The Protective Effect And Mechanism Research Of Bexarotene On Blood-Brain Barrier In Cerebral Ischemia-Reperfusion Injured Rats

PART â…  THE EFFECT OF BEXAROTENE ON BLOOD-BRAIN BARRIER IN CEREBRAL ISCHEMIA-REPERFUSION INJURED RATSObjective:Researchs have comfirmed that bexarotene as a retinoic acid X receptor agonist could improve the level of apoE in brain tissue. Because research has proven that the protective effect of apoE on BBB, the part â…  of reaseach will observe the protective effect of bexarotene on BBB of CIR injured rats.Methods:A total of 180 rats were randomized into three groups (n=60 each):(â…°) a sham-operation group, (â…±) a cerebral ischemia-reperfusion (CIR) group, and (â…²) an CIR+bexarotene group. After 24 h,48 h, and 72 h post-I/R, 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. claudin-5, and occludin expression were analyzed by Western blotting.Results:After 24 h,48 h, and 72 h post-I/R, several effects were observed with bexarotene administration:(â…°) brain water content was significantly reduced (P<0.01); (ii) the EB content in brain tissue and MRI signal value were significantly reduced (P<0.01); (iii) claudin-5 and occludin expression were significantly increased (P<0.01)Conclusions:Bexarotene could decrease BBB permeability in rats with CIR injury, reduce brain wrater content and suppress the degradation of tight junction proteins (claudin-5 and occludin). This work offers insight to aid future development of therapeutic agents for CIR injury in human patients.PART II THE MECHANISM RESEARCH OF BEXAROTENE ON BLOOD-BRAIN BARRIER IN CEREBRAL ISCHEMIA-REPERFUSION INJURED RATSObjective:Evalue the effects of bexarotene on apoE, MMP-9 and JNK signaling pathway.Methods:A total of 80 rats were randomized into four groups (n=20 each):(i) a sham-operation group, (â…±) a cerebral ischemia-reperfusion (CIR) group, (â…²) CIR+SP600125 group and(â…³) CIR+bexarotene group. After 24 h,48 h, and 72 h post-I/R, 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), p-JNK, and JNK expression were analyzed by Western blotting.Results:After 24 h,48 h, and 72 h post-I/R, several effects were observed with bexarotene administration:(i) MMP-9 mRNA, protein expression as well as activity were significantly decreased (P<0.01); (ii) apoE expression was significantly increased (P<0.05, P<0.01); (iii) p-JNK and JNK expression were significantly decreased (P<0.05, P<0.01)Conclusions:The protective mechanism of bexarotene on BBB may be that the damage of BBB with MMP-9 was reduced by increasing the apoE expression, inhibiting JNK signaling pathway and decreasing the expression and activation of MMP-9.