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mechanism is activated in neurons at the injury site and spreads to adjacent and distant oligodendrocytes.
Thus, the primary injury caused by spinal cord trauma progresses into nearby tissue cells, leading to
secondary injury.

2+
In SCI, increased intracellular Ca influx as a result of glutamate induction is one of the major apoptotic
insults leading to overactivation of certain proteases which subsequently cause proteolytic degradation of
myelin and cytoskeletal proteins and degeneration of axons. These are all hallmarks of secondary injury and
contribute to the progression of SCI [30-34] . One of these proteases - calpain - is known to be a highly effective
neurodegenerator. Upon its overactivation, calpain increases p53 and caspase-3 activation, causing neurons to
[13]
degenerate through apoptosis . In addition, calpain overactivity has been shown to disrupt the regulation of
[11]
mitogenic ERK/MAPK and survival PI3K/AKT signaling cascades in a p53-dependent manner .
Based upon these findings, it is evident that glutamate-mediated p53 induction is the prominent reason
for apoptosis in SCI. The p53-dependent anti-apoptotic function of Speedy/RINGO makes it an excellent
therapeutic candidate for treatment of SCI.

CURRENT STUDIES fOR ThE RECOVERY Of SCI
Current research approaches for developing novel therapeutic regimens target both primary and secondary
injuries, which are the hallmarks of SCI. Since more complex, multifaceted neurodegenerative progression
occurs in secondary injury, the main aim of such investigations is to understand the underlying molecular
mechanisms and find the potential key molecules to target for effective SCI treatment. Since the complex
molecular mechanisms of SCI have only been partially elucidated, most efforts so far have had limited
efficacy. These efforts mainly involve providing anti-neuro-inflammatory conditions [30,35-37] preventing
excitotoxicity in neurons [38,39] , reducing oxidative damage [31,40,41] and regulating the effects of intracellular
2+
ionic changes, such as altered Ca homeostasis.

Spinal cord injury results in loss of oligodendrocytes which, in turn, causes demyelination of axons. Since
demyelination largely impedes functional recovery from SCI, an important treatment modality involves
[42]
preventing oligodendrocytic death and/or enhancing myelin formation by regulating myelin-related
factors such as Nogo, ephrins, semaphorins, oligodendrocyte-myelin glycoprotein, and/or myelin-associated
glycoprotein, all of which have been shown to increase neuroregeneration after spinal cord injury [43-49] .
Neurotrophins and neurotrophin receptors are reported to provide neuronal survival [43,50-55] and enhance
behavioral recovery in SCI [56-58] , so another potential treatment strategy would be to enhance the expression
[50]
of regeneration-associated genes such as neurotrophins, integrins, GAP-43 and CAP-23 .

In addition to genetic and molecular-based studies, some researchers are studying the efficacy of transplanting
stem cells, Schwann cells, peripheral blood stem cells and bone marrow to replace lost tissue [57,59,60] .

Numerous studies on spinal cord injury in rodents, primates and humans have indicated that the level of
inflammation increases as a result of glial cell activation and filtration of somatic immune cells through
[61]
mechanically disrupted spinal cord tissue . The effect of inflammation in the secondary mechanism of SCI
has not yet been clarified. However, it is known that inflammation induces astrocytic gliosis. This, in turn,
results in glial scar formation, spread of the inflammatory response and damage to the surrounding healthy
[62]
neurons, leading to their apoptotic deaths . In a study aiming to prevent astrocytic gliosis, researchers
focused on the role of the mitogenic ERK/MAPK signaling cascade in astrocytic proliferation, since mitosis
[63]
is the most important feature of reactive astrocytes . In their experiments, an increase in expression and
phosphorylation of ERK/MAPK members was observed in reactive proliferating astrocytes of SCI lesions.
In order to downregulate ERK/MAPK signaling, liposomes containing the interferon-β (IFN-β) gene were