Adenoviral vector-induced silencing of RGMa attenuates blood-brain barrier dysfunction in a rat model of MCAO/reperfusion

作者：Li, Min; Wen, Yuetao; Zhang, Rongrong; Xie, Fei; Zhang, Gang; Qin, Xinyue^*

来源：Brain Research Bulletin, 2018, 142: 54-62.

DOI：10.1016/j.brainresbull.2018.06.010

• Repulsive guidance molecule A
• Blood-brain barrier
• Ischemia-reperfusion injury
• Middle cerebral artery occlusion

Background: Repulsive guidance molecule A (RGMa) is implicated in focal cerebral ischemia-reperfusion (I/R) injury, but its mechanisms are still largely unknown. This work focused on the effects of RGMa on the blood-brain barrier (BBB) after focal cerebral I/R injury.
Methods: Sprague-Dawley (SD) rats were randomly divided into four groups: sham, middle cerebral artery occlusion (MCAO)/reperfusion (I/R), MCAO/reperfusion administered recombinant adenovirus expressing sh-con (I/R + sh-con) and MCAO/reperfusion administered recombinant adenovirus expressing sh-RGMa (I/R + shRGMa) groups. Infarct volume, brain edema and neurological scores were evaluated at 3 day after reperfusion. Evens blue leakage and transmission electron microscopy was performed. And the expression level of claudin-5 and ZO-1, CDC-42 and PAK-1, RGMa were detected by western blot.
Results: Compared with I/R or I/R + sh-con groups, I/R + sh-RGMa group showed smaller infarction volume, attenuated brain edema, improved neurological scores and better BBB integrity, such as reduced Evans blue leakage and ultra-structural change. We also observed improved BBB function followed by down-regulation of MMP-9 and up-regulation of claudin-5 and ZO-1 in the I/R + sh-RGMa group. In addition, up-regulation of the CDC-42 and PAK-1 in the I/R + sh-RGMa group was obtained.
Conclusions: RGMa may be involved in I/R injury associated with BBB dysfunction via the CDC-42/PAK-1 signal pathway and may be a promising therapeutic target for I/R injury.

• 出版日期2018-9
• 单位重庆医科大学