Abstract
BackgroundMatrix metalloproteinase-9 (MMP-9) over-expression disrupts the blood-brain barrier (BBB) in the ischemic brain. The retinoid X receptor agonist bexarotene suppresses MMP-9 expression in endothelial cells and displays neuroprotective effects. Therefore, we hypothesized that bexarotene may have a beneficial effect on I/R-induced BBB dysfunction.MethodsA total of 180 rats were randomized into three groups (n = 60 each): (i) a sham-operation group, (ii) a cerebral ischemia-reperfusion (I/R) group, and (iii) an I/R+bexarotene group. Brain water content was measured by the dry wet weight method. BBB permeability was analyzed by Evans Blue staining and the magnetic resonance imaging contrast agent Omniscan. MMP-9 mRNA expression, protein expression, and activity were assessed by reverse transcription polymerase chain reaction, Western blotting, and gelatin zymography, respectively. Apolipoprotein E (apoE), claudin-5, and occludin expression were analyzed by Western blotting.ResultsAfter 24 h, 48 h, and 72 h post-I/R, several effects were observed with bexarotene administration: (i) brain water content and BBB permeability were significantly reduced; (ii) MMP-9 mRNA and protein expression as well as activity were significantly decreased; (iii) claudin-5 and occludin expression were significantly increased; and (iv) apoE expression was significantly increased.ConclusionsBexarotene decreases BBB permeability in rats with cerebral I/R injury. This effect may be due in part to bexarotene’s upregulation of apoE expression, which has been previously shown to reduce BBB permeability through suppressing MMP-9-mediated degradation of the tight junction proteins claudin-5 and occludin. This work offers insight to aid future development of therapeutic agents for cerebral I/R injury in human patients.
Highlights
The activation and up-regulation of matrix metalloproteinase-9 (MMP-9) in the ischemic brain can lead to brain edema and hemorrhagic transformation through disrupting the bloodbrain barrier (BBB) [1]
After 24 h, 48 h, and 72 h post-I/R, several effects were observed with bexarotene administration: (i) brain water content and BBB permeability were significantly reduced; (ii) MMP-9 mRNA and protein expression as well as activity were significantly decreased; (iii) claudin-5 and occludin expression were significantly increased; and (iv) apolipoprotein E (apoE) expression was significantly increased
At 24 h, 48 h, and 72 h post-I/R, both claudin-5 and occludin protein expression in the I/R+bexarotene group were significantly higher than those in the I/R group (P0.05; Fig 7C and 7D)
Summary
The activation and up-regulation of matrix metalloproteinase-9 (MMP-9) in the ischemic brain can lead to brain edema and hemorrhagic transformation through disrupting the bloodbrain barrier (BBB) [1]. Reperfusion with recombinant tissue plasminogen activator (tPA) can sometimes produce catastrophic hemorrhagic transformation in the ischemic brain by triggering MMP-9 activation [2]. On this basis, therapeutic targeting that inhibits MMP-9 activity may be a promising approach to minimizing secondary brain injury in acute stroke patients. Therapeutic targeting that inhibits MMP-9 activity may be a promising approach to minimizing secondary brain injury in acute stroke patients To this end, bexarotene (LGD1069) is a selective retinoid X receptor (RXR) agonist currently used in treating cutaneous T-cell lymphoma that has been shown to suppress MMP-9 expression in endothelial cells [3,4]. We hypothesized that bexarotene may have a beneficial effect on I/R-induced BBB dysfunction
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