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Page 6 of 11 Almurshidi et al. Neuroimmunol Neuroinflammation 2019;6:11 I http://dx.doi.org/10.20517/2347-8659.2019.19
[53]
inhibits the JAK/STAT3 pathway in SCI animals . The expression of miR-124 mainly in neurons is found
throughout the brain and spinal cord. A recent study has corroborated the sensitivity of miRNAs to SCI
by showing that expression of miR-124 in neurons is significantly decreased within 7 days after SCI to
[54]
show the severity of injury . The dynamic changes in expression of miRNAs play multiple regulatory
mechanisms that may be leveraged to reduce neuropathic pain and potentially shed new light on the
[55]
progression of maladaptive plasticity in SCI .
[56]
It has been demonstrated that miR-146a and miR-129-2 regulate pain during the early stages of SCI . In
this study, the investigators validated the expression of miRNAs by quantitative reverse transcription-
polymerase chain reaction and in situ hybridization assays, revealing that SCI affected miRNA expression
that persisted up to 14 days and expanded both anteriorly and caudally beyond the lesion site. It has
been suggested that the effect of miRNAs on pain is not necessarily limited to the lesion site. It has been
suggested that SCI induces changes in the expression of miRNAs in higher cortical structures, which
control neuropathic and inflammatory pain, and miRNAs may serve as specific biomarkers for future
[57]
targeted therapy of neuropathic and inflammatory pain conditions .

MOLECULAR INSIGHTS INTO ROLES OF MIR-96 IN SCI
miR-96 in neuroprotective therapy in SCI
It is essential to mention that miR-96 is one of three miRNAs that make up the miR-183 cluster (the other
two miRNAs of this cluster are miR-183 and miR-182) . Recent studies confirm that expression of miR-96
[58]
is dramatically decreased after SCI, favoring induction of apoptosis due to increase in expression of its
targets, which are pro-apoptotic proteins . Another recent research showed that increase in expression
[59]
of miR-96 suppressed microglia activation marker proteins and inhibited inflammatory cytokines
such as tumor necrosis factor-α and interleukin-1β to promote recovery in SCI . Additionally, it has
[60]
been reported that miR-96-5p regulates cysteine transporters such as the excitatory amino acid (EAA)
transporter 3/EAA carrier 1 (one of the amino acid carriers involved in neuronal glutathione synthesis),
[61]
which produces neuroprotective benefits against oxidative stress . According to these researchers,
rhythmic diurnal fluctuations of glutathione levels occur when miR-96-5p is blocked indirectly influencing
[62]
the neuroprotective effect . The subsequent section of this article will describe recent research related to
roles of miR-96 in inhibition of apoptosis, promotion of cell proliferation, and alteration of other molecular
pathways.

miR-96 in inhibition of apoptosis
Research shows that miR-96 may target and inhibit apoptotic factors at the protein and mRNA levels.
For instance, miR-96 indirectly inhibits apoptosis through its effect on the forkhead transcription factor
[63]
of the O class 1 (FOXO1) transcription factor . Studies have shown that FOXO1 induces apoptosis
via mitochondria-independent and mitochondria-dependent pathways. Also, miR-96-5p decreases the
levels of caspase-9 (an important caspase in the mitochondrial pathway of apoptosis) by binding to the
[64]
CASP9 3’-untranslated region (3’UTR) . Overexpression of miR-96-5p is associated with inhibition of
[65]
apoptosis .
miR-96 in cell proliferation
There is a growing interest in the study of miR-96, its effect on FOXO1 levels, and how this affects
cell proliferation. For example, it has been shown that breast cancer causes upregulation of miR-96 by
targeting protein tyrosine phosphatase, non-receptor type 9, this increases cell migration and proliferation
and indirectly affects the pathophysiology mechanisms of breast carcinogenesis . Studies on miR-96,
[66]
specifically its role in hepatocarcinogenesis and treatment of hepatocellular carcinoma (HCC), have shown
that miR-96 is significantly upregulated in HCC . Studies also demonstrate that miR-96 targets the
[67]