Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition

Abstract

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is known to protect against cerebral ischemia. The effects of VPA on blood-brain barrier (BBB) disruption were investigated in rats subjected to transient middle cerebral artery occlusion (MCAO). Postischemic VPA treatment remarkably attenuated MCAO-induced BBB disruption and brain edema. Meanwhile, VPA significantly reduced MCAO-induced elevation of matrix metalloproteinase-9 (MMP-9), degradation of tight junction proteins, and nuclear translocation of nuclear factor-κB (NF-κB). Sodium butyrate, another HDAC inhibitor, mimicked these effects of VPA. Our findings suggest that BBB protection by VPA involves HDAC inhibition-mediated suppression of NF-κB activation, MMP-9 induction, and tight junction degradation.

Figure 1

Valproic acid (VPA) attenuated transient middle cerebral artery occlusion (MCAO)-induced blood–brain barrier (BBB) disruption, matrix metalloproteinase-9 (MMP-9) elevation, and tight junction degradation. (A) Postischemic treatment with VPA significantly attenuated transient MCAO-induced Evans blue extravasation. (B) Representative brains. (C) IgG extravasation was markedly ameliorated by postischemic VPA treatment. (D) Transient MCAO-induced brain edema was dose dependently reduced by VPA. (E) Human recombinant MMP-2/9 standards used in zymography. (F–H) Postischemic treatment with 200 mg/kg VPA inhibited the elevation of total MMP-9 activities 24 hours after reperfusion. (I–L) VPA suppressed MMP-9 overexpression and restored claudin-5 and zonula occludens-1 (ZO-1) downregulation. ^*P<0.05, ^**P<0.01, n=8/group.

Figure 2

Valproic acid (VPA)-induced blood–brain barrier (BBB) protection was associated with inhibition of histone deacetylases (HDACs) and nuclear factor-κB (NF-κB) activation. (A, B) Postischemic treatment with 200 mg/kg VPA increased acetylated histone-H3 levels in both ipsilateral and contralateral cortex and striatum 24 hours after reperfusion. (C, D) VPA significantly suppressed middle cerebral artery occlusion (MCAO)-induced nuclear translocation of NF-κB p65 in ipsilateral cortex and striatum. (E, F) Evans blue and IgG extravasation at 24 hours were attenuated by postischemic treatment with 300 mg/kg sodium butyrate (SB). (G) SB blocked the elevation of matrix metalloproteinase-9 (MMP-9) activities induced by transient MCAO. (H, I) Nuclear translocation of NF-κB p65 was inhibited by SB. ^*P<0.05, ^**P<0.01, n=8/group.