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.