after
[29]
trauma, and that the effect of the injury could be decreased as late as 3 weeks after SCI . A caspase