5-lipoxygenase Inhibitor Zileuton Attenuates Ischemic Brain Damage: Involvement of Matrix Metalloproteinase 9

Objectives: Cerebral ischemia causes an increased expression and activation of 5-lipoxygenase (5-LOX) and matrix metalloproteinase 9 (MMP-9). Recent works demonstrated that the selective 5-LOX inhibitor zileuton down-regulates MMP-9 expression in vascular diseases and cancer. In the present work, we first studied the neuroprotective effect of zileuton on focal cerebral ischemia in rats and further investigated the effect of zileuton on the expression of 5-LOX and MMP-9 in ischemic brain.

Methods: Adult Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). The rats then received treatment with zileuton 5, 10 or 50 mg/kg or vehicle. Cerebral water content and infarct volume were measured 24 hours after pMCAO. Expression of 5-LOX messenger RNA (mRNA) and MMP-9 mRNA were determined by reverse transcription polymerase chain reaction. The levels of the proform and the active form of MMP-9 were detected by gelatin zymography.

Results: Oral treatment of zileuton at 10 or 50 mg/kg significantly reduced cerebral water content and infarct volume. It also down-regulated the expression of 5-LOX mRNA and MMP-9 mRNA. Zileuton at 50 mg/kg could inhibit the active form of MMP-9.

Conclusion: These results suggest that selective 5-LOX inhibitor zileuton attenuates ischemic brain damage in rats, which may be partly associated with MMP-9 inhibition.