Introduction
As a highly selective permeable vascular endothelial structure, the
blood-spinal cord barrier (BSCB) provides a particular environment for
the cellular constituents of the spinal cord. Impairment of the BSCB
plays an important role in the pathogenesis or development of some
pathological conditions of the spinal cord because the BSCB mainly
regulates the entry of plasma components and blood cells into the spinal
cord (Hawkins & Davis, 2005). Spinal
cord injury (SCI) is one of the most severe traumatic injuries and
results in primary mechanical injury causing axonal and vascular damage
at the lesion site; then, a series of pathological events are initiated
in response to the primary injury to further impair the wound site and
its surrounding regions (Edwards et al.,
2014; Giuliano et al., 1999). When the
BSCB integrity is damaged after SCI, blood cells such as neutrophils and
macrophages are infiltrated into the spinal cord parenchyma and produce
inflammatory mediators such as proinflammatory cytokines, contributing
to secondary damage (Abbott et al., 2006;
Hausmann, 2003;
Hawkins & Davis, 2005;
Zlokovic, 2008). These secondary injuries
cause apoptotic cell death of neurons and oligodendrocytes resulting in
a perpetual neurological deficiency. Therefore, drugs targeting for the
prevention of BSCB disruption should facilitate the restriction of
cellular damage and functional recovery after SCI.
Histone modification has emerged as a critical regulator of gene
expression and has been known to regulate biological events such as
development, metabolism, pathogenesis, and diverse cellular responses
(Bannister & Kouzarides, 2011). Recently,
our reports showed that the histone H3K27me3 demethylase Jmjd3 is an
important epigenetic factor that regulates the integrity of the
blood-brain barrier (B-BB) following central nervous system (CNS) injury
including SCI (Lee et al., 2016;
Lee et al., 2012c;
Na et al., 2017). We also reported that
Jmjd3 is abruptly upregulated in the blood vessels of injured spinal
cord and Jmjd3 functions as an important epigenetic regulator of
interleukin-6 (IL-6) gene activation using an in vitroendothelial cell model of ischemia/reperfusion injury
(Lee et al., 2012c). Furthermore, Jmjd3
played a critical role in the regulation of B-BB/BSCB integrity by
directly upregulating the matrix metalloprotease (MMP) genes, based onin vitro cellular and in vivo animal models
(Lee et al., 2016;
Na et al., 2017). Therefore, targeting
Jmjd3 should be an effective therapeutic strategy to attenuate secondary
events after SCI.
Gallic acid (GA, 3, 4, 5-trihydroxy benzoic acid) is a phenolic compound
in plants and is estimated to be a putative active compound in tannin.
GA and its derivatives are considered to be major polyphenols in grapes,
different berries, mango, areca nut, walnut, green tea, and other fruits
including wine (Giftson et al., 2010). The
diverse pharmacological properties of GA, including antiallergic,
anticancer, antioxidant, anti-inflammatory, and neuroprotective effects
have previously been reported (Lu et al.,
2006; Nabavi et al., 2012;
Patel & Goyal, 2011;
Yang et al., 2015;
You et al., 2011). Recently, the
neuroprotective effect of GA has been reported in several animal models
of CNS disorders, such as depression, seizure, Parkinson’s disease,
Alzheimer’s disease, brain trauma, and SCI
(Chhillar & Dhingra, 2013;
Huang et al., 2012;
Mansouri et al., 2013a;
Mansouri et al., 2013b;
Sarkaki et al., 2015;
Yang et al., 2015). For example, GA
improves cognitive, hippocampal long-term potentiation deficits and
brain damage induced by chronic cerebral hypoperfusion in rats
(Sarkaki et al., 2014). GA also exhibits
anti-depressant-like activity in a mouse model of unpredictable chronic
mild stress (Chhillar & Dhingra, 2013)
and improves behavior, brain electrophysiology, and inflammation in a
rat model of traumatic brain injury via decreasing cerebral
pro-inflammatory cytokines (Sarkaki et
al., 2015). In addition, GA mitigates SCI-induced oxidative stress and
the inflammatory response by increasing the antioxidant status of cells
and decreasing the expression of inflammatory factors
(Yang et al., 2015). However, the effect
of GA on BSCB impairment after SCI has not been investigated yet. Thus,
we examined whether GA regulates Jmjd3-mediated BSCB disruption and
thereby improves functional recovery by mitigating the apoptosis of
neurons and oligodendrocytes after SCI.