PPARγ激活剂对实验性大鼠缺血脑组织血脑屏障的保护作用及机制分析

Protective Effects of PPARγ Agonist on the Blood Brain Barrier (BBB) and Its Mechanisms after Cerebral Ischemia-Reperfusion

目的探讨过氧化小体增殖剂激活型受体γ（peroxisome proliferator-activated receptor gamma,PPAEγ）激活剂对实验性大鼠缺血脑组织血脑屏障的保护作用，结合其对基质金属蛋白酶9（Matrix metalloproteinase-9，MMP-9）的信使核糖核酸（Messenger ribonucleic acid，mENA）表达的影响分析其可能机制。 方法健康成年雄性SD大鼠，分为假手术组、生理盐水干预组、小剂量PPARY激活剂干预组、大剂量PPAEY激活剂干预组。线栓法制备大脑中动脉闭塞动物模型。术前5d分别给予盐酸吡咯列酮（PPARγ激活剂），每日1次灌胃给药，小剂量组为10mg·kg·d，大剂量组为15mg·kg·d。以缺血后24h作为观察时间点，逆转录多聚酶链反应（reverse transcription polymerase chain reaction，RT-PCR）测定缺血脑组织PPAEγ的mENA表达，分光光度法测定缺血脑组织伊文氏蓝含量。 结果小剂量吡格列酮干预组脑组织伊文氏蓝含量和大剂量吡格列酮干预组伊文氏蓝含量均较生理盐水干预组低（0．062±0．014A／g vs 0．081±0．015A／g，P〈0．05；0．045±0．011A／g vs 0．081士0．015A／g，P〈0．05）；小剂量吡格列酮干预组脑组织MMP9的mRNA表达和大剂量吡格列酮干预组脑组织MMP-9的mENA表达均较生理盐水干预组显著性降低（0．268±0．021vs0．571±0．019，P〈0．05；0．194±0．017vs 0．571±0．019，P〈0．05），小剂量干预组和大剂量干预组间比较无统计学差异。 结论PPAPγ激活剂通过下调缺血脑组织区MMP-9的表达而改善血脑屏障的功能可能是PPARγ激活后发挥抗脑缺血再灌注损伤的机制之一。

Objective To investigate the protective effects of peroxisome proliferator-activated receptor gamma （PPART） agonist on the blood brain barrier （BBB） of the experimental ischemics brain tissue. Furthermore, to analyze its probable mechanism combining with its effect on the expression of the MM P-9 mRNA. Methods Adult male SD rats were divided into four groups： sham-operation＋normal saline （NS）, ischemia-reperfusion （I/R） ＋NS, I/R＋ low-dose Pioglitazone （PGZ, PPARγ agonists, 10 mg/kg, once daily）, and I/R＋high-dose PGZ （15 mg/kg, once daily）.The mode of transient middle cerebral artery occulision was made by using the suture of Longa. By intragastric administration ,all the rats were given PGZ daily for 3 days before operation, the low-dose group with 10mg·kg^-1·d^-1 and the high-dose group with 15mg·kg^-1·d^-1. The content of Evans Blue （EB） and the expression of MMP-9 mRNA were measured by Spectrophotometry and RT-PCR at 24 hrs after ischemia. Results The content of EB of the low-dose PGZ group （0.062±0.014A/g） and the high-dose PGZ group （0.043±0.011A/g） were significantly reduced compared with that of the I/R＋NS group （0.081±0.015A/g） （P〈0. 05）, with significance difference during any two groups; the expression of MMP-9mRNA of the low-dose PGZ group （0.268±0.021） and the high-dose PGZ group （0.194±0.017） were significantly reduced compared with that of the I/R＋NS group （0.371±0.019） （P〈0. 05）, but no significance difference between low-dose PGZ and high-dose PGZ groups. Conclusion PPARyagonists can improve the permeation of blood brain barrie in the ischemia brain tissue by down-regulate the expression of MMP-9mRNA, and it may be one of the mechanisms in the protective action of PPARy on ischemia-reperfusion injury.