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Figure 2. Regulation of apoptosis by miRNAs. All of miR-16, miR-15b, and miR-21 act on several molecular pathways, including Bak, Bcl-
2, and Bax pathways during this process. miR-15b, miR-16, and Let-7 down regulate the expression of Bcl-2 (an anti-apoptotic protein)
and trigger the release of cytochrome c (a pro-apoptotic factor). Down regulation of Bcl-2 reduces the mitochondrial membrane
potential while cytosolic cytochrome c activates the caspase cascade, which subsequently leads to apoptosis. The role of miR-21 is two-
fold: protection of neural cells and inhibition of apoptosis. Also, miR-21 down regulates PDCD4 to limit the activation of pro-apoptotic
molecular pathways involving Bak and Bax. This, in turn, hinders apoptosis. Also, pro-apoptotic PTEN is down regulated by miR-21,
resulting in an anti-apoptotic effect

[42]
exercise-induced enhancement of neuronal regeneration in SCI . In another study, it has been shown that
upregulation of mTOR occurs by deleting the PTEN gene in mice, resulting in axon regeneration in the
injured optic nerves [43,44] . Attenuation of axonal damage and neuronal death is highly crucial for recovery
[45]
of locomotor function in preclinical models of SCI . Animal model research also suggests that miR-210
[46]
carries regenerative properties to cause axon growth in the context of SCI . Administration of miR-210 to
SCI mice decreased the expressions of protein-tyrosine phosphate 1B and ephrin-A3 to contribute to spinal
cord repair by promoting angiogenesis.

miRNAs in neuronal cell cycle and functional recovery
There is evidence to show that miRNAs not only contribute to regeneration but also stimulate neuron
[47]
growth and promote functional recovery . Bioinformatic studies propose that miRNAs promote balance
between the cell division cycle 42 gene and the brain-derived neurotrophic factor (BDNF) gene, both of
[48]
which influence self-repair in SCI . Studies show that miR-124 is associated with inhibition of neuronal
apoptosis and improvement of motor scores in SCI, with the possibility of even restoring limb functionality
[49]
after SCI . Study suggests that miR-133b promotes neurite outgrowth via ERK1/2 and PI3K/Akt signaling
[50]
pathway by RhoA suppression . In terms of functional recovery, evidence shows that miR-133b has the
ability to suppress the molecules that inhibit axon regrowth and thereby promote recovery of locomotor
[51]
function after SCI .
miRNAs and neuropathic pain
A rich body of evidence has linked miRNAs to the regulation of SCI-related pain, both neuropathic and
inflammatory . According to researchers, the changes in miRNA expression induce increase in insulin-
[52]
like growth factor-1 expression and down regulation of BDNF. This study concludes that the combination
of these changes results in a decrease in inflammation and pain in SCI animals. Down regulation of
miR-218 alleviates neuropathic pain by controlling the expression of cytokine signaling, which in turn