A Lipoxin A4 Analog Ameliorates Blood–Brain Barrier Dysfunction and Reduces MMP-9 Expression in a Rat Model of Focal Cerebral Ischemia–Reperfusion Injury

LXA4 methyl ester (LXA4ME), a lipoxin A4 analog, reduces ischemic insult in the rat models of transient or permanent cerebral ischemic injury. We investigated whether LXA4ME could ameliorate blood–brain barrier (BBB) dysfunction after stroke by reducing matrix metalloproteinase (MMP)-9 expression. Adult male rats were subjected to 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Brain infarctions were detected by triphenyltetrazolium chloride (TTC) staining. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Temporal expression of MMP-9 was determined by zymography and Western blot. The presence of tissue inhibitors of metalloproteinase-1 (TIMP-1) was also determined by Western blot in tissue protein sample. Brain edema and Evans Blue leakage were significantly reduced after stroke in the LXA4ME group and were associated with reduced brain infarct volumes. MMP-9 activity and expression were inhibited by LXA4ME after stroke. In addition, LXA4ME significantly increased TIMP-1 protein levels. Our results indicate that LXA4ME reduces brain injury by improving BBB function in a rat model of MCAO, and that a relationship exists between BBB permeability and MMP-9 expression following ischemic insult. Furthermore, these results suggest that LXA4ME-mediated reduction of MMP-9 following stroke are attributed to increased TIMP-1 expression.