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Page 2 of 15 Kaya et al. Neuroimmunol Neuroinflammation 2019;6:5 I http://dx.doi.org/10.20517/2347-8659.2018.70

INTRODUCTION
Spinal cord injury (SCI) can be defined as an endogenous or exogenous trauma resulting in the loss of
motor, autonomic, sensory and/or reflex functions. SCI is a major cause of permanent disability. Researchers
estimate that 230,000 people in the United States are living with an SCI, and that 10,000 new patients are
[1-7]
diagnosed each year .
The pathology of human spinal cord injury is the result of two main mechanisms known as “primary” and
“secondary” injury. Primary injury begins at the moment of trauma and is characterized by hemorrhage
and rapid cell death. Secondary injury is an extension of the original injury and occurs when vascular and
[8,9]
biochemical effects cause tissue loss and functional disorders . It is important to state that primary injury
always serves as the nidus of secondary injury. Secondary injury mechanisms primarily involve neurogenic
shock, vascular damage, ischemia and hemorrhage, immunologic secondary injury, glutamate excitotoxicity
and subsequent apoptosis.

Among all, the most destructive cellular mechanism underlying secondary injury is glutamate excitotoxicity,
2+
which overactivates calpain protease via excessive Ca influx and induces neuronal apoptosis via p53
[10]
2+
induction . Furthermore, intracellular Ca influx has an apoptotic effect, particularly through p53
induction on mitogenic extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK)
[11]
and survival phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways . Therefore, a primary goal
of SCI treatment could involve the prevention p53-induced apoptosis caused by glutamate excitotoxicity.

Speedy/rapid inducer of G2/M progression in oocytes (Speedy/RINGO) is a cell cycle regulatory protein
[12]
that increases survival of p53-positive mitotic cells by inhibiting the apoptotic machinery . Moreover, this
protein elicits p53-dependent anti-apoptotic effects on calpain-induced degenerating primary hippocampal
[14]
[13]
neurons , amyotrophic lateral sclerosis (ALS) motor neurons and in astrocytes and microglia in spinal
[15]
cord lesions . In addition, evidence from breast and testis cancer studies strongly implicates the direct
or indirect interaction of Speedy/RINGO as a p53-dependent anti-apoptotic factor for ERK/MAPK and
PI3K/AKT pathways [16-18] . These findings strongly suggest a role for Speedy/RINGO as a shield against p53-
mediated apoptotic death in SCI.

As yet, there is not any proven treatment regimen for SCI probably due to its lesser known pathophysiology.
Revealing cellular mechanisms of SCI and correlating them with the clinical symptoms are of primary
importance for developing effective SCI recovery treatments. In this regard, this review focuses on the
underlying molecular mechanisms of Speedy/RINGO’s anti-apoptotic function by correlating these
mechanisms with the complex pathophysiology of SCI. Furthermore, this review discusses how this
protective function could possibly be exploited to facilitate recovery from SCI. Particular attention is paid to
reversal of the negative effects on the ERK/MAPK and PI3K/AKT pathways via induction of p53. This new
approach may assist in identifying the most promising molecular targets for effective treatment modalities
and may also uncover the molecular basis of SCI.

GLUTAMATE EXCITOTOXICITY AND DOWNSTREAM APOPTOTIC EVENTS IN SCI
Excitotoxicity is defined as cell damage or cell death resulting from exposure to excitatory amino acids such
as glutamate. Glutamate is a major neurotransmitter that plays an important role in the central nervous
[19]
system . After spinal cord injury, glutamate levels increase in and around the trauma site. As a result of
glutamate release, glutamatergic activity contributes to induction and progression of secondary injury in
[10]
SCI . When an excessive amount of glutamate is released from presynaptic nerve terminals and from
astrocytes into the extracellular space, glutamate receptors (N-methyl-d-aspartate receptor, α-amino-3-
[20]
hydroxy-5-methyl-4-isoxazole propionate receptor) are over stimulated . Glutamate excitotoxicity leads
2+
2+
to Ca imbalance, free radical formation, and apoptosis. An excessive amount of Ca influx into the cell is