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Page 2 of 11 Almurshidi et al. Neuroimmunol Neuroinflammation 2019;6:11 I http://dx.doi.org/10.20517/2347-8659.2019.19

INTRODUCTION
Spinal cord injury (SCI) results from contusion/compression or transection of the spinal cord. SCI is
a significant health issue with an estimate putting the number of people living with this neurological
[1]
condition at more than 300,000 in the United States . Because of the high number of casualties, SCI is also
[2]
associated with various socio-economic challenges . Hence, it is essential to understand the molecular
mechanisms of pathogenesis in SCI in animal models and to elucidate novel therapeutic interventions for
this devastating neurological condition . The emergence of microRNAs (miRNAs) as potent regulators of
[3]
gene expression at the post-transcriptional level has vast implications in many critical biological processes
[4]
that include cell proliferation, differentiation, survival, and metabolism . Studies indicate that miRNAs are
currently attractive candidates as the upstream regulators of secondary injury progression in SCI because
miRNAs are known to regulate entire sets of genes post-transcriptionally. Specific miRNAs (such as miR-96
and miR-544a) are potentially deregulated after SCI and the impact of this deregulation is an area of great
[5]
interest .

Bioinformatic analysis indicates that the potential targets of miRNAs altered after SCI include genes
encoding components that are involved in inflammation, oxidative stress, and apoptosis, all of which
are known to be crucial for progressive pathogenesis in SCI, suggesting that abnormal expression of
miRNAs may contribute to the pathogenesis in SCI. Levels of expression of miRNAs were identified to be
[6]
deregulated (decreased or increased) in SCI animals . A later investigation showed dramatic decreases
[7]
in the expression of miRNAs including miR-96 in SCI . Upregulation of miR-96 is likely to promote
[8]
cell proliferation and prevent neurodegeneration for contribution to functional neuroprotection in
[9]
SCI. Because miRNAs highly decrease specific gene expression and deregulation of miRNAs does occur
in SCI, the potential of particular miRNAs as therapeutic agents should now be explored for functional
[10]
neuroprotection in SCI . This review article mainly focuses on recent research related to changes in
expression of miRNAs following induction of SCI and effects of modulation of levels of miRNAs on critical
molecular processes including neuroplasticity, astrogliosis, neuropathic pain, inflammation, apoptosis,
and functional recovery in SCI. The last section of this review article focuses explicitly on miR-96 as an
emerging post-transcriptional regulator that has the potential to revolutionize SCI clinical interventions.

SCI PATHOPHYSIOLOGY AND MIRNAS
The occurrence of SCI is classified into two different stages: primary stage (a few moments following the
initial injury) and secondary stage (hours, days, or weeks after the initial injury). Research shows that the
first phase of SCI is the best predictor of future prognosis [11,12] . During the first phase, SCI is manifested
2+
with immediate changes in pathophysiology such as hemorrhage, Ca overload, and activation of the
2+
Ca -dependent cysteine protease calpain causing necrotic and apoptotic neuronal death at the site of
[13]
impact . The secondary phase begins with molecular and physiological changes responsible for bleeding,
loss of neurological functions, expansion of the lesion area, and overall amplification of the injury [14,15] .
The secondary phase is also characterized by biochemical reactions, vascular alterations, inflammation,
and edema . The main pathological mechanisms responsible for the changes during the secondary phase
[16]
are the depletion of energy, which is caused by ischemia and oxidative stress, neuroinflammation, and
activation of calpains and caspases for cell death at the site of injury and the penumbra . The combination
[17]
of cellular and molecular modifications leads to various pathological events ranging from astrogliosis to
[18]
apoptosis and tissue atrophy . Understanding the pathological events is highly crucial for modulating
progression of pathogenesis leading to activation of cysteine proteases in both acute and chronic SCI and
for implementing therapeutic interventions . It has been shown that attenuation of neuroinflammation
[19]
and neurodegeneration with appropriate therapeutic interventions is essential for functional recovery in
preclinical models of SCI [20,21] . A relatively novel therapeutic intervention evaluated for the treatment of SCI
[22]
in preclinical models is the utilization of miRNAs . The miRNAs are small non-coding RNA molecules