5-lipoxygenase inhibitor zileuton attenuates ischemic brain damage: involvement of matrix metalloproteinase 9.
OBJECTIVE
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.


CONCLUSIONS
These results suggest that selective 5-LOX inhibitor zileuton attenuates ischemic brain damage in rats, which may be partly associated with MMP-9 inhibition.
Tu
Xian-Kun
XK
Department of Neurosurgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Yang
Wei-Zhong
WZ
Shi
Song-Sheng
SS
Chen
Chun-Mei
CM
Wang
Chun-Hua
CH
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016859:Lipoxygenase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D001094:Arachidonate 5-Lipoxygenase; D020780:Matrix Metalloproteinase 9; C063449:zileuton; D006918:Hydroxyurea