Valproic acid attenuates blood–spinal cord barrier disruption by inhibiting matrix metalloprotease‐9 activity and improves functional recovery after spinal cord injury

Abstract

The blood-brain barrier (BBB) including blood-spinal cord barrier (BSCB) is a highly specialized brain endothelial structure of the fully differentiated neurovascular system. When damaged by various insults including traumatic spinal cord injury (SCI), the BBB or BSCB disruption elicits blood infiltration and inflammation, thereby generating neurotoxic products that can compromise synaptic and neuronal functions (Hawkins and Davis 2005;Zlokovic 2005;Abbott et al. 2006) and induces the ''programmed death'' of neurons and glia, leading to permanent neurological deficits (Xu et al. 2001;Noble et al. 2002;Gerzanich et al. 2009 Seoul, KoreaAbstract The disruption of blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) elicits an intensive local inflammation by the infiltration of blood cells such as neutrophils and macrophages, leading to cell death and permanent neurological disability. SCI activates matrix metalloprotease-9 (MMP-9), which is known to induce BSCB disruption. Here, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, would attenuate BSCB disruption by inhibiting MMP-9 activity, leading to improvement of functional outcome after SCI. After moderate spinal cord contusion injury at T9, VPA (300 mg/kg) were immediately injected subcutaneously and further injected every 12 h for 5 days. Our data show that VPA inhibited MMP-9 activity after injury, and attenuated BSCB permeability and degradation of tight junction molecules such as occludin and ZO-1. In addition, VPA reduced the expression of inflammatory mediators including tumor necrosis factor-a. Furthermore, VPA increased the levels of acetylated histone 3, pAkt, and heat-shock protein 27 and 70, which have antiapoptotic functions after SCI. Finally, VPA inhibited apoptotic cell death and caspase 3 activation, reduced the lesion volume and improved functional recovery after injury. Thus, our results demonstrated that VPA improves functional recovery by attenuating BSCB disruption via inhibition of MMP-9 activity after SCI.

Effect of lycopene on the blood-spinal cord barrier after spinal cord injury in mice

“…Spinal cord edema induces openings in the BSCB, leading to an exchange of harmful substances between blood and tissue. Disruption of the BSCB elicits marked local inflammation with the infiltration of neutrophils and macrophages, leading to cell death and permanent neurological disability (21,22). The current study found that lycopene significantly reduced the level of edema after SCI.…”

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

“…Changes in the expression and distribution of TJ and AJ proteins are closely related to the permeability of BSCB during SCI [38]. The levels of occludin, or zonula occludens 1 (ZO-1), are decreased at 1 or 3 d after SCI [25,39]. It has been reported that occludin, claudin-5, and ZO-1 are lost or degraded at 48 h postinjury, which aggravates the disruption of BSCB integrity [40].…”

Pathobiology of radiation myelopathy and strategies to mitigate injury

“…The improved functional recovery appeared to be owing to inhibition of inflammatory mediator expression including matrix metalloprotease activity, which is known to induce BSCB disruption. 40,41 These approaches are attractive, as they use established drugs in clinical practice.…”