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Polcyn et al. NSE in neural survival and death

converted into β-enolase (enolase 3, muscle specific (TNF-α, IL-1β, and IL-6) and chemokines (MIP-
[2]
enolase, ENO3) in muscle tissue. NSE exists as both 1α and IP-10), and glial activation . Elevated
αγ and γγ isoforms in neurons, γγ in microglia and MMP-9 expression can promote the activation of
oligodendrocytes, and αγ in astrocytes [3,4] . Notably, microglia and astrocytes, leading to the release of
enolase levels have been shown to be significantly inflammatory cytokines and chemokines that promote
increased in astrocytes and microglia following spinal cell death. Expression of these pro-inflammatory
cord injury (SCI), an observation indicating a possible cytokines (TNF-α, IL-1β, and IL-6) is known to induce
role for NSE in different pathologies associated with hyperalgesia, allodynia, and apoptosis of neuronal
the neuroinflammatory, apoptotic, and neuroprotective and glial cells in association with the secondary
activity of these interacting glial cells [6,7] . Due to its damages of SCI [2,12-15] . Additionally, MIP-1α has
specific location in neurons and neuroendocrine been shown to mediate microglia accumulation and
cells and its upregulated secretion following axonal neuroinflammation in brain injury [16] . IP-10, expressed
damage, NSE has been implicated as a biomarker by astrocytes in response to N-methyl-D-aspartate-
of functional damage to neurons in SCI and several dependent excitotoxicity, activates the mitogen-
other pathophysiological conditions: traumatic brain activated protein kinase (MAPK)/extracellular signal-
injury, stroke, ischemia-reperfusion injury, cardiac regulated kinase (ERK) pathway in mouse cortical
arrest, neuroblastoma, small-cell lung cancer, and neurons, indicating a role for this chemokine in
Alzheimer’s disease (AD) [2-5] . mediating cell proliferation and apoptosis under
neurodegenerative conditions [17,18] . The reduction of
SCI is a debilitating neurological disorder that occurs MMP-9 and the aforementioned pro-inflammatory
in two main phases: primary and secondary injury [3,8] . cytokines and chemokines by ENOblock indicates
The initial primary injury, resulting from laceration, the potential for this treatment in attenuating neural
contusion, compression, and/or contraction of the damages associated with inflammatory response
neural tissue, is the immediate, irreversible damage during secondary injury mechanisms of SCI.
to the spinal cord and associated axons, cells, and While previous research on the role of NSE in
blood vessels. However, a diverse array of secondary secondary injury mechanisms of SCI has focused on
injury mechanisms, including hypoxia, ischemia, neurodegenerative effects, namely the association
excitotoxicity, inflammation, and apoptosis, expands between the overexpression of NSE and an
the injury site and impairs pro-survival activity inflammatory cascade leading to neuronal cell
[9]
following primary injury . These secondary processes death, future studies should additionally investigate
are reversible and as such have been a principle the role of NSE in pro-survival and regeneration
[8]
target of SCI treatment research . Substantial activity via cellular signaling pathways in acute
reduction in blood supply from primary injury triggers and chronic SCI. NSE has been shown to exhibit
ischemia, oxidative stress, and microglial activation neurotrophic activity in controlling neuronal survival,
that drive the release of pro-inflammatory cytokines differentiation, and neurite regeneration of human
and chemokines at the injury site. Under the hypoxic- neuroblastoma SH-SY5Y cells via activation of the
ischemic conditions immediately following SCI, an phosphoinositide 3-kinase (PI3K)/Akt and MAPK/
2+
influx of Ca results in activation of calpain, caspase, ERK signaling pathways, which regulate cytoskeleton
and phospholipases [10,11] . Calpain then degrades reorganization and transcriptional factor activation in
cytoskeletal proteins and leads to apoptosis. Additional promotion of cell survival and neurite outgrowth . A
[1]
neuronal death can be attributed to glutamate neuroprotective effect of NSE expression and activity
[9]
excitotoxicity following the injury . Though these was also observed in a mouse model of AD against
effects are primarily neurodegenerative, macrophages amyloid-β-related neurodegeneration . Additionally,
[5]
may function as pro- or anti-inflammatory agents in the neuritogenic activity of NSE is associated
SCI, depending on the M1/M2 macrophage cell ratio in with RhoA kinase inactivation within the PI3K/
the injured microenvironment. Akt pathway and affects neurite outgrowth through
[1]
rapid actin polymerization . NSE likely exhibits
Our group has shown that SCI treatment in a male similar neuroprotective activity for cell survival,
Sprague-Dawley rat model using ENOblock, a differentiation, and migration following SCI and other
small molecule inhibitor of enolase, corresponded neurodegenerative conditions via the PI3K/Akt and
to a reduction of NSE expression in SCI tissues MAPK/ERK pathways. Further research evaluating the
and a significant decrease in serum NSE, matrix interaction between NSE and these pathways in SCI
metallopeptidase (MMP)-9 protein expression in secondary injury mechanisms for more clarification
injured tissue, serum pro-inflammatory cytokines would be interesting.

Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ December 6, 2017 255